Parameter* are Corrected for Mean Amyed Tablet Lot Potency.
^ 236 (558) 773(191) 250(668) 791 (195) 0.0001 AC(c) AUCSa-4 (nexbn'mL) gy-(gj)information hydrocodone 258 (53 8) 2£Itf (3) XANAX X£(r) Tablets 1 nyr at ltkOO pm Muitipia amputeooa woo made naing tha WalW-Duncan tRatio t taat. connected by a Una an Dot significantly different (p 45 years versus 45 years old than in patients 85%). Similarly, the majority of subjects that participated in BA/BE studies were White, Comment: The sponsor should further explore the ethnic-effect on the PK and safety/efficacy from the available sources (such as literature & post-marketing experience from over the 50 countries outside of U.S. that XR formulation has been marketed) and incorporate relevant information into the label. Following are the bases: (a) Ethnic differences in the alprazolam PK parameters (Cmax, AUC, Cl; tl/2) had been reported in the literature (Lin KM et al (1988)*); (b) Ethnic differences in CYP3A4 enzyme activity have been reported in the literature and CYP3A4 pathway is the major route of elimination for alprazolam. Note: The sponsor indicated that Xanax XR had been marketed in over 50 countries outside of U.S. * Lin KM et al 1988 Psychopharmacology (Berl) 1988;96(3): 365-9 Comparison of information hydrocodone alprazolam plasma levels in normal Asian and Caucasian male volunteers from a PubMed search by this reviewer. 4.6 Extrinsic factors 4.6.1Food-effect [M/2000/0275 (reviewed by Hossain), P/2002/0013 (reviewed by Hossain), M/2002/0017(reviewed by Chou)] The sponsor conducted three food effect studies: one on the 1.0 mg XR tablet [M/2000/0275 (Hossain), two on the 3.0mg tablet [P/2002/0013 (Hossain), M/2002/0017(Effect of meal timing, Chou)]. Detailed discussion can be found in section 7.2.1 (page 49). 18.104.22.168Does food affect the bioavailability of the Xanax XR?
Yes, high fat meal when given immediately before or 2 hours before information hydrocodone the dosing of 3mg XR tablet significantly affects the bioavailability of Xanax XR tablet by shortening tmax and increasing Cmax (on average, by 21-26%) (Table 4-8; Table 4-9; Table 4-10; Fig 5; Fig 6). The 90% Cl of test (fed)-to- referencs (fasted) ratio fell outside the 0.80-1.25 goal post for average BE assessment for the log transformed PK parameter [Cmax with 90% Cl of 116-128 (M/2002/0017) and 116.16-135.87 (P/2002 0013); 115-127 (P/2002/0017] and these differences were statistically significant (p6) 7.52 >12-05) 6.41 (0.983) 609 (1-34) 6.10 (34)7) 0.0001 (1/hr) 4.S3 (1-63) 4.73 (157) 430 (106) 4-88 (1-46) 4.61 (1.48) 0.1277 CLro (g-Vmin/fcg) 1.09 (0-376) 1.07 C 2-364) 1.11 hydrocodone cod lortab (0.342) 1.09 (0.329). . 1.06 (0.357) 0.1705 Yd* CL) 97.3 (25.5) 56-S flS.6) 93J (16.5) 66.0 (14.9) 92.4 (18.0) 0.0087 V0.tti)- 22.214.171.124 Is sponsor's proposed Xanax XR dose administration relative to the food intake adequate? If not, what would be the Agency's recommendation on XR tablet dosing in relation to meals?
Note: As per Dr Robert Levin, the medical officer, the pivotal clinical trial was conducted with l-10mg XR tablet given once daily at nighttime with no regard of food intake. Based on the PK perspective, Hossain recommended that in order to insure the integrity of the dosage form and to minimize side- effects, XR tablet should be administered on an empty stomach or preferably at least 2 hours after a meal.
Sponsor proposed:' " Despite the existence information hydrocodone of significant food effect, the sponsor proposed no specific instructions regarding XR tablet dosing in relation to meals is warranted. High-fat meal taken immediately before the dosing of 3mg XR tablet significantly affects: information hydrocodone the bioavailability of alprazolam by increasing Cmax (an average of 21 -26% with 90% Cl of 116-135, which fell outside of goal post) and shortening tmax (an average of a 21-34% earlier tmax).
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