PFIZER INC. THERAPEUTIC AREA AND FDA APPROVED INDICATIONS: See USPI

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1 PFIZER INC. These results are supplied for informational purposes only. Prescribing decisions should be made based on the approved package insert. For publications based on this study, see associated bibliography. PROPRIETARY DRUG NAME/INN: Xanax XR / Alprazolam THERAPEUTIC AREA AND FDA APPROVED INDICATIONS: See USPI PROTOCOL NO.: A PROTOCOL TITLE: Comparison of the Pharmacokinetics of an Extended Release Formulation of Alprazolam (Xanax XR ) in Healthy Normal Adolescent and Adult Volunteers Study Center(s): One (1) center in the United States Study Initiation and Completion Dates: 23 October 2003 to 15 November 2003 Phase of Development: Phase 1 Study Objective(s): The purpose of this study was to estimate (1) the pharmacokinetics and (2) the safety and tolerability of single doses of alprazolam extended release in adolescent and adult healthy volunteers. METHODS Study Design: This was a randomized, open-label, single-dose, 2-period crossover study. Eligible subjects received single doses of alprazolam extended release 1 mg or 3 mg tablets in a crossover fashion. Subjects underwent a 7-day washout period between doses. Number of Patients (planned and analyzed): Planned: 24 healthy volunteers (12 adolescents and 12 adults) Analyzed: 24 healthy volunteers (12 adolescents and 12 adults) Diagnosis and Main Criteria for Inclusion: Health status was determined by a detailed medical history, full physical examination (including blood pressure [BP] and heart rate [HR] measurement), 12-lead electrocardiogram (ECG), and clinical laboratory tests. The adolescent volunteers were comprised of males and females between the ages of 13 and 17 years of age, inclusive. Adult volunteers were comprised of males and females between the ages of 20 and 45 years of age, inclusive. Study Treatment: Alprazolam extended release 1 mg or 3 mg tablets for oral administration Efficacy Evaluations: No efficacy evaluations were performed in this study. Pharmacokinetic Evaluations: Blood samples were collected at 0 (just prior to dosing), 1, 2, 3, 4, 6, 8, 10, 12, 24, 36, and 48 hours postdose on study Day 1 of each study period. The following

2 pharmacokinetic (PK) parameters were determined for alprazolam: area under the curve (AUC) from time 0 hours to the final measurable time point (AUC(0-t)), area under the curve extrapolated to infinity (AUC(0- )), maximum plasma concentration (Cmax), time-to-maximum plasma concentration or first occurrence of Cmax (Tmax), and terminal elimination half-life (t½). AUC(0-t), Cmax, and Tmax were determined for the 2 major metabolites α-hydroxy-alprazolam and 4-hydroxy-alprazolam. Safety Evaluations: Safety assessments included clinical laboratory tests, vital signs, and adverse event monitoring. Statistical Methods: Log-transformed dose-normalized AUC(0- ) and Cmax were analyzed by mixed effects analysis of variance (ANOVA), with age-group, dose, and period effects and interaction terms, period*dose and age-group*dose, considered fixed and subject considered random. For the comparison between the adults and adolescents, 95% confidence intervals on the adjusted mean ratio of AUC(0-t) and AUC(0- ) for the adolescents vs the adults was computed. For the dose comparisons with each group, the 90% confidence interval on the dose adjusted mean ratio of AUC(0-t), and AUC(0- ) for the 3 mg vs the 1 mg dose was compared to the equivalence limits (80, 125%). An exploratory regression analysis was performed for the adolescent subset to assess the effects of age, weight, and sex on the endpoints AUC(0- ) and Cmax. For each endpoint, the fixed independent factors were dose, age, weight, and sex; subject was a random effect. Vital signs were summarized using descriptive statistics (means and change from baseline). RESULTS Subject Disposition and Demography: A total of 24 healthy volunteers were recruited to this study - 12 adolescents and 12 adults. All subjects completed the study. There were 5 male and 7 female adolescent subjects and 4 male and 8 female adults aged between 13 and 44 years. Twenty-three of the 24 volunteers were white and one was black. Efficacy Results: There were no efficacy evaluations performed in this study. Pharmacokinetic Results: The mean pharmacokinetic profiles of alprazolam, α-hydroxyalprazolam, and 4-hydroxy-alprazolam were similar in adolescent and adult subjects after administration of 1 mg and 3 mg alprazolam (Table S1). Protocol A / Page 2 of 5

3 Table S1 Arithmetic Means (SD) for Cmax, Tmax, AUC, and T½ N Cmax (ng/ml) Tmax* (hr) AUC(0- ) T½ (hr) (ng hr/ml) Alprazolam Adolescent, 1 mg (1.4) 9.82 (2.8) (67.8) (3.6) Adult, 1 mg (1.4) 8.33 (3.3) (66.9) (3.1) Adolescent, 3 mg (4.7) (5.8) (144.3) (3.6) Adult, 3 mg (4.4) 9.00 (4.1) (243.5) (4.7) 4OH-Alprazolam Adolescent, 1 mg (0.6) (0.8) (15.7) (11.0) Adult, 1 mg (0.5) (5.0) (18.5) (10.8) Adolescent, 3 mg (1.5) (5.7) (56.7) (6.3) Adult, 3 mg (1.5) (5.3) (55.5) (3.4) αoh-alprazolam Adolescent, 1 mg (0.2) (2.8) 4.95 (5.4) (6.5) Adult, 1 mg (0.2) (5.1) 2.21 (2.9) NA Adolescent, 3 mg (0.4) (3.7) (9.3) (10.0) Adult, 3 mg (0.2) (6.5) (7.6) (11.8) *Median (range); NA= Not Assessed. Between-age-groups comparison (adolescent to adults) of 1 mg and 3 mg alprazolam were made separately and as combined doses (Table S2). Dose-proportionality comparisons of 3 mg to 1 mg of alprazolam were made within the adult group and within the adolescent group (Table S3). Table S2 Summary of Statistical Analyses of Alprazolam PK Parameters for Alprazolam Extended Release 1 mg, Alprazolam Extended Release 3 mg, and Doses Combined: Between-Age-Groups Comparison Parameter Comparison (Test/Reference) Ratio (%) 95% CI Between Group: Adolescent (Test) vs Adult (Reference) AUC(0- ) (ng h/ml) Adolescent, 1 mg/adult, 1 mg , 150 Adolescent, 3 mg/adult, 3 mg , 141 Adolescent, Combined/Adult, Combined , 143 Cmax (ng/ml) Adolescent, 1 mg/adult, 1 mg , 137 Adolescent, 3 mg/adult, 3 mg , 125 Adolescent, Combined/Adult, Combined , 129 CI = confidence interval Table S3 Summary of Statistical Analyses of Alprazolam PK Parameters for Adolescents and Adults: Within-Age-Groups Comparison Parameter Comparison (Test/Reference) Ratio (%) 90% CI Adolescent Within Group AUC(0- ) (ng h/ml) 3 mg / 1 mg 94 86, 103 Cmax (ng/ml) 3 mg / 1 mg 89 83, 95 Adult Within Group AUC(0- ) (ng h/ml) 3 mg / 1 mg , 116 Cmax (ng/ml) 3 mg / 1 mg 97 88, 107 CI = confidence interval Exploratory Regression Analysis for Adolescent Subjects: The weight and dose effects for lncmax PK parameter were found to be statistically significant (p<0.0337). There were no Protocol A / Page 3 of 5

4 significant age and gender effects for lnauc(0- ) and lncmax PK parameters (p>0.4841). For lnauc(0- ), there were no significant weight and dose effects (p>0.2495). Table S4 presents the predicted mean Cmax for age, weight and gender. Table S4 Predicted Mean Cmax for Age and Weight Dose Age Weight Gender Predicted Cmax 1 mg Male Female Male Female Male Female Male Female mg Male Female Male Female Male Female Male Female Safety Results: There were a total of 31 treatment-emergent adverse events (AEs) reported by 20 subjects. All AEs were either mild (N=13) or moderate (N=18) in severity. All treatment emergent adverse events are presented in Table S5, below. Table S5 Treatment-Emergent Adverse Events Alprazolam Extented Release Body System / COSTART Preferred Term Adolescents 1 mg Adults 1 mg Adolescents 3 mg Adults 3 mg Body as a Whole Headache Abdominal pain Digestive Nausea Nervous Somnolence Dizziness Respiratory Hiccups Skin and Appendages Rash Total Number of AEs Total Number of Subjects with AEs Total Number of Subjects Exposed Protocol A / Page 4 of 5

5 There were no deaths, serious adverse events or discontinuations due to adverse events reported in this study. None of the clinical laboratory parameters or vital signs measurements were of clinical concern. CONCLUSION(S): The AUC(0- ) and Cmax results demonstrate dose proportionality of alprazolam after single 1 mg and 3 mg doses for both adolescents and adults. Mean concentration-time profiles were similar for both groups of subjects. Compared with adults, relative AUC(0- ) and Cmax in adolescents, expressed as ratios of the estimated geometric means for both dose levels, were 115% and 111%, respectively. These differences are thought not to be of clinical relevance. In this study, single-dose administration of 1 mg and 3 mg Alprazolam extended release tablets was safe in both adolescent and adult subjects. Somnolence was noted in a dose-related fashion in both study populations. All cases of somnolence resolved without intervention. Based on a report completed on: 06 October 2004 Protocol A / Page 5 of 5