CENTER FOR DRUG EVALUATION AND
`
`RESEARCH
`
`APPLICATION NUMBER:
`
`21-926
`
`CLINICAL PHARMACOLOGY AND
`
`BIOPHARMACEUTICS REVIEW! S 2
`
`

`

`CLINICAL PHARMACOLOGY AND BIOPHARMACEUTICS REVIEW
`
`NDA#
`
`21-926 amendment 025
`
`Submission Date:
`Consult to OCP:
`
`10/11/2007 & e-mail response of 3/19/08
`- 3/ 12/2008
`
`Drug and dosage form:
`Indication:
`Sponsor:
`Reviewer:
`Submission Type:
`
`Treximet tablets (sumatriptan 85 mg/naproxen 500 mg)
`Migraine
`Pozen Pharmaceuticals
`Ramana Uppoor, PhD
`Response to the second Approvable letter
`
`BACKGROUND
`
`This NDA for a combination product of sumatriptan and naproxen was originally
`submitted on 8/5/2005 and the Clinical Pharmacology section was reviewed by Dr. Sally
`Yasuda as the primary reviewer. An approvable letter was sent in June 2006. There were
`no major issues from Clinical Pharmacology except labeling comments. The responses
`to this first approvable letter did not involve Clinical Pharmacology.
`
`CURRENT SUBMISSION
`
`From a Clinical Pharmacology perspective, this submission (response to 2nd approvable
`letter) contains the sponsor’s modifications to the label (see attachment 1 for the Clin.
`Pharm. section of the label). The sponsor made the following changes to the label:
`
`1. Trade name was replaced by ‘Treximet’ (this has been provided in the most recent
`version of the label on 1/15/2008), and MAO was expanded to Monoamine
`oxidase. This is acceptable.
`In the PK section, the following sentence was previously recommended by the
`FDA reviewer:
`
`2.
`
`This second change above is not supported by the data reviewed in the original NDA i.e.
`study MT400—101.
`The sponsor states that
`this is obtained from a new study #
`TRX106396 submitted on l/31/2007 to the FDA as amendment # 016. The sponsor
`provided the following justification to use this study instead of MT400-101. This
`justification seems reasonable. However, this study was not previously reviewed by
`OCP. Therefore, this study is being reviewed here.
`
`Sponsor ’s justification: At the time of the original NDA submission, MT400-101 was the
`only pharmacokinetic study that directly compared the pharmacokinetic profile of
`
`

`

`to that of sumatriptan when
`sumatriptan, when administered as [TRADENAME]
`administered as IMITREX 100 mg. However, several design aspects ofthis study limit the
`utility of data from MT400-] 01 to support
`labeling statements. A more recently
`completed study, TRX106396 (submitted to FDA in the January 31, 2007 Full Response,
`NDA 21-926, Amendment 016) provides a more scientifically robust comparison of the
`pharmacokinetic profile ofsumatriptan when administered as [TRADENAME] and when
`administered as [MITREX 100 mg. TRX106396 is a more appropriate study from which to
`draw data for inclusion in the package insert because:
`
`.
`
`TRX106396 employed a crossover study design with 32 subjects that compared the
`commercial formulation of Treximet to the current commercial lmitrex 100mg, which
`includes RT techno/09y, while MT400-101 was an exploratory study that employed
`the Treximet tablet formulation made in the RTP pilot plant, which was not a
`proposed commercial batch manufactured in Ware (GSK UK site).
`
`° ,
`
`Thus, we think the comparisons in TRX106396 would be more relevant.
`
`o
`
`9
`
`o
`
`The size of study TRX106396 makes the data more robust than study MT400-101, in
`which only 8 of the 24 subjects received both a dose of lmitrex 100mg (non-RT) and
`Treximet, as this study used an uneven block study design (not a balanced cross-
`over design).
`
`the arithmetic mean for Treximet = 46ng/m/ vs
`80, using data from TRX106396:
`53ng/ml for lmitrex 100mg (RT). The average sumatriptan Cmax for lmitrex 100mg is
`15% greater than the average Cmax for Treximet (Table 9.3, page 103 of 937, Study
`# TRX106396). The statistical analysis performed in TRX106396 shows there is no
`statistical difference between these formulations with regards to sumatriptan Cmax
`(ratio is 0.90 and 90% Cl is 0.804 - 1.00).
`
`The data from Study TRX106396 are more consistent with those generated in the 3
`other Treximet NDA studies (MT400-102, MT400-104 and MT400-105) that
`employed the proposed commercial formulation.
`
`STUDY TRX106396 (submitted on 1/31/07)
`(Note: Treximet is same as Trexima)
`
`-
`
`Study Title: An open-label, randomized, single-dose, 2-period crossover study to
`evaluate sumatriptan pharmacokinetics from a TREXIMA (sumatriptan 85mg/naproxen
`sodium 500mg) Tablet compared with an IMITREX (sumatriptan) 100mg Tablet.
`
`Investigator(s): - ,
`
`Study center(s): —
`
`Study Period: 10 Feb 2006 — 18 Mar 2006
`
`Objectives: The primary objective was to evaluate sumatriptan exposure (as measured by
`AUC(O-2) and Cmax) during the first 2 hours following administration of a single
`TREXIMA tablet and a single IMITREX 100mg tablet. The secondary objectives were to
`
`

`

`evaluate sumatriptan AUC(0-°°), AUC(O-t), tmax, and %Cmax at 15, 20, 25, and
`30 minutes postdose; to assess the time required to achieve sumatriptan concentrations of
`5, 10, and 20 ng/mL following administration of a TREXIMA tablet and a single
`IMITREX 100mg tablet; to evaluate naproxen pharrnacokinetics following administration
`of a single TREXIMA tablet; and to assess the safety and tolerability of a single
`TREXIMA tablet and a single IMITREX 100mg tablet.
`
`Note: Given the focus of this review, this reviewer is focusing only on Cmax, AUC and
`Tmax for sumatriptan and naproxen.
`
`Methodology: This was a single-center, randomized, open-label, single-dose, 2—period
`crossover pharmacokinetic study in healthy adult males and females, ages 18 to 55 years.
`A minimum of 7 days separated the dosing sessions to allow for complete washout of
`residual drugs from the previous dosing session.
`
`Number of subjects: Thirty-two subjects (26 females and 6 males) were enrolled,
`received both treatments, and completed the study.
`
`Investigational products: Subjects received the following treatments in a crossover
`fashion, administered as single doses with 240 ml of water following a minimum 8 hour
`fast:
`
`Treatment A: TREXIMA tablets _ an investigational product containing 1 19mg of
`sumatriptan succinate, equivalent to 85mg of sumatriptan, and 500mg of
`naproxen sodium (Batch B916681)
`Treatment B: IMITREX tablets — an approved, marketed product containing 140mg of
`sumatriptan succinate, equivalent to 100mg of sumatriptan (commercially
`available product purchased by the site)
`
`BLOOD SAMPLING AND SAFETY ASSESSMENTS: Blood samples were collected
`predose and at specified time points up to 72 hours (0, 5, 10, 15, 20, 25, 30, 40, 50, 60,
`75, 90 minutes and 2, 2.5, 3, 4, 6, 8, 10, 12, 16, 24, 48 and 72 hours) following a single
`dose of TREXIMA and for up to 24 hours (0, 5, 10, 15, 20, 25, 30, 40, 50, 60, 75, 90
`minutes and 2, 2.5, 3, 4, 6, 8, 10, 12, 16 and 24 hours) following a single dose of
`IMITREX 100mg.
`
`Continuous cardiovascular monitoring (5-lead ECG telemetry monitoring and serial
`blood pressure measurements) was performed for both treatments, beginning 1 hour prior
`to treatment administration and until 10 hours postdose.
`
`PK endpoints:
`' Sumatriptan AUC(0-2) and Cmax
`° Sumatriptan AUC(O-t), AUC (0-°°), and tmax
`° Naproxen AUC(O-t), AUC (0-°°), Cmax, and tmax
`0 Sumatriptan: %Cmax at 15, 20, 25, and 30 minutes postdose
`° Times to achieve sumatriptan concentrations of 5, 10, and 20ng/mL
`
`

`

`Statistical analysis: The point estimate and 90% confidence interval for the ratio
`between a single TREXIMA tablet and a single IMITREX 100mg tablet (TREXIMA-
`IMITREX) were determined for sumatriptan pharmacokinetic parameters. This analysis
`used log transformed PK parameters and were analysed by mixed model ANOVA fitting
`subject(sequence) as a random effect and period, sequence, and regimen as fixed effect
`terms.
`
`Results:
`
`Assay: Plasma samples were analyzed for sumatriptan (GR43 175) by g
`—— using a validated analytical method based on w followed
`by HPLC-MS/MS analysis. The lower limit of quantification (LLQ) was 0.1 ng/mL for
`sumatriptan, using a 100 pL aliquot of EDTA plasma. The higher limit of quantification
`(HLQ) was 100 ng/mL for sumatriptan (GlaxoSmithKline Document number
`FD2006/00077/00).
`
`Plasma samples were analyzed for naproxen (BRL- 19255) using a validated analytical
`method based on — followed by HPLC-MS/MS analysis. The LLQ for
`naproxen was 2.5 pg/mL, using a 25 11L aliquot of plasma with a HLQ of 250 ug/mL
`(GlaxoSmithKline Document number WD2005/00471/00).
`
`The method validation for sumatriptan and naproxen looks reasonable, and the detailed
`reports can be found1n the NDA 21 -926 submission date 01/31/07, module 5, under
`study TRX106396.-
`
`For each analytical method, Quality Control (QC) samples, containing the relevant
`analytes at 3 different acncentrations and stored with study samples, were analyzed with
`each batch of samples against separately prepared calibration standards. For the analysis
`to be acceptable, no more than one-third of the QC results had to deviate from the
`nominal concentration by more than 15%, and at least 50% of the results from each QC
`concentration had to be within 15% of nominal. According to the sponsor, the applicable
`analytical runs met all predefined run acceptance criteria.
`
`WITHIN STUDY ASSAY PERFORMANCE: A set of 8 calibration standards ranging
`from 0.1 ng/mL to 100 ng/mL and Quality Control (QC) samples at three different
`concentrations (0.4, 4.0, and 80 ng/mL) of the analyte were prepared and stored at -
`20°C. Between-batch precision and accuracy for analysis of the QC samples were
`determined from batch analyses of clinical samples in this study. The inter-assay
`precision of the quality controls for the sumatriptan runs ranged from 10.2% to 20.2%
`(20.2% at the lowest QC), with accuracy ranging from -4.9% to 4.1%. The back-
`calculated calibration curve values expressed as a percent of the nominal value ranged
`from 96.2% to 102.3%.
`
`PK results: The results from PK analyses of sumatriptan and naproxen and the statistical
`comparisons of sumatriptan parameters are presented in the following figures and tables.
`_ Plasma concentration time profiles for sumatriptan and naproxen as shown below:
`
`

`

`SUMATRIPTAN:
`
`man-IL) Pimnefi Heiallve Time (Hrs)
`
`Cancefihafim
`
`
`
`NAPROXEN:
`
`WWW}
`
`.21..8 WK (“n—4*12’
`
`AUC (0-2), ng*hr/mL
`
`
`
`
`
`
`
`
`
`
`Trexima
`PKarameters
`Sumatri u tan
`
` Mean: 56.05
`Mean: 59.16
`
`
`SD: 26.79
`SD: 19.78
`
`
`
`Rane: 27.56 — 167.20
`
`Rane: 24.12 — 116.29
`Mean: 201.07
`Mean: 241.07
`
`
`
`SD: 76.18
`
`
`
`Rane: 93.98 — 455.95
`Ran_e: 95.66 — 349.05 .
`
`
`Mean: 45.98
`Mean: 52.70
`
`
`SD: 20.99
`SD: 13.24
`
`
`
`
`Rane: 24.27 — 124.86
`‘
`Rane: 27.07 —— 82.68
`
`
`Median: 0.83
`
`
`. AUC (0—int), ng*hr/mL
`
`SD: 60.44
`
`Cmax, ng/mL
`
`

`

`
`
`
`Ran-6' 042—600
`_ Ram: 0-35 -4-00
`
`
`
`Na n roxen
`
`NA
` Mean: 944.86
`
`AUC (0-inf), ug*hr/mL
`
`
`
`
`
`
`SD: 308.44
`
`
`
`
`
`
`
`
`Ran_e: 523.38 — 1740.86
`
`Cmax, pg/mL
`
`,
`
`
`
`Mean: 54.86
`SD: 18.82
`Rane: 28.58 — 96.19
`
`
`Ran e: 0.17~ 10.02
`
`
`
`Geometric ideas: {Nb-'15 Sumatri'
`Treatment n n fiIImL
`: hm gnhrfm l
`mats-5mm
`52.8 36.5)
`19:1:
`9.5
`1Q2’322i‘
`tamer
`543322.51
`222 33.;
`22mg.
`.
`1 35:28
`
`
`
`nlmL
`$4.3 27.9}
`49.4 3w
`
`
`
`
` Median Rang» . " . '
`
`
`
`_IlI-_ m hr
`721) hr
`
`
`mam
`0.32;: 0.32.4.er
`0.2:} mm (momma
`5.43: 9.24.9.
`
`
`
`Immex
`1.5:: 0.42.5361
`9.2% {1.1.3.3 magmas;
`9.4m 9.2.1.93
`Steam: {Ra e] Sumakitan 9116mm: Farms
`9:5 '1'?»
`025 "2%-
`amass—70.4
`5?.2191-35312
`
`42511014031
`
`3’73: {23.240331
`
`
`—I2I
`
`TREXlliii-h
`
`
`
`
`
`
`90% confidence intervals:
`
`l-‘K 9arameterrs
`
`Statistleamna sisaé‘Sumaifi ='
`Ram
`Parameter
`335
`swam;
`m
`Cum
`(ms
`AUG m
`0.55
`warm
`$.83
`km W
`‘ R- merits esfimaied median of fire differences between animals
`
`21%
`353%
`823%
`1158‘:
`
`5 N=2§
`
`Semitic m CVb%- Rx; nmxen Phannamkfnetic Parameters
`-nm
`1‘35le
`1'85 35.3
`Sow-031311371193 MS and 9.14.”
`5 Median (rangei
`
`90032.13
`
`51.8 35.9}
`
`8.0010. 140.92-
`
`CONCLUSIONSf The arithmetic mean Cmax of sumatriptan from Treximet tablets is
`46 ng/ml with a range of 27 to 83 ng/ml, and is similar between the two treaments
`(Treximet and Imitrex). The median of the differences indicated that the sumatriptan
`tmax occurred 53 minutes earlier for TREXIMA, as compared to IMITREX.
`
`

`

`LABELING COMMENTS
`
`1. From Clinical Pharmacology perspective, the minor changes such as ‘trade name’ and
`‘MAO to Monoamine oxidase’ are acceptable.
`
`2. Use of study TRX 106396 for
`acceptable.
`
`labeling statements related to sumatriptan is
`
`—
`
`RECOMMENDATIONS
`
`Please forward the above comments to the medical
`appropriate.
`
`reviewer and the sponsor as
`
`Ramana Uppoor, PhD
`Deputy Director/Neurology CP Team Leader
`Division of Clinical Pharmacology 1
`
`Mehul Mehta, PhD
`Director
`
`Division of Clinical Pharmacology 1
`
`cc:
`
`HFD-120
`
`NBA 21 -926
`
`HFD-860
`
`Mehul Mehta, Ramana Uppoor
`
`Date
`
`Date
`
`

`

`3
`
`Page(s) Withheld.
`
`Trade Secret / Confidential
`
`a/ Draft Labeling
`
`Deliberative Process .
`
`Withheld Track Number: Administrative
`
`Z 3
`
`

`

`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`
`Ramana S. Uppoor
`3/19/2008 01:26:58 PM
`BIOPHARMACEUTICS
`
`Mehul Mehta
`
`4/3/2008 12:37:58 PM
`BIOPHARMACEUTICS
`
`

`

`NDA 21,926
`TREXIMA
`
`Clinical Pharmacology and Biopharmaceutics Review
`
`
`21-926 3505§bQ§2n
`NDA:
`
` Brand Name: Trexima
`
`Sumatriptan Succinate/Nagroxen Sodium
`Tablet
`85 mg sumatriEtan/S 00 mg nagroxen sodium
`Acute Migraine
`Standard
`Pozen
`August 5, 2005
`October 27, 2005
`November 16, 2005
`December 12, 2005
`December 8, 2005
`January 27, 2006
`February 22, 2006
`April 7, 2006
`April 14, 2006
`Agri128, 2006
`OCPB Division: DCP-I
`
`
`
`0ND Division:
`OCPB Reviewer:
`
`Division of Neurology Drug Products HFD-120
`Sally Usdin Yasuda, MS, PharmD
`
`W T
`
`able of Contents
`
`2
`
`Table of Contents........................................................................................................................................................... 1
`lExecutive Summary ..................................................................................................................................................... 2
`1.1
`Recommendations ....................................................................................................................................... 2
`1.2
`Phase 4 Commitments ................................................................................................................................... 2
`1.3
`Summary of Clinical Pharmacology and Biopharmaceutics Findings ........................................................... 2
`Question-Based Review......................................................................................................................................... 6
`2.1 General Attributes................................................................................................................................................ 6
`2.2
`General Clinical Pharmacology ..................................................................................................................... 8
`2.3 Intrinsic Factors ................................................................................................................................................. 14
`2.4
`Extrinsic Factors .......................................................................................................................................... 16
`2.5
`General Biopharmaceutics ........................................................................................................................... 19
`2.6
`Analytical Section ........................................................................................................................................21
`Detailed labeling recommendations (only the changed sections are included here) ............................................ 23
`3
`4 Appmdz’cey........................................................................................................................................................... 27
`4.1
`Package Insert .............................................................................................................................................. 27
`4.2
`Clinical Pharmacology and Biopharmaceutics Individual Study Reviews ..................................................49
`4.2.1
`BIOANALYTICAL METHOD FOR NAPROXEN - PROJECT 54076) .......................... 49
`4.2.2
`BIOANALYTICAL METHOD FOR NAPROXEN - I METHOD LC 72.2) ................................. 51
`4.2.3
`BIOANALYTICAL METHOD FOR SUMATRIPTAN (LMS-M-6410-00) ...................................... 53
`4.2.4
`BIOANALYTICAL METHOD FOR SUMATRIPTAN (LCMS 174) ............................................... 55
`4.2.5
`BIOAVAILABILITY STUDY MT 400-101 ....................................................................................... 57
`4.2.6
`FOOD EFFECT STUDY MT 400-102 ................................................................................................ 65
`
`Generic Name:
`Type of Dosage Form:
`Strengths:
`Indications:
`Type of Submission:
`Sponsor:
`Submission Date:
`
`~
`
`

`

`NDA 21,926
`TREXIMA
`
`BIOAVAILABILITY STUDY MT 400-103 ....................................................................................... 72
`4.2.7
`EFFECT OF MIGRAINE ON TREXIMA PK (Study MT 400-104) .................................................. 79
`4.2.8
`REPEAT DOSE STUDY MT 400-105 ............................................................................................... 84
`4.2.9
`LITERATURE REVIEW OF DRUG TNTERACTIONS .................................................................... 90
`4.2.10
`TREXIMA DISSOLUTION METHOD AND SPECIFICATIONS .................................................... 94
`4.2.11
`4.3
`Consult Reviews ........................................................................................................................................ 100
`4.4
`Cover Sheet and OCPB F iling/Review Form ............................................................................................ 101
`
`I lExecutive Summary
`
`1.1 Recommendations
`
`1)
`
`The clinical pharmacology and biopharmaceutics information submitted to NDA 21926
`is acceptable provided that satisfactory agreement is reached between the Sponsor and the
`Agency regarding labeling (Please refer to Section 3 of thls review)
`
`2)
`
`The Sponsor proposed the following dissolution method and specifications:
`
`Apparatus:
`Medium:
`Volume:
`
`USP. Apparatus 1 (Basket)
`USP Phosphate Buffer pH 6.8
`900 ml
`
`75 rpm
`
`Rotation Speed:
`Specification:
`Sumatriptan:
`Naproxen sodium:
`
`15 minutes:
`30 minutes:
`
`Q=’
`Q=
`
`The Office of Clinical Pharmacology finds the proposed dissolution method and
`specification acceptable.
`
`1.2 Pkwy 4 Commime/zzf
`
`None.
`
`131521111121447) q/CYi/llk’fl/Pflfll‘lllflt’fl/flgl alt/fliqofiar/Imceufl'cs fi'lm’i/zgs
`
`NDA 21-926 has been submitted to support the approval of TREXIMA (sumatriptan 85 mg -
`/naproxen sodium 500 mg) for acute treatment of migraine attacks with or without aura in adults.
`(Sumatriptan is given as 119 mg sumatriptan succinate). The proposed dose is 1 tablet given
`orally.
`
`The formulation of sumatriptan contains sodium bicarbonate (referred to by the Sponsor as RT
`technology) that is the same technology used in the 25, 50, and 100 mg IMITREX tablets that are
`
`

`

`NDA 21,926
`TREXIMA
`
`currently marketed, although not the same technology as in the IMITREX tablets available
`during the development program and to which the PK has been compared. However, since the
`RT sumatriptan replaced the non-RT formulation, it is expected that these have equivalent in
`vivo performance. Naproxen is currently available in comparable strengths of immediate
`release tablets as naproxen 500 mg and naproxen sodium 550 mg (ANAPROX DS).
`
`The following clinical pharmacology studies have been submitted and reviewed:
`
`
`
`MT400-101
`
`MT400-102
`
`' MT400-103
`
`MT400-104
`
`MT400-105
`
`
`
`
`Descri'tion
`BA of TREXIMA, each com onent, and marketed versions of comonents
`
`Food Effect Stud
`
`BA of TREXIMA and combinations of various formulations
`
`Effect of Mi raine on PK
`
`PK of 2 sin_le tablets iven 2 hours aart
`
`
`The Sponsor states that the to-be-marketed formulation was used in each of the clinical
`pharmacology and pivotal clinical studies. However, the clinical trial batch was not debossed,
`whereas the to-be-marketed tablet is debossed m
`
`- The key findings with respect to the Clinical Pharmacology and Biopharmaceutics ofTREXIMA
`are as follows:
`
`Pharmacokinetics
`
`Campy/"13012 0 [ZZZ/11%! to re ere/ice fib’lm’pradzzc/Jz'
`
`(Non-RT)
`IMITREX (100 mg)
`
`ANAPROX
`
`550 mg naproxen
`
`/ \
`
`
`
`
`
`TREXIMA
`(85 mg sumatriptan
`RT/SOO mg naproxen
`
`sodium)
`
`
`
`
`
`
`For Cmax, neither naproxen nor sumatriptan fell within the BE limit of 80-125% when given as
`TREXIMA compared to the reference listed products (non-RT IMITREX or ANAPROX 550
`mg). Cmax values for sumatriptan were approximately 20% higher from TREXIMA than from
`IMITREX (90% CI 0.94-1.31). Cmax values for naproxen were approximately 36% lower from
`TREXIMA than from ANAPROX 550 mg (90% CI 0.67-0.79). In addition, the median tmax for
`naproxen was delayed after administration of TREXIMA relative to ANAPROX (approximately
`6 hr vs 1 hr). The median tmax for sumatriptan was approximately 1-1.5 hr. For AUC the BE
`criteria were met for either analyte.
`
`

`

`NDA 21,926
`TREXIMA
`
`Campy/737012 offM/W! to 1'1249'1/1'0’1/4/campwze/z/J'give/z yepara/eé/x
`
`500 mg naproxen
`
`——"
`
`Sumatriptan RT 85 mg
`
`TREXIMA
`(85 mg sumatriptan
`RT/500 mg naproxen
`sodium)
`
`—->
`
`For sumatriptan, Cmax was approximately 17% greater (90% CI 1.02-1.34) from TREXIMA
`than from the individual sumatriptan 85 mg (RT) tablet (Study MT 400-102). The Cmax for
`naproxen from TREXIMA was 26% lower (90% CI 0.67-0.79) than from naproxen given alone
`(Study MT 400-101). There were no differences in AUCs.
`
`[FEE/17M! PK1'12 Mgrm’lza'
`PK of naproxen and sumatriptan were similar in terms of Cmax and AUC for naproxen or
`sumatriptan when TREXIMA was given during or outside of a migraine. Median Tmax was
`slightly earlier during a migraine (1.5 hr, range 0.5-4.0) than outside of a migraine (2.0 hr, range
`0.5-4.1).
`
`Foodiflct'
`After TREXIMA administration with a high fat meal, there was no difference (90% CI within
`80-125% BE criteria) in Cmax or AUC or in Tmax for naproxen compared to TREXIMA given
`in a fasted state in 21 healthy subjects. For sumatriptan, there was no difference (90% CI within
`80-125% BE criteria) in Cmax or AUC, although food delayed the sumatriptan Tmax by
`approximately 36 minutes. The labeling may state that TREXIMA can be given without regard
`to food. The fasting PK parameters fi‘om this study are in agreement with the PK parameters for
`other Phase I studies in NDA 21926.
`
`Other relevant aspects of the clinical pharmacology of sumatriptan and naproxen are described in
`the current labels for the approved marketed products and can be extended to the labeling for
`TREXIMA.
`
`Biopharmaceutics
`
`The Sponsor proposed the following dissolution method and specifications:
`
`Apparatus:
`Medium:
`Volume:
`
`USP Apparatus 1 (Basket)
`USP Phosphate Buffer pH 6.8
`900 ml
`
`75 rpm
`
`Rotation Speed:
`Specification:
`Sumatriptan:
`Naproxen sodium:
`
`~
`
`15 minutes:
`30 minutes:
`
`=
`= /
`
`

`

`NDA 21,926
`TREXIMA
`
`The Office of Clinical Pharmacology finds the proposed dissolution method and specifications
`acceptable.
`
`In addition, the dissolution profile of the debossed tablet that is the to-be-marketed tablet is
`similar to that of the biobatch/clinical trial tablet.
`
`Sally Usdin Yasuda, MS, PharmD
`Reviewer, Neurology Drug Products, DCP I
`Office of Clinical Pharmacology
`
`Concurrence: Ramana Uppoor, PhD
`Team Leader, Neurology Drug Products, DCP I
`Office of Clinical Pharmacology
`
`cc:
`
`HFD-120
`
`NDA 21-926
`CSO/T. Wheelous
`
`/Biopharm/S. Yasuda
`/TL Biopharm/R. Uppoor
`
`

`

`NDA 21,926
`TREXIMA
`
`2
`
`Question-Based Review
`
`2.1 General Attributes
`
`Sumatriptan succinate and naproxen sodium have been previously approved for use under NDAs
`20132 (Imitrex) and 18164 (Anaprox), respectively. Imitrex is indicated for acute treatment of
`migraine. Anaprox does not have an indication for migraine. Sumatriptan succinate is marketed
`as Imitrex tablets (GlaxoSmithKline) and for migraine it is given as single doses up 25mg-100
`mg that may be repeated after 2 hours, not to exceed a total daily dose of 200 mg. NDA
`21,926 has been submitted as a 505(b)(2) and the Sponsor references Imitrex (sumatriptan) and
`Anaprox D8 (550 mg of naproxen sodium). The current IMITREX tablet has sumatriptan in a
`formulation that uses the same “rapid release technology” (RT) as the sumatriptan in the
`TREXIMA tablet (contains sodium bicarbonate). However, the IMITREX tablet (non-RT) used
`in the Phase I studies did not have this technology.
`
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`mama, andMefilmy/41w}: oflfle drz/gprae’z/c/EP
`
`TREXIMA contains sumatriptan (as the succinate) and naproxen sodium. Sumatriptan succinate
`has an empirical formula of C14H21N3OzS'C4H604 and is designated as 3-[2-
`dimethylamino)ethyl]-N-methyl-indole—5-methanesulfonamide succinate (1:1) with a molecular
`weight of 413.5. Naproxen sodium has an empirical formula of C14H1303Na and is designated
`as(-)-sodiUm (S)—6-methoxy-a-methyl-2-naphthaleneacetic acid with a molecular weight of
`252.24 . The structures are shown below:
`
`Sumatriptan succinate
`
`Naproxen sodium
`
`CHzCHzMCHalz
`
`me coon
`
`\
`
`fl
`
`/
`9'2
`‘ on,
`\ coon
`
`0Q coma
`
`H300
`
`.
`
`TREXIMA tablets are . immediate release, film coated tablets. Each tablet contains 85
`mg sumatriptan (as 119 mg sumatriptan succinate) and 500 mg naproxen sodium. The
`composition of the TREXIMA formulation used in all of the Phase 1 and Phase 3 clinical studies
`is shown in the table below, as provided by the Sponsor.
`
`

`

`NDA 21,926
`TREXIMA
`
` u
`
`Tohufihnmtemw _III_
`r _ .
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`3' ’
`
`
`
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`
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`MSWSZPL Tabk l
`
`The Sponsor states that the to-be-marketed formulation was used in each of the studies. Batch
`916681 was used in the PK studies MT 400—102, MT 400-104, and MT 400-105 and the Phase
`III clinical studies MT 400-301, MT 400-302, and MT 400-303. This batch was manufactured at
`the site of commercial manufacture (Glaxo, UK) according to the commercial process.
`Additional PK studies MT 400-101 and MT 400-103 also used Trexima tablets prepared
`according to the commercial process but from a pilot scale batch. The biobatch was not
`debossed, although the commercial tablet will be debossed on 1 side. The dissolution profiles of
`the debossed tablet and the biobatch are similar.
`
`Imitrex is currently available as 25, 50, and 100 mg of sumatriptan (base) as the succinate. The
`current formulation that incorporates the RT Technology was approved in June 2003 under NDA
`20—132/S-015. Since the RT formulation replaced the non-RT formulation, bioequivalence of
`this formulation to the standard sumatriptan tablet for the 50 mg and 100 mg tablets is assumed.
`In the present submission, TREXIMA was evaluated against Imitrex 50 mg (non-RT) and
`Imitrex 100 mg (non-RT) as they were the marketed products at the time of the beginning of the
`
`

`

`NDA 21,926
`TREXIMA
`
`development program. Other comparators were Anaprox 550 mg, naproxen sodium 500 mg,
`sumatriptan 85 mg (RT), and sumatriptan 85 mg (non-RT).
`
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`111c’1cc/1'011?
`
`Sumatriptan is a 5-HT receptor agonist that blocks the release of vasodilating neuromodulators
`and blocks the transmission of pain. Naproxen is an NSAID that inhibits synthesis of
`inflammatory mediators of pain (Via inhibition of cyclooxygenase). The proposed indication for
`TREXIMA is for the acute treatment of migraine attacks with or without aura in adults.
`
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`
`The proposed recommended dose is 1 tablet given orally.
`
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`cuppa/’1‘ dosing or clef/115'?
`
`The two pivotal efficacy studies were identical studies that compared a single TREXIMA tablet
`with placebo for relief of migraine pain and associated symptoms at 2 hours, and compared
`TREXIMA to the individual active components 85 mg sumatriptan RT or 500 mg naproxen
`sodium for sustained pain relief through 24 hours. The long-term safety study was a multiple-
`attack, open label study, that allowed for a second dose of study medication to treat the same
`migraine attack at least 2 hours after taking the first dose if needed, with no more than 2 tablets
`allowed in any 24 hour period.
`
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`[fley measured1'11 cfl'mcclpéc/mecclcg/ 4111/cfl'lzfcclslacks?
`
`The primary pharmacodynamic endpoints, that are typical for migraine studies, were pain relief
`and incidence of photophobia, phonophobia, and nausea at 2 hours post-dose, and sustained pain
`free over 24 hours.
`'
`
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`response rele/fczzcég‘cc?
`
`The active moieties are considered to be naproxen and sumatriptan, and these were appropriately
`determined in the pharrnacokinetic studies.
`
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`
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`c/fs'et cf/ée c’eczfcélepflcrmecclcgkclreggae/ice or cé'lzz'celeimjccz'lzl.
`
`Only 1 dosage strength (85 mg sumatriptan succinate/SOO mg naproxen sodium) was evaluated
`in the pivotal efficacy studies. The primary endpoint for efficacy was pain free at 2 hours.
`TREXIMA was superior to placebo in 2-hour relief of pain and for relief of associated symptoms
`
`

`

`NDA 21,926
`TREXIMA
`
`of photophobia and phonophobia. Knowing that sumatriptan is effective in doses as low as 25
`mg (as labeled), ideally lower dose combinations should be studied.
`
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`MIL? coméz'fld/z'wz ofa’ams'?
`The Sponsor states that the symptom complex in migraine may result from more than 1
`mechanism, and that headache recurrence occurs in patients treated with sumatriptan. Therefore,
`the rationale for developing the combination of sumatriptan and naproxen sodium was to provide
`rapid and sustained relief of migraine pain and associated symptoms, reducing headache
`recurrence and the need for rescue medication. The rationale for selecting the 85 mg sumatriptan
`dose was to produce a PK profile during the first 2-3 hours that is generally similar to that
`following 100 mg Imitrex. The naproxen dose was chosen based on efficacy of a combination of
`Imitrex 50 mg and naproxen sodium 500 mg in a proof of concept study.
`
`Imitrex tablets are given for migraine as 25, 50, or 100 mg single doses that may be repeated
`after 2 hours, not to exceed a total daily dose of 200 mg. Naproxen sodium is given indoses up
`to 550 mg twice daily for management of pain, and the initial total daily dose should not exceed
`1375 mg naproxen sodium, and thereafter the total daily dose should not exceed 1100 mg of
`naproxen sodium.
`
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`reiwoflye, concefl/ra/iofl-raspaflygflr 54/651? Ire/611412! 112016426 ffle [1}726 to Me 01256/
`mm’0/319! oftée dew/124M?péarmacolog/az/raspam'e or 6/1121'64/6124001'121
`Exposure-response relationships for safety were not evaluated in this submission. The labeling
`of Anaprox refers to more frequent and severe gastrointestinal reactions in rheumatoid arthritis
`patients taking daily doses of 1500 mg naproxen compared to 750 mg naproxen. However, these
`adverse effects, including GI ulceration and bleeding, can occur with low doses and the Anaprox
`labeling provides specific warnings regarding these adverse effects. In addition, a risk of cardiac
`adverse events in patients taking NSAIDs has been identified. Other serious adverse effects of
`NSAIDs including naproxen are anaphylactoid reactions, hepatotoxicity, and nephrotoxicity.
`For sumatriptan, serious adverse cardiac events have been reported as well as increases in blood
`pressure and the labeling for Imitrex includes contraindications to use in patients with history,
`symptoms, or signs of ischemic cardiac, cerebrovascular, or peripheral Vascular syndromes, or
`patients with other significant underlying cardiovascular disease.
`
`2. 2. 43Does M131 drugpro/012g [fie QfarQIZ' 11216111447
`QT prolongation is not identified in the labels of either Imitrex or Anaprox and has not been
`addressed in the present submission.
`
`2.