STRATTERA (Page 6 of 7)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis — Atomoxetine HCl was not carcinogenic in rats and mice when given in the diet for 2 years at time–weighted average doses up to 47 and 458 mg/kg/day, respectively. The highest dose used in rats is approximately 8 and 5 times the maximum human dose in children and adults, respectively, on a mg/m2 basis. Plasma levels (AUC) of atomoxetine at this dose in rats are estimated to be 1.8 times (extensive metabolizers) or 0.2 times (poor metabolizers) those in humans receiving the maximum human dose. The highest dose used in mice is approximately 39 and 26 times the maximum human dose in children and adults, respectively, on a mg/m2 basis.

Mutagenesis — Atomoxetine HCl was negative in a battery of genotoxicity studies that included a reverse point mutation assay (Ames Test), an in vitro mouse lymphoma assay, a chromosomal aberration test in Chinese hamster ovary cells, an unscheduled DNA synthesis test in rat hepatocytes, and an in vivo micronucleus test in mice. However, there was a slight increase in the percentage of Chinese hamster ovary cells with diplochromosomes, suggesting endoreduplication (numerical aberration).

The metabolite N–desmethylatomoxetine HCl was negative in the Ames Test, mouse lymphoma assay, and unscheduled DNA synthesis test.

Impairment of fertility — Atomoxetine HCl did not impair fertility in rats when given in the diet at doses of up to 57 mg/kg/day, which is approximately 6 times the maximum human dose on a mg/m2 basis.

14 CLINICAL STUDIES

14.1 ADHD studies in Children and Adolescents

Acute Studies — The effectiveness of STRATTERA in the treatment of ADHD was established in 4 randomized, double–blind, placebo–controlled studies of pediatric patients (ages 6 to 18). Approximately one–third of the patients met DSM–IV criteria for inattentive subtype and two–thirds met criteria for both inattentive and hyperactive/impulsive subtypes.

Signs and symptoms of ADHD were evaluated by a comparison of mean change from baseline to endpoint for STRATTERA- and placebo–treated patients using an intent–to–treat analysis of the primary outcome measure, the investigator administered and scored ADHD Rating Scale–IV–Parent Version (ADHDRS) total score including hyperactive/impulsive and inattentive subscales. Each item on the ADHDRS maps directly to one symptom criterion for ADHD in the DSM–IV.

In Study 1, an 8–week randomized, double–blind, placebo–controlled, dose–response, acute treatment study of children and adolescents aged 8 to 18 (N=297), patients received either a fixed dose of STRATTERA (0.5, 1.2, or 1.8 mg/kg/day) or placebo. STRATTERA was administered as a divided dose in the early morning and late afternoon/early evening. At the 2 higher doses, improvements in ADHD symptoms were statistically significantly superior in STRATTERA–treated patients compared with placebo–treated patients as measured on the ADHDRS scale. The 1.8 mg/kg/day STRATTERA dose did not provide any additional benefit over that observed with the 1.2 mg/kg/day dose. The 0.5 mg/kg/day STRATTERA dose was not superior to placebo.

In Study 2, a 6–week randomized, double–blind, placebo–controlled, acute treatment study of children and adolescents aged 6 to 16 (N=171), patients received either STRATTERA or placebo. STRATTERA was administered as a single dose in the early morning and titrated on a weight–adjusted basis according to clinical response, up to a maximum dose of 1.5 mg/kg/day. The mean final dose of STRATTERA was approximately 1.3 mg/kg/day. ADHD symptoms were statistically significantly improved on STRATTERA compared with placebo, as measured on the ADHDRS scale. This study shows that STRATTERA is effective when administered once daily in the morning.

In 2 identical, 9–week, acute, randomized, double–blind, placebo–controlled studies of children aged 7 to 13 (Study 3, N=147; Study 4, N=144), STRATTERA and methylphenidate were compared with placebo. STRATTERA was administered as a divided dose in the early morning and late afternoon (after school) and titrated on a weight–adjusted basis according to clinical response. The maximum recommended STRATTERA dose was 2.0 mg/kg/day. The mean final dose of STRATTERA for both studies was approximately 1.6 mg/kg/day. In both studies, ADHD symptoms statistically significantly improved more on STRATTERA than on placebo, as measured on the ADHDRS scale.

Examination of population subsets based on gender and age (<12 and 12 to 17) did not reveal any differential responsiveness on the basis of these subgroupings. There was not sufficient exposure of ethnic groups other than Caucasian to allow exploration of differences in these subgroups.

Maintenance Study — The effectiveness of STRATTERA in the maintenance treatment of ADHD was established in an outpatient study of children and adolescents (ages 6-15 years). Patients meeting DSM-IV criteria for ADHD who showed continuous response for about 4 weeks during an initial 10 week open-label treatment phase with STRATTERA (1.2 to 1.8 mg/kg/day) were randomized to continuation of their current dose of STRATTERA (N=292) or to placebo (N=124) under double-blind treatment for observation of relapse. Response during the open-label phase was defined as CGI-ADHD-S score ≤2 and a reduction of at least 25% from baseline in ADHDRS-IV-Parent:Inv total score. Patients who were assigned to STRATTERA and showed continuous response for approximately 8 months during the first double-blind treatment phase were again randomized to continuation of their current dose of STRATTERA (N=81) or to placebo (N=82) under double-blind treatment for observation of relapse. Relapse during the double-blind phase was defined as CGI-ADHD-S score increases of at least 2 from the end of open-label phase and ADHDRS-IV-Parent:Inv total score returns to ≥90% of study entry score for 2 consecutive visits. In both double-blind phases, patients receiving continued STRATTERA treatment experienced significantly longer times to relapse than those receiving placebo.

14.2 ADHD studies in Adults

The effectiveness of STRATTERA in the treatment of ADHD was established in 2 randomized, double–blind, placebo–controlled clinical studies of adult patients, age 18 and older, who met DSM–IV criteria for ADHD.

Signs and symptoms of ADHD were evaluated using the investigator–administered Conners Adult ADHD Rating Scale Screening Version (CAARS), a 30–item scale. The primary effectiveness measure was the 18–item Total ADHD Symptom score (the sum of the inattentive and hyperactivity/impulsivity subscales from the CAARS) evaluated by a comparison of mean change from baseline to endpoint using an intent–to–treat analysis.

In 2 identical, 10–week, randomized, double–blind, placebo–controlled acute treatment studies (Study 5, N=280; Study 6, N=256), patients received either STRATTERA or placebo. STRATTERA was administered as a divided dose in the early morning and late afternoon/early evening and titrated according to clinical response in a range of 60 to 120 mg/day. The mean final dose of STRATTERA for both studies was approximately 95 mg/day. In both studies, ADHD symptoms were statistically significantly improved on STRATTERA, as measured on the ADHD Symptom score from the CAARS scale.

Examination of population subsets based on gender and age (<42 and ≥42) did not reveal any differential responsiveness on the basis of these subgroupings. There was not sufficient exposure of ethnic groups other than Caucasian to allow exploration of differences in these subgroups.

16 HOW SUPPLIED/STORAGE AND HANDLING

16.1 How Supplied

*
Atomoxetine base equivalent.

STRATTERA® Capsules

10 mg *

18 mg *

25 mg *

40 mg *

60 mg *

80 mg *

100 mg *

Color

Opaque White,Opaque White

Gold,Opaque White

Opaque Blue,Opaque White

Opaque Blue,Opaque Blue

Opaque Blue,Gold

Opaque Brown,Opaque White

Opaque Brown,Opaque Brown

Identification

LILLY 3227

LILLY 3238

LILLY 3228

LILLY 3229

LILLY 3239

LILLY 3250

LILLY 3251

10 mg

18 mg

25 mg

40 mg

60 mg

80 mg

100 mg

NDC Codes:

Bottles of 30

0002-3227-30

0002-3238-30

0002-3228-30

0002-3229-30

0002-3239-30

0002-3250-30

0002-3251-30

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