The development program was initially designed to support once daily dosing of the XR formulation; however, information on the diet pill phentermine the mean Cmin for this formulation fell below that for the IR formulation. Additional biopharmaceutical studies were conducted to establish that a twice-daily dosing regimen with the XR tablets would result in a Cmin that would fall within an acceptable range. The program consisted of 23 clinical studies, the; results of which will be strattera adderall summarized in this section. Full analyses of 21 studies were not included in the submission under review. PHARMACOKINETIC PROFILE SUMMARY TABLE Mean Clinical Pk Parameters with Alprazolam Extended-Release Tablets Single Dose AUC C max t max t'A Vd/F Clearance (mg) (ng- h/ mL) (ng/mL) (h) 0") (L/kg) (mL/ min/ kg) 1 mg 267.3 11.1 5.6 13.8 6 me 1166.1 43.3 8.4 11.7 1.24 1.22 Mean Dose Corrected Alprazolam AUC and Cmax Resulting from the strattera adderall Oral Administration of Three Different Single Doses of a Sustained Release Formulation of Alprazolam (Protocol M/2000/0253) Parameter Treatment B C D Dose 1 mg 3 mg 6 mg AUCJJ (ng x h/mL)* 230 (96.6) 217 (78.2) 264 (65.8) CmaxD (ng/mL)* 7.82(1.71) 8.31 (3.13) 8.39(3.46) 3.In Vitro-In Vivo Correlation The dissolution profiles for the 4 strengths of Xanax XR tablets differ; however, the various in vitro behaviors of the different strengths do not result in differences in the in vivo absorption of alprazolam, as illustrated by the bioequivalence of the 0.5, 1, 2, and 3 mg XR tablets. 4.Absorption Results of clinical studies across various doses of Xanax XR indicate that alprazolam is well absorbed from XR tablets, to the same extent as from the immediate release form of green oxycontin alprazolam. Relative bioavailability in studies ranged from 0.969-0.981.
The differences in AUC between the XR and IR formulations were very small. 5.Distribution The distribution of alprazolam is not influenced by its rate of absorption. Results from clinical studies indicate that there is no difference in the alprazolam volume of distribution (Vd/F) after administration of the XR and IR formulations.
6.Metabolism ' Alprazolam is metabolized via oxidation in the liver. Its primary metabolites are the pharmacologically active compounds, 4-hydroxyalprazolam and alpha-hydroxy- alprazolam. It is thought that 4-hydroxyalation is the major metabolite in strattera adderall humans, probably mediated by CYP3 A4 activity. Ketaconazole substantially inhibits metabolism of alprazolam. Activity of the following human enzymes do not produce significant quantities of the alprazolam metabolites 4-hydroxyalprazolam and alpha-hydroxy- alprazolam: CYP1A2, CYP2A6, CYP2B6, CYP2D6, and CYP2E1. Cells expressing CYP2C9 and CYP2C19 produced 4-hydroxyalprazolam, but the rate of production by cells expressing C!fP3A4 was 84 times greater. The metabolism of 15 ml phentermine without prescription alprazolam following administration of the XR formulation has been assessed by comparing the oral clearance of alprazolam after single and multiple doses of XR and IR tablets. Metabolite PK profiles of the 2 formulations darvocet tramadol have also been compared. Metabolism of alprazolam is not affected by absorption rate. 7.Excretion The sponsor states that the excretion of alprazolam after administration of XR tablets has not been studied, because metabolism is the major route of elimination.
Since metabolism is unchanged by absorption rate, excretion of unchanged alprazolam would also be expected to tie unchanged. 8.Factors Affecting Pharmacokinetics a.Food Effect The alprazolam AUC for the XR tablet administered with food was 7% below the AUC when alprazolam XR was administered in the fasting state. The alprazolam AUC for the fed and fasting admi nistration of the XR tablet were 2% lower and 5% greater, respectively, than those following the administration of the IR tablet. The Cmax for alprazolam XR treatment in the fed state was 12% greater than that for treatment in the fasting state. The Cmax values were 31% and 39% lower for the strattera adderall respective IR treatments.
The Tmax for alprazolam XR was unchanged with feeding. The sponsor concludes that no specific instructions are warranted regarding alprazolam XR tablet dosing in relation to meals. b.Steady-State Fo rmulation Performance With once daily dosing of the XR tablet (6 mg QD) and QID dosing with IR tablets (1.compare tramadol and tramadol hc 5 mg QID), the extent of absorption was equivalent. Steady-state Cmax did not differ strattera adderall between treatments , although Tmax was later for IR tablets, occurring after the second daily dose given 5 hours after the first dose.
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