Clozaril® (clozapine) Tablets

 

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

 

 

Appendix 1:  Post-text tables (United States Data)

 

 

 

 

 

Document status:

Final

Release date:

May 19, 2003

Number of pages:

90

 

 

Available for public disclosure without redaction


 

1            Post-text tables

 

United States Data

 

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 1-Apr-1998 for cohorts 1 and 2

 

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

 

 


 

     Novartis Pharmaceuticals Corporation                                                                             Page 1 of 2

     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 Dec. 1, 1997. All data will be excluded

                     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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     Novartis Pharmaceuticals Corporation                                                                             Page 2 of 2

     Clozaril (clozapine)

     ____________________________________________________________________________________________________________________________

 

                                                   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 Dec. 1, 1997. All data will be excluded

                     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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     Novartis Pharmaceuticals Corporation                                                                             Page 1 of 2

     Clozaril (clozapine)

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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 01-Apr-1998 for cohorts 1 and 2

 

     ____________________________________________________________________________________________________________________________

 

                                   ----------------------------------------- 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 Dec. 1, 1997. All data will be excluded

                     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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     Novartis Pharmaceuticals Corporation                                                                             Page 2 of 2

     Clozaril (clozapine)

     ____________________________________________________________________________________________________________________________

 

                                                   Post-text table 3.1-2 (Continued)

                                             Summary of demographic information by cohort

                                                Patients with moderate leukopenia [1]

                                      With data cut-off date of 01-Apr-1998 for cohorts 1 and 2

 

     ____________________________________________________________________________________________________________________________

 

                                   ----------------------------------------- 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 Dec. 1, 1997. All data will be excluded

                     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)

     ____________________________________________________________________________________________________________________________

 

                                                         Post-text table 3.1-3

                                             Summary of demographic information by cohort

                                                 Patients with severe leukopenia [1]

                                      With data cut-off date of 01-Apr-1998 for cohorts 1 and 2

 

     ____________________________________________________________________________________________________________________________

 

                                   ----------------------------------------- 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 Dec. 1, 1997. All data will be excluded

                     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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     Novartis Pharmaceuticals Corporation                                                                             Page 2 of 2

     Clozaril (clozapine)

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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 01-Apr-1998 for cohorts 1 and 2

 

     ____________________________________________________________________________________________________________________________

 

                                   ----------------------------------------- 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 Dec. 1, 1997. All data will be excluded

                     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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     Novartis Pharmaceuticals Corporation                                                                             Page 1 of 2

     Clozaril (clozapine)

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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 01-Apr-1998 for cohorts 1 and 2

 

     ____________________________________________________________________________________________________________________________

 

                                   ----------------------------------------- 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 Dec. 1, 1997. All data will be excluded

                     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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     Novartis Pharmaceuticals Corporation                                                                             Page 2 of 2

     Clozaril (clozapine)

     ____________________________________________________________________________________________________________________________

 

                                                   Post-text table 3.1-4 (Continued)

                                             Summary of demographic information by cohort

                                                    Patients with agranulocytosis

                                      With data cut-off date of 01-Apr-1998 for cohorts 1 and 2

 

     ____________________________________________________________________________________________________________________________

 

                                   ----------------------------------------- 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 Dec. 1, 1997. All data will be excluded

                     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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     Novartis Pharmaceuticals Corporation                                                                             Page 1 of 2

     Clozaril (clozapine)

     ____________________________________________________________________________________________________________________________

 

                                                         Post-text table 3.1-5

                                             Summary of demographic information by cohort

                                                    Patients who discontinued [1]

                                      With data cut-off date of 01-Apr-1998 for cohorts 1 and 2

 

     ____________________________________________________________________________________________________________________________

 

                                   ----------------------------------------- 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 Dec. 1, 1997. All data will be excluded

                     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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     Novartis Pharmaceuticals Corporation                                                                             Page 2 of 2

     Clozaril (clozapine)

     ____________________________________________________________________________________________________________________________

 

                                                   Post-text table 3.1-5 (Continued)

                                             Summary of demographic information by cohort

                                                    Patients who discontinued [1]

                                      With data cut-off date of 01-Apr-1998 for cohorts 1 and 2

 

     ____________________________________________________________________________________________________________________________

 

                                   ----------------------------------------- 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 Dec. 1, 1997. All data will be excluded

                     after the first generic clozapine.

     [3] From Pearson Chi-square test (excluding missing values) to compare Cohorts 1 and 2 with Cohort 3

 

 

 

 

 

 

 

 

     C:\NOVARTIS\CLOZARIL\STAT\PROGRAM\TABLES\APPEND_3\DRAFT15\DEMO_DC.SAS  09MAY03:09:32                                       


 

     Novartis Pharmaceuticals Corporation                                                                             Page 1 of 2

     Clozaril (clozapine)

     ____________________________________________________________________________________________________________________________

 

                                                         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 Dec. 1, 1997. All data will be excluded

                     after the first generic clozapine.

 

 

 

 

 

 

 

     C:\NOVARTIS\CLOZARIL\STAT\PROGRAM\TABLES\APPEND_3\DRAFT8\DEMO_BW.SAS  02MAY03:11:11                                        


 

     Novartis Pharmaceuticals Corporation                                                                             Page 2 of 2

     Clozaril (clozapine)

     ____________________________________________________________________________________________________________________________

 

                                                   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 Dec. 1, 1997. All data will be excluded

                     after the first generic clozapine.

 

 

 

 

 

 

 

 

 

 

 

 

     C:\NOVARTIS\CLOZARIL\STAT\PROGRAM\TABLES\APPEND_3\DRAFT8\DEMO_BW.SAS  02MAY03:11:11                                         

 


 

     Novartis Pharmaceuticals Corporation                                                                             Page 1 of 2

     Clozaril (clozapine)

     ____________________________________________________________________________________________________________________________

 

                                                         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 Dec. 1, 1997. All data will be excluded

                     after the first generic clozapine.

 

 

 

 

 

 

 

 

     C:\NOVARTIS\CLOZARIL\STAT\PROGRAM\TABLES\APPEND_3\DRAFT14\DEMO_WK.SAS  08MAY03:15:45                                       


 

     Novartis Pharmaceuticals Corporation                                                                             Page 2 of 2

     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 Dec. 1, 1997. All data will be excluded

                     after the first generic clozapine.

 

 

 

 

 

 

 

 

 

 

 

 

 

     C:\NOVARTIS\CLOZARIL\STAT\PROGRAM\TABLES\APPEND_3\DRAFT14\DEMO_WK.SAS  08MAY03:15:45                                       


 

     Novartis Pharmaceuticals Corporation                                                                             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 01-Apr-1998 for cohorts 1 and 2

                                       (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 Dec. 1, 1997. All data

                     will be excluded after the first generic clozapine.

 

 

 

 

 

     C:\NOVARTIS\CLOZARIL\STAT\PROGRAM\TABLES\APPEND_3\DRAFT14\AG_USA.SAS  08MAY03:14:50                                        


 

     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 01-Apr-1998 for cohorts 1 and 2

                                       (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 Dec. 1, 1997. All data

                     will be excluded after the first generic clozapine.

 

 

 

 

 

 

 

 

     C:\NOVARTIS\CLOZARIL\STAT\PROGRAM\TABLES\APPEND_3\DRAFT14\AG_USA.SAS  08MAY03:14:50                                        

 


 

     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 01-Apr-1998 for cohorts 1 and 2

                                       (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 Dec. 1, 1997. All data

                     will be excluded after the first generic clozapine.

 

 

 

 

     C:\NOVARTIS\CLOZARIL\STAT\PROGRAM\TABLES\APPEND_3\DRAFT14\AG_6MON.SAS  08MAY03:14:45                                       


 

     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 01-Apr-1998 for cohorts 1 and 2

                                       (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 Dec. 1, 1997. All data

                     will be excluded after the first generic clozapine.

 

 

 

 

 

 

     C:\NOVARTIS\CLOZARIL\STAT\PROGRAM\TABLES\APPEND_3\DRAFT14\AG_6MON.SAS  08MAY03:14:45                                        

 


 

     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 01-Apr-1998 for cohorts 1 and 2

                                       (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 Dec. 1, 1997. All data

                     will be excluded after the first generic clozapine.

 

 

 

     C:\NOVARTIS\CLOZARIL\STAT\PROGRAM\TABLES\APPEND_3\DRAFT5\AG_18_52.SAS  21APR03:17:06                                       


 

     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 01-Apr-1998 for cohorts 1 and 2

                                       (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 Dec. 1, 1997. All data

                     will be excluded after the first generic clozapine.

 

 

 

 

 

 

     C:\NOVARTIS\CLOZARIL\STAT\PROGRAM\TABLES\APPEND_3\DRAFT5\AG_18_52.SAS  21APR03:17:06                                       


 

     Novartis Pharmaceuticals Corporation                                                                             Page 1 of 1

     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 01-Apr-1998 for cohorts 1 and 2

                                       (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 Dec. 1, 1997. All data will be excluded

                     after the first generic clozapine.

 

 

 

 

 

 

 

 

 

 

 

 

 

     C:\NOVARTIS\CLOZARIL\STAT\PROGRAM\TABLES\APPEND_3\DRAFT19\AG_1000.SAS  13MAY03:18:36                                       

 


                                                           

                  Post-text table 3.2-2: Life table for incidence of agranulocytosis for Cohorts 1 & 2

                                          with data cut-off date of 1-Apr-1998

                                     (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 1-Apr-1998 for Cohorts 1 & 2

                                     (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 01-Apr-1998 for cohorts 1 and 2

                                       (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 Dec. 1, 1997. All data

                    will be excluded after the first generic clozapine.

 

 

 

 

 

 

    C:\NOVARTIS\CLOZARIL\STAT\PROGRAM\TABLES\APPEND_3\DRAFT19\AG_CALYR.SAS  13MAY03:18:54                                        


 

 

                                                   Post-text table 3.2-5 (Continued)

                                         Summary statistics for incidence of agranulocytosis

                                                           By calendar year

                                      With data cut-off date of 01-Apr-1998 for cohorts 1 and 2

                                       (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 Dec. 1, 1997. All data

                    will be excluded after the first generic clozapine.

 

 

 

 

 

 

    C:\NOVARTIS\CLOZARIL\STAT\PROGRAM\TABLES\APPEND_3\DRAFT19\AG_CALYR.SAS  13MAY03:18:54                                        


 

 

                                                         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 01-Apr-1998 for cohorts 1 and 2

 

    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 Dec. 1, 1997. All data

                    will be excluded after the first generic clozapine.

 

 

 

 

 

 

 

 

 

 

 

    C:\NOVARTIS\CLOZARIL\STAT\PROGRAM\TABLES\APPEND_3\DRAFT19\AG6CALYR.SAS  13MAY03:19:12                                        


 

 

                                                   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 01-Apr-1998 for cohorts 1 and 2

 

    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 Dec. 1, 1997. All data

                    will be excluded after the first generic clozapine.

 

 

 

 

 

 

 

 

 

 

 

    C:\NOVARTIS\CLOZARIL\STAT\PROGRAM\TABLES\APPEND_3\DRAFT19\AG6CALYR.SAS  13MAY03:19:12                                        


                                                           

                  Post-text table 3.2-7: Yearly conditional risk per 1000 patients for Cohorts 1 & 2

                                          with data cut-off date of 1-Apr-1998

                                     (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 1 of 2

     Clozaril (clozapine)

     ____________________________________________________________________________________________________________________________

 

                                                         Post-text table 3.3-1a

                                      Summary statistics for incidence of severe leukopenia [1]

                                                             All duration

                                      With data cut-off date of 01-Apr-1998 for cohorts 1 and 2

                                       (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 Dec. 1, 1997. All data

                     will be excluded after the first generic clozapine.

 

 

 

 

     C:\NOVARTIS\CLOZARIL\STAT\PROGRAM\TABLES\APPEND_3\DRAFT14\SL_USA.SAS  08MAY03:17:23                                         


 

     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 01-Apr-1998 for cohorts 1 and 2

                                       (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 Dec. 1, 1997. All data

                     will be excluded after the first generic clozapine.

 

 

 

 

 

 

 

 

     C:\NOVARTIS\CLOZARIL\STAT\PROGRAM\TABLES\APPEND_3\DRAFT14\SL_USA.SAS  08MAY03:17:23                                        


 

     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 01-Apr-1998 for cohorts 1 and 2

                                       (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 Dec. 1, 1997. All data

                     will be excluded after the first generic clozapine.

 

 

 

     C:\NOVARTIS\CLOZARIL\STAT\PROGRAM\TABLES\APPEND_3\DRAFT14\SL_6MON.SAS  08MAY03:14:27                                       


 

     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 01-Apr-1998 for cohorts 1 and 2

                                       (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 Dec. 1, 1997. All data

                     will be excluded after the first generic clozapine.

 

 

 

 

 

 

 

     C:\NOVARTIS\CLOZARIL\STAT\PROGRAM\TABLES\APPEND_3\DRAFT14\SL_6MON.SAS  08MAY03:14:27                                       

 


 

     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 01-Apr-1998 for cohorts 1 and 2

                                       (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 Dec. 1, 1997. All data

                     will be excluded after the first generic clozapine.

 

 

     C:\NOVARTIS\CLOZARIL\STAT\PROGRAM\TABLES\APPEND_3\DRAFT12\SL_18_52.SAS  05MAY03:12:25                                      


 

     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 01-Apr-1998 for cohorts 1 and 2

                                       (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 Dec. 1, 1997. All data

                     will be excluded after the first generic clozapine.

 

 

 

 

 

 

     C:\NOVARTIS\CLOZARIL\STAT\PROGRAM\TABLES\APPEND_3\DRAFT12\SL_18_52.SAS  05MAY03:12:25                                      


                                                           

                 Post-text table 3.3-2: Life table for incidence of severe leukopenia for Cohorts 1 & 2

                                          with data cut-off date of 1-Apr-1998

                                     (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 1-Apr-1998 for Cohorts 1 & 2

                                     (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 01-Apr-1998 for cohorts 1 and 2

                                       (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 Dec. 1, 1997. All data

                    will be excluded after the first generic clozapine.

 

 

 

 

 

    C:\NOVARTIS\CLOZARIL\STAT\PROGRAM\TABLES\APPEND_3\DRAFT19\SL_CALYR.SAS  13MAY03:18:46                                        


 

 

                                                   Post-text table 3.3-5 (Continued)

                                      Summary statistics for incidence of severe leukopenia [1]

                                                           By calendar year

                                      With data cut-off date of 01-Apr-1998 for cohorts 1 and 2

                                       (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 Dec. 1, 1997. All data

                    will be excluded after the first generic clozapine.

 

 

 

 

 

    C:\NOVARTIS\CLOZARIL\STAT\PROGRAM\TABLES\APPEND_3\DRAFT19\SL_CALYR.SAS  13MAY03:18:46                                         


 

 

                                                         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 01-Apr-1998 for cohorts 1 and 2

 

    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 Dec. 1, 1997. All data

                    will be excluded after the first generic clozapine.

 

 

 

 

 

 

 

 

 

 

    C:\NOVARTIS\CLOZARIL\STAT\PROGRAM\TABLES\APPEND_3\DRAFT19\SL6CALYR.SAS  13MAY03:19:09                                         


 

 

                                                   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 01-Apr-1998 for cohorts 1 and 2

 

    Cohort: Cohort 3          

    ______________________________________________________

 

    Category           1998     1999     2000     2001

    ______________________________________________________

 

    Number of patients   6328.0  13763.0  15828.0  12749.0

    taking drug during

    the year

    Patient year         2201.3   8321.7  10837.2   5657.2

 

    Number of severe        0.0      4.0      1.0      4.0

    leukopenia

    Rate of severe          0.0      0.3      0.1      0.3

    leukopenia / 1000

    patients

    Incidence / 1000        0.0      0.5      0.1      0.7

    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 Dec. 1, 1997. All data

                    will be excluded after the first generic clozapine.

 

 

 

 

 

 

 

 

 

 

    C:\NOVARTIS\CLOZARIL\STAT\PROGRAM\TABLES\APPEND_3\DRAFT19\SL6CALYR.SAS  13MAY03:19:09                                        


 

     Novartis Pharmaceuticals Corporation                                                                             Page 1 of 2

     Clozaril (clozapine)

     ____________________________________________________________________________________________________________________________

 

                                                         Post-text table 3.4-1a

                                     Summary statistics for incidence of moderate leukopenia [1]

                                                             All duration

                                      With data cut-off date of 01-Apr-1998 for cohorts 1 and 2

                                       (Excluding patient's data meeting criteria 1, 2, and 3) [2]

 

     ____________________________________________________________________________________________________________________________

 

     Cohort                                       Category                                               All Duration

     ____________________________________________________________________________________________________________________________

 

     Cohort 1                                     Incidence/1000 patient year                                11.699

                                                  Number of incidence                                      3673

                                                  Number of patient                                       97485

                                                  Total patient year                                     313963

 

     Cohort 2                                     Incidence/1000 patient year                                17.116

                                                  Number of incidence                                       811

                                                  Number of patient                                       41359

                                                  Total patient year                                      47383

 

     Cohort 3                                     Incidence/1000 patient year                                14.881

                                                  Number of incidence                                       608

                                                  Number of patient                                       39260

                                                  Total patient year                                      40858

 

     ____________________________________________________________________________________________________________________________

     [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 Dec. 1, 1997. All data

                     will be excluded after the first generic clozapine.

 

 

 

     C:\NOVARTIS\CLOZARIL\STAT\PROGRAM\TABLES\APPEND_3\DRAFT11\ML_USA.SAS  05MAY03:07:11                                        


 

     Novartis Pharmaceuticals Corporation                                                                             Page 2 of 2

     Clozaril (clozapine)

     ____________________________________________________________________________________________________________________________

 

                                                   Post-text table 3.4-1a (Continued)

                                     Summary statistics for incidence of moderate leukopenia [1]

                                                             All duration

                                      With data cut-off date of 01-Apr-1998 for cohorts 1 and 2

                                       (Excluding patient's data meeting criteria 1, 2, and 3) [2]

 

     ____________________________________________________________________________________________________________________________

 

     Cohort                                       Category                                               All Duration

     ____________________________________________________________________________________________________________________________

 

     Cohorts 1 and 2                              Incidence/1000 patient year                                12.409

                                                  Number of incidence                                      4484

                                                  Number of patient                                      138844

                                                  Total patient year                                     361346

 

     Cohorts 1, 2, and 3                          Incidence/1000 patient year                                12.660

                                                  Number of incidence                                      5092

                                                  Number of patient                                      178104

                                                  Total patient year                                     402204

 

     ____________________________________________________________________________________________________________________________

     [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 Dec. 1, 1997. All data

                     will be excluded after the first generic clozapine.

 

 

 

 

 

 

 

     C:\NOVARTIS\CLOZARIL\STAT\PROGRAM\TABLES\APPEND_3\DRAFT11\ML_USA.SAS  05MAY03:07:11                                        


 

     Novartis Pharmaceuticals Corporation                                                                             Page 1 of 2

     Clozaril (clozapine)

     ____________________________________________________________________________________________________________________________

 

                                                         Post-text table 3.4-1b

                                     Summary statistics for incidence of moderate leukopenia [1]

                                              By duration of 1 - 6 months and > 6 months

                                      With data cut-off date of 01-Apr-1998 for cohorts 1 and 2

                                       (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                           31.008                    8.760

                                        Number of incidence                                 1286                     2387

                                        Number of patient                                  97485                    75117

                                        Total patient year                                 41473                   272491

 

     Cohort 2                           Incidence/1000 patient year                           29.921                   10.311

                                        Number of incidence                                  492                      319

                                        Number of patient                                  41359                    28447

                                        Total patient year                                 16444                    30939

 

     Cohort 3                           Incidence/1000 patient year                           27.958                    7.996

                                        Number of incidence                                  394                      214

                                        Number of patient                                  39260                    22071

                                        Total patient year                                 14093                    26765

 

     ____________________________________________________________________________________________________________________________

     [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 Dec. 1, 1997. All data

                     will be excluded after the first generic clozapine.

 

 

 

 

     C:\NOVARTIS\CLOZARIL\STAT\PROGRAM\TABLES\APPEND_3\DRAFT14\ML_6MON2.SAS  08MAY03:14:28                                      


 

     Novartis Pharmaceuticals Corporation                                                                             Page 2 of 2

     Clozaril (clozapine)

     ____________________________________________________________________________________________________________________________

 

                                                   Post-text table 3.4-1b (Continued)

                                     Summary statistics for incidence of moderate leukopenia [1]

                                              By duration of 1 - 6 months and > 6 months

                                      With data cut-off date of 01-Apr-1998 for cohorts 1 and 2

                                       (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                           30.700                    8.918

                                        Number of incidence                                 1778                     2706

                                        Number of patient                                 138844                   103564

                                        Total patient year                                 57916                   303430

 

     Cohorts 1, 2, and 3                Incidence/1000 patient year                           30.163                    8.843

                                        Number of incidence                                 2172                     2920

                                        Number of patient                                 178104                   125635

                                        Total patient year                                 72009                   330195

 

     ____________________________________________________________________________________________________________________________

     [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 Dec. 1, 1997. All data

                     will be excluded after the first generic clozapine.

 

 

 

 

 

 

 

     C:\NOVARTIS\CLOZARIL\STAT\PROGRAM\TABLES\APPEND_3\DRAFT14\ML_6MON2.SAS  08MAY03:14:28                                      

 


 

     Novartis Pharmaceuticals Corporation                                                                             Page 1 of 2

     Clozaril (clozapine)

     ____________________________________________________________________________________________________________________________

 

                                                         Post-text table 3.4-1c

                                     Summary statistics for incidence of moderate leukopenia [1]

                                            By duration of 1 - 18, 19 - 52, and > 52 weeks

                                      With data cut-off date of 01-Apr-1998 for cohorts 1 and 2

                                       (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            36.436                   13.150                    8.311

                                Number of incidence                  1082                      621                     1970

                                Number of patient                   97485                    78577                    67828

                                Total patient year                  29696                    47224                   237043

 

     Cohort 2                   Incidence/1000 patient year            32.520                   15.810                    8.527

                                Number of incidence                   388                      262                      161

                                Number of patient                   41359                    30497                    20621

                                Total patient year                  11931                    16572                    18880

 

     Cohort 3                   Incidence/1000 patient year            32.864                   10.618                    7.218

                                Number of incidence                   345                      137                      126

                                Number of patient                   39260                    24951                    15797

                                Total patient year                  10498                    12903                    17457

 

     ____________________________________________________________________________________________________________________________

     [1] Moderate Leukopenia is defined as WBC counts <= 3000/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 Dec. 1, 1997. All data

                     will be excluded after the first generic clozapine.

 

 

 

 

     C:\NOVARTIS\CLOZARIL\STAT\PROGRAM\TABLES\APPEND_3\DRAFT5\ML_18_52.SAS  21APR03:17:01                                       


 

     Novartis Pharmaceuticals Corporation                                                                             Page 2 of 2

     Clozaril (clozapine)

     ____________________________________________________________________________________________________________________________

 

                                                   Post-text table 3.4-1c (Continued)

                                     Summary statistics for incidence of moderate leukopenia [1]

                                            By duration of 1 - 18, 19 - 52, and > 52 weeks

                                      With data cut-off date of 01-Apr-1998 for cohorts 1 and 2

                                       (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            35.314                   13.841                    8.327

                                Number of incidence                  1470                      883                     2131

                                Number of patient                  138844                   109074                    88449

                                Total patient year                  41627                    63796                   255923

 

     Cohorts 1, 2, and 3        Incidence/1000 patient year            34.821                   13.299                    8.256

                                Number of incidence                  1815                     1020                     2257

                                Number of patient                  178104                   134025                   104246

                                Total patient year                  52124                    76699                   273380

 

     ____________________________________________________________________________________________________________________________

     [1] Moderate Leukopenia is defined as WBC counts <= 3000/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 Dec. 1, 1997. All data

                     will be excluded after the first generic clozapine.

 

 

 

 

 

 

     C:\NOVARTIS\CLOZARIL\STAT\PROGRAM\TABLES\APPEND_3\DRAFT5\ML_18_52.SAS  21APR03:17:01                                       


                                                           

                Post-text table 3.4-2: Life table for incidence of moderate leukopenia for Cohorts 1 & 2

                                          with data cut-off date of 1-Apr-1998

                                     (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      1778           1778     138844    0.0000      0.0000      0.0000     29.3390     27.9753     30.7027 

    0.5-1         575           2353     103564   14.5627     13.8907     15.2346     11.9784     10.9993     12.9574 

      1-2         728           3081      88449   20.4470     19.6248     21.2693      9.2553      8.5830      9.9276 

      2-3         493           3574      68866   29.4713     28.4276     30.5151      8.0640      7.3522      8.7758 

      3-4         371           3945      53406   37.2662     36.0246     38.5079      7.8608      7.0609      8.6606 

      4-5         246           4191      40987   44.8044     43.3548     46.2540      7.1668      6.2712      8.0624 

      5-6         172           4363      27663   51.6256     49.9545     53.2968      7.9663      6.7758      9.1568 

      6-7          86           4449      15519   59.1507     57.1498     61.1515      7.7446      6.1078      9.3814 

      7-8          32           4481       6690   66.4091     63.9037     68.9145      7.7897      5.0908     10.4886 

      8-9           3           4484       1526   73.6533     70.1275     77.1790      3.9318      0.0000      8.3811 

 _______________________________________________________________________________________________________________________

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

                     Note:      L.C.L = Lower Confidence Limit;      U.C.L = Upper Confidence Limit


                                                           

                  Post-text table 3.4-3: Life table for incidence of moderate 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       394            394      39260    0.0000      0.0000      0.0000     25.6966     23.1594     28.2339 

    0.5-1          88            482      22071   12.7663     11.5138     14.0188      9.2954      7.3533     11.2376 

      1-2          77            559      15797   17.3441     15.7741     18.9140      6.5240      5.0669      7.9812 

      2-3          41            600       7808   23.7341     21.6230     25.8452      7.8710      5.4617     10.2802 

      3-4           8            608       2610   31.3882     28.2524     34.5239      6.1303      1.8823     10.3782 

 _______________________________________________________________________________________________________________________

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

                     Note:      L.C.L = Lower Confidence Limit;      U.C.L = Upper Confidence Limit


                                                           

                Post-text table 3.4-4: Life table for incidence of moderate leukopenia for all 3 Cohorts

                                 with data cut-off date of 1-Apr-1998 for Cohorts 1 & 2

                                     (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      2172           2172     178104    0.0000      0.0000      0.0000     28.6035     27.4006     29.8064 

    0.5-1         663           2835     125635   14.2002     13.6073     14.7931     11.5364     10.6583     12.4145 

      1-2         805           3640     104246   19.8701     19.1403     20.6000      8.8990      8.2842      9.5137 

      2-3         534           4174      76674   28.5536     27.6156     29.4917      8.0488      7.3662      8.7315 

      3-4         379           4553      56016   36.3413     35.2017     37.4809      7.8142      7.0275      8.6009 

      4-5         246           4799      40987   43.8422     42.4841     45.2003      7.1668      6.2712      8.0624 

      5-6         172           4971      27663   50.6703     49.0763     52.2644      7.9663      6.7758      9.1568 

      6-7          86           5057      15519   58.2030     56.2644     60.1415      7.7446      6.1078      9.3814 

      7-8          32           5089       6690   65.4687     63.0110     67.9263      7.7897      5.0908     10.4886 

      8-9           3           5092       1526   72.7201     69.2258     76.2144      3.9318      0.0000      8.3811 

 _______________________________________________________________________________________________________________________

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

                     Note:      L.C.L = Lower Confidence Limit;      U.C.L = Upper Confidence Limit

 


 

                                                         Post-text table 3.4-5

                                     Summary statistics for incidence of moderate leukopenia [1]

                                                           By calendar year

                                      With data cut-off date of 01-Apr-1998 for cohorts 1 and 2

                                       (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     62.0     54.1     42.0     27.6     25.2     22.4     11.7      0.0

    [3]

    Number of patients   9639.0  22209.0  40744.0  60649.0  71681.0  77779.0  85533.0  80316.0  66369.0

    taking drug during

    the year

    Patient year         4433.0  12945.3  27099.0  43657.0  54898.1  62357.7  70657.2  69217.9  16081.0

 

    Number of moderate    165.0    310.0    415.0    604.0    703.0    652.0    777.0    673.0    185.0

    leukopenia

    Rate of moderate       17.1     14.0     10.2     10.0      9.8      8.4      9.1      8.4      2.8

    leukopenia / 1000

    patients

    Incidence / 1000       37.2     23.9     15.3     13.8     12.8     10.5     11.0      9.7     11.5

    patient year

 

    ___________________________________________________________________________________________________

    [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 Dec. 1, 1997. All data

                    will be excluded after the first generic clozapine.

 

 

    C:\NOVARTIS\CLOZARIL\STAT\PROGRAM\TABLES\APPEND_3\DRAFT19\ML_CALYR.SAS  13MAY03:18:42                                        


 

 

                                                   Post-text table 3.4-5 (Continued)

                                     Summary statistics for incidence of moderate leukopenia [1]

                                                           By calendar year

                                      With data cut-off date of 01-Apr-1998 for cohorts 1 and 2

                                       (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     53.4     36.9     21.2

    [3]

    Number of patients   3206.0  15304.0  22091.0  22165.0  16451.0

    taking drug during

    the year

    Patient year          385.8   6817.2  12962.4  13849.1   6843.0

 

    Number of moderate     12.0    153.0    197.0    169.0     77.0

    leukopenia

    Rate of moderate        3.7     10.0      8.9      7.6      4.7

    leukopenia / 1000

    patients

    Incidence / 1000       31.1     22.4     15.2     12.2     11.3

    patient year

 

    _______________________________________________________________

    [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 Dec. 1, 1997. All data

                    will be excluded after the first generic clozapine.

 

 

    C:\NOVARTIS\CLOZARIL\STAT\PROGRAM\TABLES\APPEND_3\DRAFT19\ML_CALYR.SAS  13MAY03:18:42                                        


 

 

                                                        Post-text table 3.4-6

                                     Summary statistics for incidence of moderate leukopenia [1]

                                                       After 6 months treatment

                                                           By calendar year

                                      With data cut-off date of 01-Apr-1998 for cohorts 1 and 2

 

    Cohort: Cohorts 1 and 2   

    ___________________________________________________________________________________________________

 

    Category           1990     1991     1992     1993     1994     1995     1996     1997     1998   

    ___________________________________________________________________________________________________

 

    Number of patients   4230.0  12713.0  26996.0  44074.0  57296.0  64200.0  73268.0  74181.0  66221.0

    taking drug during

    the year

    Patient year         1063.3   7557.4  17948.8  33059.4  46388.7  54455.8  62532.9  64633.3  15790.4

 

    Number of moderate     11.0     99.0    144.0    312.0    460.0    447.0    523.0    532.0    178.0

    leukopenia

    Rate of moderate        2.6      7.8      5.3      7.1      8.0      7.0      7.1      7.2      2.7

    leukopenia / 1000

    patients

    Incidence / 1000       10.3     13.1      8.0      9.4      9.9      8.2      8.4      8.2     11.3

    patient year

 

    ___________________________________________________________________________________________________

    [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 Dec. 1, 1997. All data

                    will be excluded after the first generic clozapine.

 

 

 

 

 

 

 

 

 

 

    C:\NOVARTIS\CLOZARIL\STAT\PROGRAM\TABLES\APPEND_3\DRAFT19\ML6CALYR.SAS  13MAY03:19:06                                        


 

 

                                                  Post-text table 3.4-6 (Continued)

                                     Summary statistics for incidence of moderate leukopenia [1]

                                                       After 6 months treatment

                                                           By calendar year

                                      With data cut-off date of 01-Apr-1998 for cohorts 1 and 2

 

    Cohort: Cohort 3          

    _______________________________________________________

 

    Category            1998     1999     2000     2001

    _______________________________________________________

 

    Number of patients    6294.0  13664.0  15710.0  12629.0

    taking drug during

    the year

    Patient year          2185.8   8254.4  10732.1   5592.4

 

    Number of moderate      18.0     62.0     86.0     48.0

    leukopenia

    Rate of moderate         2.9      4.5      5.5      3.8

    leukopenia / 1000

    patients

    Incidence / 1000         8.2      7.5      8.0      8.6

    patient year

 

    _______________________________________________________

    [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 Dec. 1, 1997. All data

                    will be excluded after the first generic clozapine.

 

 

 

 

 

 

 

 

 

 

    C:\NOVARTIS\CLOZARIL\STAT\PROGRAM\TABLES\APPEND_3\DRAFT19\ML6CALYR.SAS  13MAY03:19:06                                        

 


 

     Novartis Pharmaceuticals Corporation                                                                             Page 1 of 2

     Clozaril (clozapine)

     ____________________________________________________________________________________________________________________________

 

                                                          Post-text table 3.5-1

                       Summary statistics of WBC counts at discontinuation by cohort and duration of treatment

                                   With patients discontinued before 1-Apr-1998 for cohorts 1 and 2

                                        (Excluding patients data meeting criteria 1, 2, and 3) [1]

 

     ____________________________________________________________________________________________________________________________

 

     Cohort                   Statistics               <= 6 months              > 6 months               All

     ____________________________________________________________________________________________________________________________

 

     Cohort 1                 N                         32629                    33285                    65914

                              Mean                       8594.1                   8467.0                   8529.9

                              5th percentile             4800.0                   5000.0                   4900.0

                              25th percentile            6400.0                   6500.0                   6500.0

                              Median                     7900.0                   7900.0                   7900.0

                              75th percentile            9700.0                   9700.0                   9700.0

                              95th percentile           13400.0                  13200.0                  13300.0

 

     Cohort 2                 N                         16691                     6161                    22852

                              Mean                       7982.0                   8059.1                   8002.8

                              5th percentile             4700.0                   4700.0                   4700.0

                              25th percentile            6200.0                   6300.0                   6200.0

                              Median                     7600.0                   7700.0                   7600.0

                              75th percentile            9300.0                   9400.0                   9300.0

                              95th percentile           12800.0                  12600.0                  12700.0

 

     ____________________________________________________________________________________________________________________________

     [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 Dec. 1, 1997. All data will be excluded

                     after the first generic clozapine.

 

 

 

 

 

     C:\NOVARTIS\CLOZARIL\STAT\PROGRAM\TABLES\APPEND_3\DRAFT8\WBCDISC1.SAS  02MAY03:00:17                                        


 

     Novartis Pharmaceuticals Corporation                                                                             Page 2 of 2

     Clozaril (clozapine)

     ____________________________________________________________________________________________________________________________

 

                                                    Post-text table 3.5-1 (Continued)

                       Summary statistics of WBC counts at discontinuation by cohort and duration of treatment

                                   With patients discontinued before 1-Apr-1998 for cohorts 1 and 2

                                        (Excluding patients data meeting criteria 1, 2, and 3) [1]

 

     ____________________________________________________________________________________________________________________________

 

     Cohort                   Statistics               <= 6 months              > 6 months               All

     ____________________________________________________________________________________________________________________________

 

     Cohort 3                 N                         18563                     3330                    21893

                              Mean                       7867.6                   7983.2                   7885.1

                              5th percentile             4600.0                   4800.0                   4600.0

                              25th percentile            6100.0                   6200.0                   6100.0

                              Median                     7400.0                   7600.0                   7500.0

                              75th percentile            9100.0                   9300.0                   9100.0

                              95th percentile           12400.0                  12300.0                  12400.0

 

     Cohorts 1 and 2          N                         49320                    39446                    88766

                              Mean                       8386.9                   8403.3                   8394.2

                              5th percentile             4800.0                   4900.0                   4800.0

                              25th percentile            6300.0                   6500.0                   6400.0

                              Median                     7800.0                   7900.0                   7800.0

                              75th percentile            9600.0                   9700.0                   9600.0

                              95th percentile           13200.0                  13200.0                  13200.0

 

     ____________________________________________________________________________________________________________________________

     [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 Dec. 1, 1997. All data will be excluded

                     after the first generic clozapine.

 

 

 

 

 

     C:\NOVARTIS\CLOZARIL\STAT\PROGRAM\TABLES\APPEND_3\DRAFT8\WBCDISC1.SAS  02MAY03:00:17                                       

     Novartis Pharmaceuticals Corporation                                                                             Page 1 of 2

     Clozaril (clozapine)

     ____________________________________________________________________________________________________________________________

 

                                                          Post-text table 3.5-2

                       Summary statistics of WBC counts at discontinuation by cohort and duration of treatment

                                   For patients with 3000<= WBC <= 6000 at time of discontinuation

                                   With patients discontinued before 1-Apr-1998 for cohorts 1 and 2

 

     ____________________________________________________________________________________________________________________________

 

     Cohort                   Statistics               <= 6 months              > 6 months               All

     ____________________________________________________________________________________________________________________________

 

     Cohort 1                 N                          6053                     5793                    11846

                              Mean                       5188.9                   5241.8                   5214.8

                              5th percentile             3900.0                   4000.0                   4000.0

                              25th percentile            4800.0                   4900.0                   4800.0

                              Median                     5300.0                   5400.0                   5300.0

                              75th percentile            5700.0                   5700.0                   5700.0

                              95th percentile            6000.0                   6000.0                   6000.0

 

     Cohort 2                 N                          3784                     1291                     5075

                              Mean                       5173.4                   5208.6                   5182.4

                              5th percentile             3900.0                   4000.0                   4000.0

                              25th percentile            4800.0                   4800.0                   4800.0

                              Median                     5300.0                   5300.0                   5300.0

                              75th percentile            5700.0                   5700.0                   5700.0

                              95th percentile            6000.0                   6000.0                   6000.0

 

     ____________________________________________________________________________________________________________________________

     [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 Dec. 1, 1997. All data will be excluded

                     after the first generic clozapine.

 

 

 

 

 

     C:\NOVARTIS\CLOZARIL\STAT\PROGRAM\TABLES\APPEND_3\DRAFT8\WBCDC3_6.SAS  02MAY03:00:18                                       


 

     Novartis Pharmaceuticals Corporation                                                                             Page 2 of 2

     Clozaril (clozapine)

     ____________________________________________________________________________________________________________________________

 

                                                    Post-text table 3.5-2 (Continued)

                       Summary statistics of WBC counts at discontinuation by cohort and duration of treatment

                                   For patients with 3000<= WBC <= 6000 at time of discontinuation

                                   With patients discontinued before 1-Apr-1998 for cohorts 1 and 2

 

     ____________________________________________________________________________________________________________________________

 

     Cohort                   Statistics               <= 6 months              > 6 months               All

     ____________________________________________________________________________________________________________________________

 

     Cohort 3                 N                          4396                      712                     5108

                              Mean                       5165.1                   5185.2                   5167.9

                              5th percentile             4000.0                   3900.0                   3900.0

                              25th percentile            4700.0                   4800.0                   4800.0

                              Median                     5300.0                   5300.0                   5300.0

                              75th percentile            5700.0                   5700.0                   5700.0

                              95th percentile            6000.0                   6000.0                   6000.0

 

     Cohorts 1 and 2          N                          9837                     7084                    16921

                              Mean                       5182.9                   5235.8                   5205.1

                              5th percentile             3900.0                   4000.0                   4000.0

                              25th percentile            4800.0                   4900.0                   4800.0

                              Median                     5300.0                   5400.0                   5300.0

                              75th percentile            5700.0                   5700.0                   5700.0

                              95th percentile            6000.0                   6000.0                   6000.0

 

     ____________________________________________________________________________________________________________________________

     [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 Dec. 1, 1997. All data will be excluded

                     after the first generic clozapine.

 

 

 

 

     C:\NOVARTIS\CLOZARIL\STAT\PROGRAM\TABLES\APPEND_3\DRAFT8\WBCDC3_6.SAS  02MAY03:00:18                                       


 

     Novartis Pharmaceuticals Corporation                                                                             Page 1 of 2

     Clozaril (clozapine)

     ____________________________________________________________________________________________________________________________

 

                                                         Post-text table 3.5-3a

                       Summary statistics of WBC counts at discontinuation by cohort and duration of treatment

                                   For patients with 3000<= WBC <= 4000 at time of discontinuation

                                   With patients discontinued before 1-Apr-1998 for cohorts 1 and 2

 

     ____________________________________________________________________________________________________________________________

 

     Cohort                   Statistics               <= 6 months              > 6 months               All

     ____________________________________________________________________________________________________________________________

 

     Cohort 1                 N                           410                      304                      714

                              Mean                       3702.3                   3708.0                   3704.7

                              5th percentile             3100.0                   3200.0                   3100.0

                              25th percentile            3500.0                   3500.0                   3500.0

                              Median                     3800.0                   3800.0                   3800.0

                              75th percentile            3900.0                   3900.0                   3900.0

                              95th percentile            4000.0                   4000.0                   4000.0

 

     Cohort 2                 N                           239                       72                      311

                              Mean                       3713.4                   3737.5                   3719.0

                              5th percentile             3100.0                   3300.0                   3200.0

                              25th percentile            3600.0                   3600.0                   3600.0

                              Median                     3800.0                   3800.0                   3800.0

                              75th percentile            3900.0                   4000.0                   3900.0

                              95th percentile            4000.0                   4000.0                   4000.0

 

     ____________________________________________________________________________________________________________________________

     [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 Dec. 1, 1997. All data will be excluded

                     after the first generic clozapine.

 

 

 

 

     C:\NOVARTIS\CLOZARIL\STAT\PROGRAM\TABLES\APPEND_3\DRAFT8\WBCDC3_4.SAS  02MAY03:00:18                                        


 

     Novartis Pharmaceuticals Corporation                                                                             Page 2 of 2

     Clozaril (clozapine)

     ____________________________________________________________________________________________________________________________

 

                                                   Post-text table 3.5-3a (Continued)

                       Summary statistics of WBC counts at discontinuation by cohort and duration of treatment

                                   For patients with 3000<= WBC <= 4000 at time of discontinuation

                                   With patients discontinued before 1-Apr-1998 for cohorts 1 and 2

 

     ____________________________________________________________________________________________________________________________

 

     Cohort                   Statistics               <= 6 months              > 6 months               All

     ____________________________________________________________________________________________________________________________

 

     Cohort 3                 N                           284                       50                      334

                              Mean                       3710.3                   3786.0                   3721.6

                              5th percentile             3200.0                   3400.0                   3200.0

                              25th percentile            3500.0                   3600.0                   3600.0

                              Median                     3800.0                   3800.0                   3800.0

                              75th percentile            3900.0                   3900.0                   3900.0

                              95th percentile            4000.0                   4000.0                   4000.0

 

     Cohorts 1 and 2          N                           649                      376                     1025

                              Mean                       3706.4                   3713.6                   3709.0

                              5th percentile             3100.0                   3200.0                   3200.0

                              25th percentile            3500.0                   3500.0                   3500.0

                              Median                     3800.0                   3800.0                   3800.0

                              75th percentile            3900.0                   3900.0                   3900.0

                              95th percentile            4000.0                   4000.0                   4000.0

 

     ____________________________________________________________________________________________________________________________

     [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 Dec. 1, 1997. All data will be excluded

                     after the first generic clozapine.

 

 

 

 

 

     C:\NOVARTIS\CLOZARIL\STAT\PROGRAM\TABLES\APPEND_3\DRAFT8\WBCDC3_4.SAS  02MAY03:00:18                                       


 

     Novartis Pharmaceuticals Corporation                                                                             Page 1 of 2

     Clozaril (clozapine)

     ____________________________________________________________________________________________________________________________

 

                                                         Post-text table 3.5-3b

                       Summary statistics of WBC counts at discontinuation by cohort and duration of treatment

                                    For patients with 4000< WBC <= 5000 at time of discontinuation

                                   With patients discontinued before 1-Apr-1998 for cohorts 1 and 2

 

     ____________________________________________________________________________________________________________________________

 

     Cohort                   Statistics               <= 6 months              > 6 months               All

     ____________________________________________________________________________________________________________________________

 

     Cohort 1                 N                          1768                     1561                     3329

                              Mean                       4643.3                   4652.2                   4647.4

                              5th percentile             4160.0                   4100.0                   4100.0

                              25th percentile            4400.0                   4500.0                   4400.0

                              Median                     4700.0                   4700.0                   4700.0

                              75th percentile            4900.0                   4900.0                   4900.0

                              95th percentile            5000.0                   5000.0                   5000.0

 

     Cohort 2                 N                          1187                      374                     1561

                              Mean                       4635.8                   4601.3                   4627.5

                              5th percentile             4100.0                   4100.0                   4100.0

                              25th percentile            4400.0                   4400.0                   4400.0

                              Median                     4700.0                   4600.0                   4700.0

                              75th percentile            4900.0                   4800.0                   4900.0

                              95th percentile            5000.0                   5000.0                   5000.0

 

     ____________________________________________________________________________________________________________________________

     [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 Dec. 1, 1997. All data will be excluded

                     after the first generic clozapine.

 

 

 

 

 

     C:\NOVARTIS\CLOZARIL\STAT\PROGRAM\TABLES\APPEND_3\DRAFT8\WBCDC4_5.SAS  02MAY03:00:18                                       


 

     Novartis Pharmaceuticals Corporation                                                                             Page 2 of 2

     Clozaril (clozapine)

     ____________________________________________________________________________________________________________________________

 

                                                   Post-text table 3.5-3b (Continued)

                       Summary statistics of WBC counts at discontinuation by cohort and duration of treatment

                                    For patients with 4000< WBC <= 5000 at time of discontinuation

                                   With patients discontinued before 1-Apr-1998 for cohorts 1 and 2

 

     ____________________________________________________________________________________________________________________________

 

     Cohort                   Statistics               <= 6 months              > 6 months               All

     ____________________________________________________________________________________________________________________________

 

     Cohort 3                 N                          1387                      216                     1603

                              Mean                       4627.6                   4667.1                   4632.9

                              5th percentile             4100.0                   4100.0                   4100.0

                              25th percentile            4400.0                   4500.0                   4400.0

                              Median                     4700.0                   4700.0                   4700.0

                              75th percentile            4900.0                   4900.0                   4900.0

                              95th percentile            5000.0                   5000.0                   5000.0

 

     Cohorts 1 and 2          N                          2955                     1935                     4890

                              Mean                       4640.3                   4642.3                   4641.1

                              5th percentile             4100.0                   4100.0                   4100.0

                              25th percentile            4400.0                   4400.0                   4400.0

                              Median                     4700.0                   4700.0                   4700.0

                              75th percentile            4900.0                   4900.0                   4900.0

                              95th percentile            5000.0                   5000.0                   5000.0

 

     ____________________________________________________________________________________________________________________________

     [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 Dec. 1, 1997. All data will be excluded

                     after the first generic clozapine.

 

 

 

 

 

     C:\NOVARTIS\CLOZARIL\STAT\PROGRAM\TABLES\APPEND_3\DRAFT8\WBCDC4_5.SAS  02MAY03:00:18                                       


 

     Novartis Pharmaceuticals Corporation                                                                             Page 1 of 2

     Clozaril (clozapine)

     ____________________________________________________________________________________________________________________________

 

                                                         Post-text table 3.5-3c

                       Summary statistics of WBC counts at discontinuation by cohort and duration of treatment

                                    For patients with 5000< WBC <= 6000 at time of discontinuation

                                   With patients discontinued before 1-Apr-1998 for cohorts 1 and 2

 

     ____________________________________________________________________________________________________________________________

 

     Cohort                   Statistics               <= 6 months              > 6 months               All

     ____________________________________________________________________________________________________________________________

 

     Cohort 1                 N                          3875                     3928                     7803

                              Mean                       5595.1                   5594.9                   5595.0

                              5th percentile             5100.0                   5100.0                   5100.0

                              25th percentile            5400.0                   5400.0                   5400.0

                              Median                     5600.0                   5600.0                   5600.0

                              75th percentile            5800.0                   5800.0                   5800.0

                              95th percentile            6000.0                   6000.0                   6000.0

 

     Cohort 2                 N                          2358                      845                     3203

                              Mean                       5592.1                   5602.7                   5594.9

                              5th percentile             5100.0                   5100.0                   5100.0

                              25th percentile            5400.0                   5400.0                   5400.0

                              Median                     5600.0                   5600.0                   5600.0

                              75th percentile            5800.0                   5900.0                   5800.0

                              95th percentile            6000.0                   6000.0                   6000.0

 

     ____________________________________________________________________________________________________________________________

     [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 Dec. 1, 1997. All data will be excluded

                     after the first generic clozapine.

 

 

 

 

 

     C:\NOVARTIS\CLOZARIL\STAT\PROGRAM\TABLES\APPEND_3\DRAFT8\WBCDC5_6.SAS  02MAY03:00:18                                       


 

     Novartis Pharmaceuticals Corporation                                                                             Page 2 of 2

     Clozaril (clozapine)

     ____________________________________________________________________________________________________________________________

 

                                                   Post-text table 3.5-3c (Continued)

                       Summary statistics of WBC counts at discontinuation by cohort and duration of treatment

                                    For patients with 5000< WBC <= 6000 at time of discontinuation

                                   With patients discontinued before 1-Apr-1998 for cohorts 1 and 2

 

     ____________________________________________________________________________________________________________________________

 

     Cohort                   Statistics               <= 6 months              > 6 months               All

     ____________________________________________________________________________________________________________________________

 

     Cohort 3                 N                          2725                      446                     3171

                              Mean                       5590.4                   5592.9                   5590.7

                              5th percentile             5100.0                   5100.0                   5100.0

                              25th percentile            5300.0                   5400.0                   5400.0

                              Median                     5600.0                   5600.0                   5600.0

                              75th percentile            5800.0                   5800.0                   5800.0

                              95th percentile            6000.0                   6000.0                   6000.0

 

     Cohorts 1 and 2          N                          6233                     4773                    11006

                              Mean                       5594.0                   5596.2                   5595.0

                              5th percentile             5100.0                   5100.0                   5100.0

                              25th percentile            5400.0                   5400.0                   5400.0

                              Median                     5600.0                   5600.0                   5600.0

                              75th percentile            5800.0                   5800.0                   5800.0

                              95th percentile            6000.0                   6000.0                   6000.0

 

     ____________________________________________________________________________________________________________________________

     [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 Dec. 1, 1997. All data will be excluded

                     after the first generic clozapine.

 

 

 

 

 

     C:\NOVARTIS\CLOZARIL\STAT\PROGRAM\TABLES\APPEND_3\DRAFT8\WBCDC5_6.SAS  02MAY03:00:18                                       


          Novartis Pharmaceuticals Corporation                                                                   Page 1 of 4

          Clozaril (clozapine)

          __________________________________________________________________________________________________________________

 

                                                         Post-text table 3.5-4

                                       Kaplan-Meier estimate of probability of discontinuation

                                       With data cut-off date of 1-Apr-1998 for cohorts 1 and 2

 

 

                              Days on                       -------- Probability of discontinuation (%) --------

                              Treatment                     Cohorts 1 and 2               Cohort 3

          __________________________________________________________________________________________________________________

 

                                 0                            0.00                          0.00

                                 1                            7.09                         10.02

                                 2                            7.16                         10.17

                                 3                            7.23                         10.28

                                 4                            7.32                         10.40

                                 5                            7.48                         10.69

                                 6                            7.71                         11.08

                                 7                            8.15                         11.79

                                 8                            9.83                         14.62

                                 9                           10.20                         15.32

                                10                           10.42                         15.74

                                11                           10.62                         16.14

                                12                           10.83                         16.57

                                13                           11.12                         17.12

                                14                           11.56                         17.79

                                21                           14.33                         22.21

                                28                           16.63                         25.95

                                35                           18.58                         29.11

                                42                           20.24                         32.07

                                49                           21.70                         34.40

                                56                           23.06                         36.47

                                63                           24.35                         38.38

                                70                           25.56                         40.28

                                77                           26.71                         41.87

                                84                           27.83                         43.43

                                91                           28.87                         44.84

                                98                           29.90                         46.19

 

          __________________________________________________________________________________________________________________

 

 

          C:\NOVARTIS\CLOZARIL\STAT\PROGRAM\TABLES\APPEND_3\DRAFT19\KM_DISC.SAS  13MAY03:16:51                             


          Novartis Pharmaceuticals Corporation                                                                   Page 2 of 4

          Clozaril (clozapine)

          __________________________________________________________________________________________________________________

 

                                                   Post-text table 3.5-4 (Continued)

                                       Kaplan-Meier estimate of probability of discontinuation

                                       With data cut-off date of 1-Apr-1998 for cohorts 1 and 2

 

 

                              Days on                       -------- Probability of discontinuation (%) --------

                              Treatment                     Cohorts 1 and 2               Cohort 3

          __________________________________________________________________________________________________________________

 

                               105                           30.87                         47.61

                               112                           31.77                         48.95

                               119                           32.67                         50.20

                               126                           33.54                         51.28

                               133                           34.42                         52.48

                               140                           35.19                         53.69

                               147                           35.96                         54.55

                               154                           36.74                         55.56

                               161                           37.43                         56.48

                               168                           38.12                         57.09

                               175                           38.82                         57.36

                               182                           39.51                         57.65

                               196                           40.80                         58.23

                               210                           42.03                         58.84

                               224                           43.25                         59.48

                               238                           44.39                         60.17

                               252                           45.45                         60.72

                               266                           46.49                         61.37

                               280                           47.50                         61.86

                               294                           48.42                         62.42

                               308                           49.32                         63.08

                               322                           50.13                         63.69

                               336                           50.99                         64.20

                               350                           51.73                         64.75

                               364                           52.49                         65.27

                               378                           53.28                         65.81

                               392                           54.02                         66.37

 

          __________________________________________________________________________________________________________________

 

 

          C:\NOVARTIS\CLOZARIL\STAT\PROGRAM\TABLES\APPEND_3\DRAFT19\KM_DISC.SAS  13MAY03:16:51                             


          Novartis Pharmaceuticals Corporation                                                                   Page 3 of 4

          Clozaril (clozapine)

          __________________________________________________________________________________________________________________

 

                                                   Post-text table 3.5-4 (Continued)

                                       Kaplan-Meier estimate of probability of discontinuation

                                       With data cut-off date of 1-Apr-1998 for cohorts 1 and 2

 

 

                              Days on                       -------- Probability of discontinuation (%) --------

                              Treatment                     Cohorts 1 and 2               Cohort 3

          __________________________________________________________________________________________________________________

 

                               406                           54.77                         66.88

                               420                           55.48                         67.49

                               434                           56.21                         67.96

                               448                           56.86                         68.46

                               462                           57.55                         68.98

                               476                           58.20                         69.47

                               490                           58.81                         69.89

                               504                           59.41                         70.40

                               518                           59.98                         70.78

                               532                           60.60                         71.16

                               546                           61.17                         71.57

                               560                           61.73                         71.98

                               574                           62.25                         72.29

                               588                           62.70                         72.73

                               602                           63.27                         73.12

                               616                           63.80                         73.55

                               630                           64.30                         73.96

                               644                           64.77                         74.28

                               658                           65.26                         74.64

                               672                           65.72                         74.93

                               686                           66.18                         75.35

                               700                           66.61                         75.70

                               714                           67.04                         75.93

                               728                           67.45                         76.30

                               742                           67.82                         76.58

                               756                           68.25                         76.91

                               770                           68.65                         77.21

 

          __________________________________________________________________________________________________________________

 

 

          C:\NOVARTIS\CLOZARIL\STAT\PROGRAM\TABLES\APPEND_3\DRAFT19\KM_DISC.SAS  13MAY03:16:51                             


          Novartis Pharmaceuticals Corporation                                                                   Page 4 of 4

          Clozaril (clozapine)

          __________________________________________________________________________________________________________________

 

                                                   Post-text table 3.5-4 (Continued)

                                       Kaplan-Meier estimate of probability of discontinuation

                                       With data cut-off date of 1-Apr-1998 for cohorts 1 and 2

 

 

                              Days on                       -------- Probability of discontinuation (%) --------

                              Treatment                     Cohorts 1 and 2               Cohort 3

          __________________________________________________________________________________________________________________

 

                               784                           69.07                         77.55

                               798                           69.52                         77.81

                               812                           69.89                         78.14

                               826                           70.25                         78.51

                               840                           70.64                         78.86

                               854                           71.00                         79.06

                               868                           71.38                         79.24

                               882                           71.72                         79.46

                               896                           72.06                         79.74

                               910                           72.41                         79.86

                               924                           72.72                         79.96

                               938                           73.06                         80.25

                               952                           73.38                         80.48

                               966                           73.70                         80.66

                               980                           74.00                         80.82

                               994                           74.28                         80.95

                              1008                           74.61                         81.20

                              1022                           74.90                         81.41

                              1036                           75.20                         81.65

                              1050                           75.46                         81.89

                              1064                           75.70                         82.02

 

          __________________________________________________________________________________________________________________

 

 

 

 

 

 

 

 

          C:\NOVARTIS\CLOZARIL\STAT\PROGRAM\TABLES\APPEND_3\DRAFT19\KM_DISC.SAS  13MAY03:16:51                             


 

                                                       Post-text table 3.6-1

                   Summary statistics on duration of prodrome and slope during  prodrome for patients

                                       who developed moderate leukopenia by cohort

                                    (Excluded patients data meeting criteria 1, 2 and 3)

 

                                                                               Duration (day)

            Cohort           Duration                 Statistics               of prodrome           Slope+  

            _______________________________________________________________________________________________

                                                                                                           

            Cohort 1 & 2     <= 6 months              n                          1778.0              1778.0

                                                      mean                         22.8               325.5

                                                      std                          14.9              1171.3

                                                      median                       21.0               170.2

                                                      25th percentile              13.0                83.5

                                                      75th percentile              31.0               321.4

                                                      min                           0.0               -43.6

                                                      max                         105.0             41100.0

                                                                                                           

                             6 months to 1 year       n                           582.0               582.0

                                                      mean                         23.3               371.1

                                                      std                          15.6              1138.6

                                                      median                       21.0               140.2

                                                      25th percentile              13.0                76.1

                                                      75th percentile              29.0               333.1

                                                      min                           0.0                 0.0

                                                      max                         119.0             24600.0

                                                                                                          

                             1-2 years                n                           775.0               775.0

                                                      mean                         24.6               346.7

                                                      std                          16.8               579.4

                                                      median                       21.0               161.4

                                                      25th percentile              14.0                73.8

                                                      75th percentile              34.0               387.0

                                                      min                           0.0                -1.0

                   __________________________________________________________________________________

    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 Dec. 1, 97. All data will       

                be excluded after the first generic clozapine                                                       

+ Slope = rate of decrease of WBC (count/day) during prodrome
                                     Post-text table 3.6-1 (Continued)

                   Summary statistics on duration of prodrome and slope during  prodrome for patients

                                       who developed moderate leukopenia by cohort

                                    (Excluded patients data meeting criteria 1, 2 and 3)

 

                                                                               Duration (day)

            Cohort           Duration                 Statistics               of prodrome           Slope+  

            _______________________________________________________________________________________________

                                                                                                           

            Cohort 1 & 2     1-2 years                max                         140.0              8766.7

                                                                                                           

                             > 2 years                n                          2223.0              2223.0

                                                      mean                         29.6               319.6

                                                      std                          21.7               618.7

                                                      median                       25.0               142.7

                                                      25th percentile              14.0                62.8

                                                      75th percentile              41.0               346.2

                                                      min                           0.0               -39.0

                                                      max                         168.0             11250.0

                                                                                                          

                             > 6 months               n                          3580.0              3580.0

                                                      mean                         27.5               333.9

                                                      std                          20.0               721.9

                                                      median                       22.0               145.2

                                                      25th percentile              14.0                66.9

                                                      75th percentile              35.0               356.7

                                                      min                           0.0               -39.0

                                                      max                         168.0             24600.0

                                                                                                          

                                                                                                           

            Cohort 3         <= 6 months              n                           394.0               394.0

                                                      mean                         22.2               310.2

                                                      std                          17.7               711.6

                                                      median                       20.0               146.9

 

                   __________________________________________________________________________________

    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 Dec. 1, 97. All data will       

                be excluded after the first generic clozapine                                                       


                                            Post-text table 3.6-1 (Continued)

                   Summary statistics on duration of prodrome and slope during  prodrome for patients

                                       who develped moderate leukopenia by cohort

                                    (Excluded patients data meeting criteria 1, 2 and 3)

 

                                                                               Duration (day)

            Cohort           Duration                 Statistics               of prodrome           Slope+  

            _______________________________________________________________________________________________

                                                                                                           

            Cohort 3         <= 6 months              25th percentile               8.0                67.4

                                                      75th percentile              29.0               298.6

                                                      min                           0.0               -13.8

                                                      max                         112.0              7650.0

                                                                                                           

                             6 months to 1 year       n                            88.0                88.0

                                                      mean                         30.3               205.5

                                                      std                          20.4               292.7

                                                      median                       26.0               125.5

                                                      25th percentile              14.0                62.2

                                                      75th percentile              41.5               235.9

                                                      min                           0.0                 0.0

                                                      max                          96.0              2250.0

                                                                                                          

                             1-2 years                n                            77.0                77.0

                                                      mean                         35.2               537.8

                                                      std                          25.1              2635.6

                                                      median                       29.0               120.7

                                                      25th percentile              14.0                56.6

                                                      75th percentile              46.0               259.2

                                                      min                           0.0                 0.0

                                                      max                         109.0             23100.0

                                                                                                          

                             > 2 years                n                            49.0                49.0

                                                      mean                         36.0               307.9

 

                   __________________________________________________________________________________

    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 Dec. 1, 97. All data will       

                be excluded after the first generic clozapine                                                      


                                            Post-text table 3.6-1 (Continued)

                   Summary statistics on duration of prodrome and slope during  prodrome for patients

                                       who develped moderate leukopenia by cohort

                                    (Excluded patients data meeting criteria 1, 2 and 3)

 

                                                                               Duration (day)

            Cohort           Duration                 Statistics               of prodrome           Slope+   

            _______________________________________________________________________________________________

                                                                                                          

            Cohort 3         > 2 years                std                          24.7               526.1

                                                      median                       28.0               167.4

                                                      25th percentile              16.0                57.9

                                                      75th percentile              42.0               363.9

                                                      min                           6.0                12.9

                                                      max                         101.0              3437.5

                                                                                                          

                             > 6 months               n                           214.0               214.0

                                                      mean                         33.4               348.5

                                                      std                          23.2              1611.7

                                                      median                       28.0               126.3

                                                      25th percentile              14.0                60.8

                                                      75th percentile              42.0               259.2

                                                      min                           0.0                 0.0

                                                      max                         109.0             23100.0

                                                                                                          

                                                                                                           

 

 

 

 

 

 

 

 

 

                   __________________________________________________________________________________

    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 Dec. 1, 97. All data will       

                be excluded after the first generic clozapine                                                      

 


                                                       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

                                    (Excluded patients data meeting criteria 1, 2 and 3)

 

                                                                               Duration (day)

            Cohort           Duration                 Statistics               of prodrome           Slope+  

            _______________________________________________________________________________________________

                                                                                                           

            Cohort 1 & 2     <= 6 months              n                           334.0               334.0

                                                      mean                         26.3               320.0

                                                      std                          13.8               365.7

                                                      median                       24.0               240.8

                                                      25th percentile              16.0               147.6

                                                      75th percentile              35.0               372.8

                                                      min                           0.0                 0.0

                                                      max                         100.0              3634.2

                                                                                                           

                             6 months to 1 year       n                            19.0                19.0

                                                      mean                         28.1               294.1

                                                      std                          14.6               238.5

                                                      median                       28.0               244.3

                                                      25th percentile              16.0               138.5

                                                      75th percentile              37.0               378.6

                                                      min                           7.0                28.2

                                                      max                          63.0               892.9

                                                                                                          

                             1-2 years                n                            32.0                32.0

                                                      mean                         30.9               182.8

                                                      std                          16.6               176.6

                                                      median                       28.0               150.2

                                                      25th percentile              21.0                59.4

                                                      75th percentile              43.5               195.0

                                                      min                           7.0                 7.5

                       __________________________________________________________________________________

    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 Dec. 1, 97. All data will       

                be excluded after the first generic clozapine                                                       

+ Slope = rate of decrease of WBC (count/day) during prodrome
                                              Post-text table 3.6-2 (Continued)

         Summary statistics on duration of prodrome and slope during  prodrome for moderate leukopenia patients

                                      who also developed agranulocytosis by cohort

                                    (Excluded patients data meeting criteria 1, 2 and 3)

 

                                                                               Duration (day)

            Cohort           Duration                 Statistics               of prodrome           Slope+  

            _______________________________________________________________________________________________

                                                                                                           

            Cohort 1 & 2     1-2 years                max                          77.0               842.9

                                                                                                           

                             > 2 years                n                            48.0                48.0

                                                      mean                         29.7               404.2

                                                      std                          16.0               770.5

                                                      median                       28.0               155.6

                                                      25th percentile              14.5                91.3

                                                      75th percentile              42.0               363.9

                                                      min                           7.0                41.4

                                                      max                          77.0              4800.0

                                                                                                           

                             > 6 months               n                            99.0                99.0

                                                      mean                         29.8               311.5

                                                      std                          15.9               561.0

                                                      median                       28.0               162.6

                                                      25th percentile              17.0                88.4

                                                      75th percentile              42.0               335.2

                                                      min                           7.0                 7.5

                                                      max                          77.0              4800.0

                                                                                                          

                                                                                                           

            Cohort 3         <= 6 months              n                            28.0                28.0

                                                      mean                         32.0               264.4

                                                      std                          19.2               254.8

                                                      median                       28.0               160.8

 

                   __________________________________________________________________________________

    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 Dec. 1, 97. All data will       

                be excluded after the first generic clozapine                                                       


                                            Post-text table 3.6-2 (Continued)

         Summary statistics on duration of prodrome and slope during  prodrome for moderate leukopenia patients

                                      who also developed agranulocytosis by cohort

                                    (Excluded patients data meeting criteria 1, 2 and 3)

 

                                                                               Duration (day)

            Cohort           Duration                 Statistics               of prodrome           Slope+  

            _______________________________________________________________________________________________

                                                                                                           

            Cohort 3         <= 6 months              25th percentile              15.0               129.2

                                                      75th percentile              48.0               285.9

                                                      min                           7.0                39.9

                                                      max                          76.0              1185.7

                                                                                                           

                             6 months to 1 year       n                             1.0                 1.0

                                                      mean                         35.0                70.7

                                                      std                           0.0                 0.0

                                                      median                       35.0                70.7

                                                      25th percentile              35.0                70.7

                                                      75th percentile              35.0                70.7

                                                      min                          35.0                70.7

                                                      max                          35.0                70.7

                                                                                                           

                             1-2 years                n                             0.0                 0.0

                                                      mean                          0.0                 0.0

                                                      std                           0.0                 0.0

                                                      median                        0.0                 0.0

                                                      25th percentile               0.0                 0.0

                                                      75th percentile               0.0                 0.0

                                                      min                           0.0                 0.0

                                                      max                           0.0                 0.0

                                                                                                          

                             > 6 months               n                             1.0                 1.0

                                                      mean                         35.0                70.7

 

                   __________________________________________________________________________________

    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 Dec. 1, 97. All data will       

                be excluded after the first generic clozapine                                                      


                                             Post-text table 3.6-2 (Continued)

         Summary statistics on duration of prodrome and slope during  prodrome for moderate leukopenia patients

                                      who also developed agranulocytosis by cohort

                                    (Excluded patients data meeting criteria 1, 2 and 3)

 

                                                                               Duration (day)

            Cohort           Duration                 Statistics               of prodrome           Slope+  

            _______________________________________________________________________________________________

                                                                                                          

            Cohort 3         > 6 months               std                           0.0                 0.0

                                                      median                       35.0                70.7

                                                      25th percentile              35.0                70.7

                                                      75th percentile              35.0                70.7

                                                      min                          35.0                70.7

                                                      max                          35.0                70.7

                                                                                                          

                                                                                                           

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

                   __________________________________________________________________________________

    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 Dec. 1, 97. All data will       

                be excluded after the first generic clozapine                                                      

 


                                               Post-text table 3.6-3

         Summary statistics on duration of prodrome and slope during  prodrome for moderate leukopenia patients

                                    who did not developed agranulocytosis by cohort

                                    (Excluded patients data meeting criteria 1, 2 and 3)

 

                                                                               Duration (day)

            Cohort           Duration                 Statistics               of prodrome           Slope+  

            _______________________________________________________________________________________________

                                                                                                          

            Cohort 1 & 2     <= 6 months              n                          1444.0              1444.0

                                                      mean                         22.0               326.8

                                                      std                          15.0              1287.9

                                                      median                       21.0               149.5

                                                      25th percentile              10.0                75.0

                                                      75th percentile              30.0               304.0

                                                      min                           0.0               -43.6

                                                      max                         105.0             41100.0

                                                                                                          

                             6 months to 1 year       n                           563.0               563.0

                                                      mean                         23.2               373.7

                                                      std                          15.6              1156.8

                                                      median                       21.0               135.2

                                                      25th percentile              13.0                75.0

                                                      75th percentile              29.0               328.6

                                                      min                           0.0                 0.0

                                                      max                         119.0             24600.0

                                                                                                           

                             1-2 years                n                           743.0               743.0

                                                      mean                         24.4               353.8

                                                      std                          16.7               589.6

                                                      median                       21.0               161.4

                                                      25th percentile              14.0                74.0

                                                      75th percentile              33.0               396.3

                                                      min                           0.0                -1.0

 

                   __________________________________________________________________________________

    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 Dec. 1, 97. All data will       

                be excluded after the first generic clozapine                                                      


                                            Post-text table 3.6-3 (Continued)

         Summary statistics on duration of prodrome and slope during  prodrome for moderate leukopenia patients

                                    who did not developed agranulocytosis by cohort

                                    (Excluded patients data meeting criteria 1, 2 and 3)

 

                                                                               Duration (day)

            Cohort           Duration                 Statistics               of prodrome           Slope+  

            _______________________________________________________________________________________________

                                                                                                          

            Cohort 1 & 2     1-2 years                max                         140.0              8766.7

                                                                                                           

                             > 2 years                n                          2175.0              2175.0

                                                      mean                         29.6               317.8

                                                      std                          21.8               615.0

                                                      median                       24.0               141.9

                                                      25th percentile              14.0                61.7

                                                      75th percentile              41.0               344.7

                                                      min                           0.0               -39.0

                                                      max                         168.0             11250.0

                                                                                                           

                             > 6 months               n                          3481.0              3481.0

                                                      mean                         27.4               334.5

                                                      std                          20.1               726.0

                                                      median                       22.0               144.0

                                                      25th percentile              14.0                65.9

                                                      75th percentile              35.0               357.1

                                                      min                           0.0               -39.0

                                                      max                         168.0             24600.0

                                                                                                          

                                                                                                           

            Cohort 3         <= 6 months              n                           366.0               366.0

                                                      mean                         21.4               313.7

                                                      std                          17.4               735.0

                                                      median                       19.5               144.1

                         __________________________________________________________________________________

    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 Dec. 1, 97. All data will       

                be excluded after the first generic clozapine                                                      

+ Slope = rate of decrease of WBC (count/day) during prodrome
                                             Post-text table 3.6-3 (Continued)

         Summary statistics on duration of prodrome and slope during  prodrome for moderate leukopenia patients

                                    who did not developed agranulocytosis by cohort

                                    (Excluded patients data meeting criteria 1, 2 and 3)

 

                                                                               Duration (day)

            Cohort           Duration                 Statistics               of prodrome           Slope+  

            _______________________________________________________________________________________________

                                                                                                          

            Cohort 3         <= 6 months              25th percentile               7.0                66.7

                                                      75th percentile              28.0               298.6

                                                      min                           0.0               -13.8

                                                      max                         112.0              7650.0

                                                                                                          

                             6 months to 1 year       n                            87.0                87.0

                                                      mean                         30.3               207.1

                                                      std                          20.5               294.0

                                                      median                       25.0               125.9

                                                      25th percentile              14.0                61.7

                                                      75th percentile              42.0               236.0

                                                      min                           0.0                 0.0

                                                      max                          96.0              2250.0

                                                                                                          

                             1-2 years                n                            77.0                77.0

                                                      mean                         35.2               537.8

                                                      std                          25.1              2635.6

                                                      median                       29.0               120.7

                                                      25th percentile              14.0                56.6

                                                      75th percentile              46.0               259.2

                                                      min                           0.0                 0.0

                                                      max                         109.0             23100.0

                                                                                                           

                             > 2 years                n                            49.0                49.0

                                                      mean                         36.0               307.9

 

                   __________________________________________________________________________________

    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 Dec. 1, 97. All data will       

                be excluded after the first generic clozapine                                                      


                                               Post-text table 3.6-3 (Continued)

         Summary statistics on duration of prodrome and slope during  prodrome for moderate leukopenia patients

                                    who did not developed agranulocytosis by cohort

                                    (Excluded patients data meeting criteria 1, 2 and 3)

 

                                                                               Duration (day)

            Cohort           Duration                 Statistics               of prodrome           Slope+  

            _______________________________________________________________________________________________

                                                                                                           

            Cohort 3         > 2 years                std                          24.7               526.1

                                                      median                       28.0               167.4

                                                      25th percentile              16.0                57.9

                                                      75th percentile              42.0               363.9

                                                      min                           6.0                12.9

                                                      max                         101.0              3437.5

                                                                                                           

                             > 6 months               n                           213.0               213.0

                                                      mean                         33.4               349.8

                                                      std                          23.3              1615.4

                                                      median                       28.0               126.5

                                                      25th percentile              14.0                60.8

                                                      75th percentile              42.0               259.2

                                                      min                           0.0                 0.0

                                                      max                         109.0             23100.0

                                                                                                           

                                                                                                          

 

 

 

 

 

 

 

 

 

                   __________________________________________________________________________________

    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 Dec. 1, 97. All data will       

                be excluded after the first generic clozapine                                                      


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

                                              (Excluded patients’ data meeting criteria 1, 2 and 3)

 

                                 _______No. of cases _________                 ___Rate per 1000 patient-years____  

                   Change                                No          Patient                                                                                              No             

                   monitoring     Bi-weekly   Monthly  Monitoring    Year       Bi-weekly   Monthly   Monitoring                                    

                   after          (actual)                                      (actual)

___________________________________________________________________________________________________________________

                                                                                                                                  

     Agran          Six months      7*        45      157            27017       0.26         1.68       5.81                                            

                    One year        2         28       88            17595       0.11         1.57       4.98                                            

Two years       0          9       34             6030       0.00         1.51       5.66                                            

 

 

    Severe          Six months      9        100      230            27017       0.33         3.68       8.51                                            

    Leukopenia      One year        5         61      128            17595       0.28         3.46       7.27                                            

                    Two years       4         20       50             6030       0.66         3.29       8.29

                                    

                                                                               

_______________________________________________________________________________________________________________

                                                                                                                                 

          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 Dec. 1, 97. All data will              

                      be excluded after the first generic clozapine                                                             

                                                                     

                      * Excluded 3 patients with less than 6 months of treatment but the reporting date of 

               agranulocytosis was more than 6 months from start of therapy.                                                      


 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

                                      (Excluded patients’ data meeting criteria 1, 2 and 3)

 

                                 _______No. of cases _________                 ___Rate per 1000 patient-years____  

                   Change                                No          Patient                                                                                              No             

                   monitoring     Bi-weekly   Monthly  Monitoring    Year       Bi-weekly   Monthly   Monitoring                                    

                   after          (actual)                                      (actual)

___________________________________________________________________________________________________________________

                                                                                                                                 

     Agran          Six months      7#        45        157           27017     0.26         1.68       5.81                                            

                    One year        7#        33         93           27017      0.26         1.21       3.43                                            

Two years       7#        16         41           27017      0.26         0.60       1.52                                            

 

 

    Severe          Six months      9        100        230          27017      0.33         3.68       8.51                                            

    Leukopenia      One year        9         65        132           27017      0.33         2.40       4.89                                            

                    Two years       9         25         55           27017      0.33         0.92       2.04

                                                                                     

 

_______________________________________________________________________________________________________________

                                                                                                                                  

          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 Dec. 1, 97. All data will              

                      be excluded after the first generic clozapine                                                              

                              

                                  
             * Actual number of cases occurred after 6 months of treatment and before change monitoring were added to

               the projected number of cases so that cumulative number of cases were comparable under different monitoring

               systems.

                      # Excluded 3 patients with less than 6 months of treatment but the reporting date of 

               agranulocytosis was more than 6 months from start of therapy.                                                      

 


 Post-text table 3.6-6

Additional cases of agranulocytosis and severe leukopenia projected to occur after 6 months as a result of switching from bi-weekly to less-frequent WBC monitoring for Cohort 3

                                      (Excluded patients’ data meeting criteria 1, 2 and 3)

 

                                     ______No. of cases ______               ___Rate per 1000 patient-years____ 

 

                    Change                           No          Patient                        No      

                    Monitoring          Monthly    Monitoring     Year         Monthly    Monitoring            ____________________after___________________________________________________________________________________

                                                                                                                                  

     Agran          Six months             38        150           27017          1.42                                                  5.55           

                    One year               26         86           27017          0.95                                                  3.17                 

                    Two years               9         34           27017          0.34                                                  1.26           

 

    Severe          Six months             91        221           27017          3.35                                        8.18      

    Leukopenia      One year               56        123           27017          2.07                                        4.55                    

                    Two years              16         46           27017         0.59                                                  1.70                      

 

_______________________________________________________________________________________________________________

                                                                                                                                  

          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 Dec. 1, 97. All data will              

                      be excluded after the first generic clozapine


Post-text table 3.6-7:  Projection of Total Number of Deaths for Different Monitoring Systems

 

                              The estimated proportions of deaths due to agranulocytosis for cohort 3 are:

 

                                             3.55% for Clozaril treated Cohort 3 patients under the current bi-weekly monitoring.

                                             15% under no monitoring or other causes of agranulocytosis.

 

                              Assuming these death rates, the following table shows the estimated total

                              number of deaths due to agranulocytosis that would have occurred between

                              10/1/97 and 9/1/01 if monitoring was changed.

 

 

(N=39,260)

(Person Year=41,172)

Death Rate

Due to Agranulocytosis

 

 

 

At Six Months of Therapy

 

 

At One Year of Therapy

 

 

At Two Years of Therapy

 

 

 

 

 

Monthly

(Projected)