CENTER FOR DRUG EVALUATION AND RESEARCH
`
`APPROVAL PACKAGE FOR:
`
`APPLICATION NUMBER
`
`NBA 21 -574
`
`Clinical Pharmacology and Biopharmaceutics
`Review
`
`

`

`CLINICAL PHARMACOLOGY AND BIOPHARMACEUTICS REVIEW
`
`
`
`NDA:
`Submission Type:
`
`21-574
`Relevant IND(s):
`55,962
`Amendment (A2) — Response to 17 October 2003 Approvable Letter
`
`Submission Date(s):
`
`19 December 2003
`
`Sponsor Name:
`
`Brand Name:
`
`Andrx Laboratories, Inc., Hackensack, NJ
`
`FORTAMETTM
`
`Generic Name:
`
`Metformin Hydrochloride Extended Release Tablets
`
`lndication(s):
`
`Strength(s):
`
`Reviewer:
`
`Team Leader:
`OCPB Division:
`
`Treatment of Type 2 Diabetes Mellitus
`
`500-mg and 1000-mg
`
`Steven B. Johnson, Pharm.D. l Xiao Xiong "Jim" Wei, MD, Ph.D.
`
`Hae-Young Ah‘n, PhD.
`DPE-2 (HFD-870) I
`
`0ND Division: DMEDP (HFD—510)
`
`
`
`Executive Summary
`This submission was the response to the approvable letter issued by the Agency on 17 October 2003 for
`NDA 21—574.
`The letter stated that
`the following Clinical Pharmacology and Biopharmaceutics
`requirements were necessary for the approval of FORTAMETTM:
`
`it will be necessary for you to provide sufficient data to demonstrate dosage form
`equivalence between the 500-mg and 1000-mg tablets."
`
`it will be necessary for you to submit revised labeling with the revisions
`"In addition,
`indicated in the enclosed labeling.
`Revise the language under the CLlNlCAL
`PHARMACOLOGY section, Pharmacokinetics
`and Drug Metabolism subsection,
`Immediate—Release subsection”
`
`the sponsor conducted a study to evaluate dosage-form
`In order to satisfy the first requirement,
`equivalence between two FORTAMETTM 500—mg tablets and one FORTAMETTM 1000-mg tablet. 'Results
`suggested that when these products are administered under fed conditions, then they are dosage-form
`equivalent using bioequivalence criteria.
`
`The second requirement was to address labeling issues. The sponsor complied with this request.
`
`In addition to those requirements listed above, and in consultation with Dr. Xiao Xiong “Jim" Wei, the
`primary CPB reviewer of the original application, the dissolution method and release specifications were
`inappropriate for this product. The sponsor used a 1L
`3 buffer medium with a pH L
`J This is
`generally not acceptable to the Agency, especially when the data indicates that dissolution is pH
`independent for the product — as is the case with FORTAMETTM. Therefore, a pH 6.8 phosphate buffer
`medium was recommended to the sponsor. Also, a recommendation to change the 8-hour and 16-hour
`release specifications for both strengths of FORTAMETTM was made to better reflect the dissolution
`characteristics of the product.
`
`7
`Recommendation
`The Office of Clinical Pharmacology and Biopharmaceutics finds the data submitted in NDA 21—574,
`amendment 2, to be Wproviding the sponsor agrees to the recommendations described in the
`Comments to Sponsor section of this review.
`
`JOHNSONST
`
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`
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`
`

`

`CLINICAL PHARMACOLOGY AND BIOPHARMACEUTICS REVIEW
`
`Comments to Sponsor
`
`1 buffer is inappropriate for your product given
`.
`1. The proposed dissolution medium, pHC 1f-
`the pH independent dissolution characteristics of FORTAMET M.
`In addition.
`the tolerance
`specifications are too loose for the 8 and 16-hour time points given the data presented to the Agency
`in both this and the original submission. The interim dissolution method and specifications
`recommended by the Agency for FORTAMETTM 500-mg and 1000-mg tablets are listed in the
`following table:
`
`
`
`Apparatus
`USP Apparatus 1 (basket)
`
`Medium
`
`0.05M C
`3 phosphate buffer, pH 6.8
`Volume
`900 ml
`‘
`
`
`37° C
`Temperature
`
`- RPM
`Speed
`2hr2NMT —,8hr: ’ r,16hr:NLT " a
`2 hr: NMT' ~— _ 8 hr?
`‘-
`"'16 hr: NLT
`—-
`
` Specification
`
`2. When describing discrete time points, i.e., Tmax, use range -— not standard deviation.
`
`3. Please address labeling changes as directed by the FDA Project Manager.
`
`
`Steven B. Johnson, Pharm.D.
`s
`2
`Division of Pharmaceutical Evaluation-ll
`LUWIQ/ v rv
`
`Office of Clinical Pharmacology and Biopharmaceutics
`
`M
`
`
`
`RD initialed by Hae—Young Ahn, Ph.D., Team Leader:
`
`FT initialed by Hae-Young Ahn, Ph.D., Team Leader:
`
`W 2
`
`Appears This Way
`On Original
`
`JOHNSONST
`
`Page 2
`
`2/12/2004
`
`

`

`CLINICAL PHARMACOLOGY AND BIOPHARMACEUTICS REVIEW
`
`~
`Dosage-form Proportionality (Study 155-116)
`In order to satisfy the requirement of providing sufficient evidence to demonstrate that the two strength
`of FORTAMETTM tablets were dosage-fonn proportional, the sponsor conducted a single-dose, four-
`period replicated crossover bioequivalence study comparing two 500-mg FORTAMETTM tablets with a
`single 1000-mg FORTAMETTM tablet. Thirty healthy male subjects were randomized to either a sequence
`of ABAB or BABA and received either two 500-mg tablets (Tx A) or one 1000—mg tablet
`(Tx B)
`immediately after an evening meal. Serial blood samples were then obtained from time zero to 72—hours
`post-dosing. Average bioequivalence methods were used to analyze the data and the findings are
`presented in TABLE 1 and FIGURE 1.
`
`
`Unit
`Tx A
`Tx 8
`
`ng/mL
`1086.66 i 254.97
`1119.03 4; 267.64
`ng‘hr/mL
`10904.11- : 2546.14
`10848.14 t 2473.16
`n9*hr/mL
`11090.36 1 2621.18
`10972.93 :l: 2506.18
`hr
`7.90
`'
`6.66
`—
`i
`hr
`13.84
`12.69
`tuz
`Tx A = 1000-mg (2 x 500-mg) metformin XT administered under fed conditions (test)
`Tx B = 1000-mg (1 x 1000-mg) metformin XT administered under fed conditions (reference)
`' = calculated after ln-transformation
`
`
`
`
`
`
`
`
`
`
`FIGURE 1: Plasma Profile - 2 x 500mg v5.1 x moo—mg Mettormln X‘l' Tablets
`
`
`
`
`
`Time them)
`
`
`
`
`
`
`
`3E
`8'.4
`
`n2E5u3UuE E5o2
`
`Since the 90% confidence intervals for the ln—transformed parameters Cmax (91.35% — 104.47%) and
`AUCOW (95.59% — 107.22%) fall within the regulatory range for bioequivalence, 80% to 125%, then it
`suggests that two 500-mg metformin XT tablets bioequivalent to one 1000-mg metformin XT tablet when
`administered under fed conditions, hence they are dosage—form equivalent.
`
`These results are in stark contrast to an earlier study (155-013) submitted with the original NBA in which
`the point estimates for the bioequivalence parameters, Cmax and AUC, were between C
`However,
`this earlier study was conducted using product manufactured in pilot batches — the current
`study used product from scale-up lots (500—mg — 266R021; 1000-mg — 271 R021).
`
`3
`
`JOHNSONST
`
`Page 3
`
`2/12/2004
`
`

`

`CLINICAL PHARMACOLOGY AND BIOPHARMACEUTICS REVIEW
`
`Bioanalytical Assay
`
`'Metformin levels were measured for all pharmacokinetic studies at C
`Sample extracts were analyzed by C
`3 This method was validated for metformin over the concentration range of ”' ng/mL
`7' ng/mL for plasma samples.
`
`to C
`
`A pre—study validation run was conducted to verify system performance, calibration standard, and quality
`control pool preparation, prior to the analysis of study samples. Matrix stability of metformin in human
`plasma was evaluated by analysis of quality control samples stored under the same conditions as study
`samples.
`
`Samples were analyzed in analytical runs, which consisted of a reagent blank, matrix blank, calibration
`standards, quality controls, and a set of subject samples. Assay precision and accuracy were determined
`by replicate analyses of human plasma quality control pools prepared at three concentrations spanning
`the calibration range. Precision was measured as the percent coefficient of variation of the set ofvalues
`determined for each pool (92% — 95%). Accuracy was expressed as the percent difference of mean value
`for each pool from the theoretical concentration (97.5% - 99.5%).
`
`Dissolution
`
`In addition to the dosage—form equivalence study, the sponsor also conducted a multipoint dissolution
`study on the study test lots 266R021 and 271R021, for the 500-mg and 1000-mg tablets, respectively.
`The proposed dissolution method, and the method used for this evaluation.
`is described in TABLE 2.
`Results of this study are presented in FIGURE 2.
`
`
`
` TABLE 2: Proposed Dissolution Method for FORTAMETm 500-mg and 1000-mg Tablets
`Apparatus
`USP Apparatus 1 (basket) L
`3
`Medium
`0.05M C
`’
`j 2 butter, pH C
`Volume
`900 ml
`Temperature
`37° C ‘ ~ RPM
`Speed
` Specification
`2hr: NMT "" .8hr: ‘ ,
`2 hr: NMT — 8 hr: T“,
`
`16 hr: NLT —
`16 hr: NLT "
`
`3
`
`FIGURE 2: Multipoint Dissolution Comparison
`SOD-mg and moo-mg Metfon-nin XT Tablets
`
`
`10
`
`Time (hours)
`
`
`
`
`
`AmountDlsaolved("/n)
`
`JOHNSONST
`
`Page 4
`
`2/12/2004
`
`

`

`CLINICAL PHARMACOLOGY AND BIOPHARMACEUTICS REVIEW
`
`As stated in the original CPB review by Dr. Wei, “the dissolution condition is apparently independent of
`pH changes.” As a result of this finding, and based on data provided by the sponsor, the dissolution
`media should be a phosphate buffer at a pH of 6.8. This is in line with all current guidance.
`
`In addition, the release specifications for the 8 hour time point has a C 7 range and is wider than is
`acceptable for this product. Rather, the sponsor should tighten this range to E
`g
`and
`I for the 500-mg and 1000-mg tablets, respectively).
`
`Finally, the third time point at 16 hours is also inappropriate for this product and should be adjusted from
`not less than (NLT) ‘ , to NLT “ . TABLE 3 describes the dissolution method and specifications that
`appear to be appropriate for this product, given the data provided to the Agency.
`
`
`TABLE 3: Aqenc Recommended Dissolution Method for FORTAMETE‘“ Sea-mg and iOGO-m, Tablets
`
`
`Apparatus
`USP Apparatus 1 (basket) f,
`_
`ll
`
`Medium
`0.05M E
`3 phosphate buffer, pH 6.8
`
`
`
`Volume
`900 ml
`
`
`
`Temperature
`37° C
`
`
`_
`Speed
`*— RPM
`__
`
`
`
`16 hr: NLT -
`500 mg
`S ecification
`2 hr: NMT — 8 hr:
`
`
`
`
`
`
`
`2hr: NMT —'_ 8hr.- -~ 16 hr: NLT':1000 mg ~—
`
`p
`
`
`
`
`Labeling — Clinical Pharmacology Section
`
`NOTE: For recommended labeling changes, please refer to the appendix to this review.
`
`Appears This Way
`On Original
`
`JOHNSONST
`
`Page 5
`
`2/12/2004
`
`

`

`ThisIs a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`
`Steve Johnson
`
`3/1/04 04:47:56 PM
`BIOPHARMACEUTICS
`
`Hae—Young Ahn
`3/8/04 01:47:31 PM
`BIOPHARMACEUTICS
`
`

`

`OFFICE OF CLINICAL PHARMACOLOGY AND BIOPHARMACEUTICS REVIEW
`
`21-574
`NDA:
`Brand Name
`
`Submission Date(s): 12/17/02, 09/30/03
`FortametTM
`
`Generic Name
`
`'
`
`Metformin extended—release tablets
`
`Reviewer
`
`Team Leader
`
`OCPB Division
`
`ORM division
`
`Sponsor
`
`Relevant lND(s)
`
`Xiaoxiong (Jim) Wei, MD, Ph.D.
`
`Hae-Young Ahn, PhD.
`
`Division of Pharmaceutical Evaluation ll
`
`Division of Endocrine and Metabolic Drug Products
`(HFD-510)
`
`Andrx Laboratories
`
`55,962
`
`Submission Type; Code
`
`505 (b) (2), 1S
`
`Formulation; Strength(s)
`
`Tablets; 500 mg, 1000 mg
`
`Dosing regimen
`
`Start with 1000 mg once a day up to 2500 mg dependent
`on individual patients‘ glucose levels
`
`Indication
`
`Type 2 or non-insulin-dependent diabetes mellitus
`(lNDDM)
`
`
`1
`
`Executive Summary
`
`Andrx Labs, Inc. submitted a 505 (b) (2) NDA for marketing of FortametTM, an extended
`release tablets of metformin. The marketed reference drug is an immediate release formulation
`of metformin hydrochloride (Glucophage®) manufactured by Bristol-Myers Squibb (BMS). BMS
`also manufactures extended release formulations of metformin HCL, Glucophage® XR, which
`was approved in 2000 with 500 mg strength. The second strength, 750 mg for Glucophage XR
`was approved in 2002. However, all comparisons of FortametTM relative to the reference drug
`metformin were made with immediate release forms. All pharmacokinetics/relative bioavailability
`studies to Glucophage® were performed with pilot lots except for one studv with scale-up 1000
`mg (Study 155—110). The size of these pilot lots is quite small, C
`Jfor 500 mg and for
`about L
`3 for 1000 mg, respectively.
`
`The relative bioavailability of FortametTM to Glucophage® (immediate release form of
`metformin HCL) in healthy subjects was compared between FortametTM (4 x 500 mg tablets) after
`' breakfast, FortametTM (4 x 500 mg tablets) after dinner, and Glucophage® (2 x 500 mg tablets)
`BlD (after breakfast and after dinner). FortametTM exhibited extended—release characteristics in
`terms of pharmacokinetic profiles of metformin when compared to Glucophage®. The relative
`bioavailability of FortametTM given after dinner relative to Glucophage BID was approximately
`98%. The bioavailability of FortametTM given after breakfast relative to Glucophage was about
`80%.
`
`Three additional single dose relative bioavailability studies were conducted with the doses of
`1000 mg, 1500 mg and 2500 mg between FortametTM and Glucophage.
`in all three studies,
`FortametTM was given immediately after dinner. The relative bioavailability of FortametTM to
`
`NDA21-574 Fortamet ER —121702.doc
`
`'
`
`1
`
`

`

`Glucophage® at the doses of 1000 mg, 1500 mg and 2500 mg were 1.02, 1.03 and 0.96,
`respectively.
`
`The steady state pharmacokinetics of FortametTM was compared to Glucophage® after 4
`weeks of treatment in type 2 diabetic patients. Patients took FortametT’Vl (2 x 1000 mg tablets)
`orally immediately after dinner or Glucophage® (1 x 1000 mg tablet) BID orally immediately after
`breakfast and after dinner. The results showed that the ratio of AUCo.24 hr was about 98%.
`
`Food increases the bioavailability of FortametTM by 60% after a single oral dose‘ of 2500
`mg was given to healthy male volunteers compared to overnight fasting.
`
`Two scale-up dosage forms, 500 mg and 1000 mg were used in phase 3 clinical trials.
`The firm conducted one dosage equivalence study for 500 mg and 1000 mg tablets using two
`pilot lots, which failed on bioequivalence criteria. The firm has not conducted dosage equivalence
`studies between scale—up lots or commercial formulations although the firm has proposed to
`market 500 mg and 1000 mg tablets. '
`
`in order to improve manufacturability. the formulation composition and manufacturing
`process have been modified after the phase 3 pivotal clinical trials. The formulation composition
`increased in C
`.
`3 level by “ of the total
`formulation. Subsequently, some manufacturing processes have been modified. All these
`changes are considered as Level 1 changes according to the SUPAC-MR guidance.
`
`1 .1
`
`Recommendation
`
`The Office of Clinical Pharmacology and Biopharmaceutics/Division of Pharmaceutical
`Evaluation ll (OCPB/DPE—2) has reviewed the information provided in the original NDA 21-574 for
`FortametTM in the section of human pharmacokinetics and biopharmaceutics. OCPB has found
`that there is deficiency in that the dosage form equivalence between 500 mg and 1000 mg tablets
`has not been established. From thesperspectives of clinical pharmacology and biopharmaceutics,
`the 1000 mg tablet is acceptable. However, there is no adequate information about the 500 mg
`tablet. Therefore. the 500 mg tablet can not be approved at the present time.
`
`tablets:
`
`For dissolution specifications, the Agency has the following recommendation for 1000 mg
`
`
`
`
`
`
`
`
`
`A- aratus type
`'
`USPApparatus-1 \ E_
`
`0.05M E
`7 hos hatebuffer,
`Dissolution medium
`.
`‘
`
`
`Volume of Medium
`900 ml
`
`
`
`Temperature of medium 37°C
`
`Speed of rotation
`~ RPM
`
`
`S-ecification
`1000 m-
`2 hr: NMT ‘ 8 hr: — 16 hr: NLT
`.2
`
`
`
`
`
`
`These recommendations and the reviewer's comments and labeling changes should be
`sent to the sponsor as appropriate.
`
`Reviewer’s Comments:
`
`There are no dosage form equivalence studies between 500 mg and 1000 mg tablets
`1)
`from scale—up or commercial lots. The firm did perform a dosage form equivalence study for 500
`mg and 1000 mg tablets from two pilot formulation lots, in which the bioavailability of 2x500 mg
`was about 22% less than 1X1000 mg tablets based on the AUC assessment. The dosage form
`
`NDA21—574 Fortamet ER -121702.doc
`
`2
`
`

`

`equivalence between 500 mg and 1000 mg using either scale-up or commercial formulations
`should be performed.
`
`Clinical Pharmacology and Biopharmaceutics Briefing was held on October 6, 2003. The
`following staff attended the Briefing: Drs. Hank Malinowski, John Hunt, Arzu Selen, Hae-Young
`Ahn, Raman Raweja, He Sun, Sang Chung and Robert Misbin.
`
`1 .2
`
`Phase IV Commitments
`N/A
`
`2
`
`Table of Contents
`
`1
`
`Executive Summary.......................................................................................... 1
`1.1 Recommendation ................................................................................................................ 2
`1.2
`Phase IV Commitments
`................................................................................................. 3
`Table of Contents ............................................................................................. 3
`2
`Summary of CPB Findings ............................ . .................................................... 3
`3
`4 QBR .............................................. 5
`4.1 General Attributes .........................................................' ...................................................... 5
`4.2 General Clinical Pharmacology .......................................................................................... 7
`4.3
`Intrinsic Factors ................................................................................................................. 12
`4.4 Extrinsic Factors ............................................................................................................... 12
`4.5 General Biopharmaceutics ................................................................................................ 12
`4.6 Analytical ........................................................................................................................... 17
`Labeling ........................................................................................................ 17
`Appendix..................................................................................................... 20
`Proposed labeling .............................................................................. not attached
`
`5
`6
`7
`
`3
`
`Summary of CPB Findings
`
`Pharmacokinetics
`
`. Relative bioavailability after single dose:
`
`The relative bioavailability of FortametTM to Glucophage® in healthy subjects was
`compared for the following scheme: Group A received FortametTM (4 x 500 mg tablets)
`immediately after breakfast; Group B received FortametTM (4 x 500 mg tablets) immediately after
`dinner; and Group C received Glucophage® (2 x 500 mg tablets) immediately after breakfast, and
`immediately after dinner. FortametTM exhibited extended—release characteristics in terms of
`pharmacokinetic profiles of metformin when compared to Glucophage®. The relative
`bioavailability of FortametTM given after dinner relative to Glucophage BID was approximately
`98%. The bioavailability of FortametTM given after breakfast was lower than FortametTM given
`after dinner or Glucophage given BID (about 80%). The total exposure of FortametTM given
`immediately after dinner was comparable to Glucophage BID dosing with the same dose. This
`study laid a basis for the further clinical pharmacology biopharmaceutics studies to be given after
`dinner.
`
`Three additional single dose relative bioavailability studies were conducted with the doses of
`1000 mg, 1500 mg and 2500 mg between FortametTM and Glucophage. The relative
`bioavailability of FortametTM given after dinner to Glucophage® at the doses of 1000 mg, 1500
`mg and 2500 mg were 1.02, 1.03 and 0.96, respectively.
`
`. Relative bioavailability after multiple doses:
`
`NDA21—574 Fortamet ER -121702.doc
`
`3
`
`

`

`The steady state pharmacokinetics of FortametTM was compared with
`Glucophage® after 4 weeks of treatment in type 2 diabetic patients. Patients took Fortametm (2
`x 1000 mg tablets) orally immediately after dinner or Glucophage® (1 x 1000 mg tablet) BID
`orally immediately after breakfast and after dinner. The results showed that the ratio of AUCo.24 h,
`for equivalent doses of FortametTM administered qd and Glucophage® administered bid was
`about 98%.
`
`0 Dose proportionality:
`
`A dose proportionality; study of FortametTM at the dosage levels of 1000, 1500, 2000, and
`2500 mg in healthy male volunteers was conducted under fed conditions (after dinner). All
`pain/vise comparisons between doses shows significant difference (p<0.05) with respect to dose-
`normalized Cmax, AUCo-72 hr, and AUCo.inf except for the comparison between 2000 and 2500 mg.
`Although dose-associated increase in metformin exposure within the dose range of 1000 mg to
`2500 mg was observed, the lack of dose proportionality was concluded. However, the firm’s '
`conclusion may not be granted because the dosage equivalence has never been established
`between 500 mg and 1000 mg tablets and these two dosage forms were mixed in the study.
`
`- Elimination:
`
`Following oral administration of 2500 mg FortametTM for 14 days in 18 healthy volunteers,
`the amount of metformin excreted in the urine and renal clearance after oral administration of
`
`FortametTM on Days I and 14 were generally comparable. Mean 1 SD values of these parameters
`at Da 3 l and 14 are summarized in the followin table:
`
`Mean i SD (N=18)
`% of metformin dose excreted
`Renal clearance (mlJmin)
`. COHECtiOH
`in the urine
`Interval (hrs)
`
`483 i 97
`542 1- 310
`
`
`
`0 Food effect:
`
`The effect of food on the absorption of FortametTM after a single oral dose of 2500 mg in
`healthy male volunteers was assessed. The bioavailability (AUCWZ hr, and AUCWM) of 2500 mg
`FortametTM taken after breakfast was approximately 160% of that taken after an overnight fast.
`The results suggested that food increases the bioavailability of FortametTM. Similar results were
`also observed for the extended-release dosage form of Glucophage (Glucophage XR), in which
`the extent of metformin absorption (as measured by AUC) increased by approximately 50% when
`Glucophage XR was given with food.
`
`. Analytical assay:
`
`3 method was used for the measurement of metformin
`A [
`over the concentration range of '~— ng/mL to - ng/mL with a lower limit of quantitation equal to
`the lowest calibration level of ‘
`.2 ng/mL.
`
`Biopharmaceutics
`
`o Formulation and manufacturing changes:
`
`NDA21—574 Fortamet ER —121702.doc
`
`4
`
`

`

`in order to improve manufacturability, the formulation composition and manufacturing
`process have been modified after the phase 3 pivotal clinical trials. The formulation composition
`Increased .C
`J level by —- )f the total formulation.
`Subsequently, some manufacturing processes have been modified. All these changes are
`considered as Level 1 changes according to the SUPAC-MR guidance.
`
`. Dosage equivalence:
`
`The firm conducted one dosage equivalence study for 500 mg and 1000 mg tablets from
`two pilot lots throughout the drug development program. The bioavailability (Cmax, AUC 0.72 h, and
`AUG 04,”) of metformin after receiving two 500 mg FortametTM tablets relative to receiving one
`1000 mg tablet was approximately 76-79%. The 90% confidence intervals were not contained in
`the [BO-125%] range. Therefore, bioequivalence between the two dosage strengths from these
`two pilot lots was not established. The firm has not conducted dosage equivalence studies
`between scale-up lots or commercial lots although two dosage strengths, 500 mg and 1000 mg
`are proposed for marketing.
`
`4
`
`QUESTION BASED REVIEW
`
`4.1
`
`GENERAL ATTRIBUTES
`
`-
`
`What are the highlights of the chemistry and physical-chemical properties of the
`drug substance?
`-
`
`FortametTM is an extended release formulation of metformin HCL. Metformin
`
`hydrochloride (N, N-dimethylimidodicarbonimidic diamide hydrochloride) is a member of the
`biguanide class of oral antihyperglycemics and is not chemically or pharmacologically related to
`any other class of oral antihyperglycemic agents.
`
`The empirical formula of metformin hydrochloride is C4H11N5-HC1 and its molecular
`weight is 165.63. Metformin hydrochloride is a white to off-white crystalline powder that is freely
`soluble in water and is practically insoluble in acetone, ether, and chloroform. The pKa of
`metformin is 12.4. The pH of a 1% aqueous solution of metformin hydrochloride is 6.68.
`
`o
`
`What are the highlights of the formulation of drug product?
`
`The composition of formulations has been modified frequently. The majority of studies of
`clinical pharmacology and biopharmaceutics were conducted using pilot formulations. Phase 3
`clinical trials were conducted with scale-up forrnulations. The firm has commercial formulation for
`the to-be-marketed drug products. The scale-up (phase 3) and to-be—marketed formulations have
`the same composition qualitatively and quantitatively except for the amount of C . I The
`composition and comparison among these formulations is summarized in Table 1 and Table 2 for
`FortametTM 500 mg and 1000 mg tablets, respectively.
`
`
`Table 1. Formulation comparison of FortametTM 500 mg tablets
`I
`__L
`Fortamet'”l 500 mg
`
`NDA21—574 Fortamet ER —121702.doc
`
`5
`
`

`

`Active
`
`Components
`
`Metformin
`hydrochloride, BP
`Sodium lauryl
`sulfate, NF
`
`Povidone K-90
`USP
`Magnesium
`stearate, NF
`
`Cellulose acetate,
`,NF .,
`
`Triacetin, USP
`
`Polyethylene
`Glycol 400, NF
`
`Candelilla Wax
`
`Scale-up Lot
`266R003 (phase 3)
`
`Commercial
`formulation
`
`Pilot Lot
`P99148
`. hase 1
`% wlw
`
`m - Itablet % wlw m -Itablet
`500.00
`500.00
`
`
`
`
`
`
`Table 2. Formulation com-arison of FortametTM 1000 mo tablets
`FortametmI 1000 m-
`Pilot Lot
`Scale-up Lot
`Commercial
`P99218
`271 R002 (phase 3)
`formulation
`
`(p_hase 1)
`% wlw_
`
`m Itablet % vy/w m - Itablet
`
`l
`
`1000.00
`
`Components
`
`_
`
`Metformin
`hydrochloride, BP
`Sodium lauryl
`sulfate, NF
`
`Povidone K-90
`USP
`
`Active
`
`% wlw
`
`1000.00
`
`,
`
`’
`
`i
`
`l
`
`Magnesium
`
`stearate,NF
`
`Cellulose acetate,
`NF l
`Triacetin, USP
`
`I:
`
`
`
`
`Polyethylene
`
`Glycol 400, NF
`Candelilla Wax
`
` -¥,_‘ _
`
`.7
`
`,
`
`‘
`
`/ / /
`
`.
`
`:
`
`T
`
`o
`
`What is the proposed mechanism of drug action and the therapeutic indications?
`
`NDA21-574 Fortamet ER -121702.doc
`
`‘
`
`6
`
`

`

`Metformin is an antihyperglycemic agent which improves glucose tolerance in patients
`with type 2 diabetes, lowering both basal and postprandial plasma glucose. lts pharmacologic
`mechanisms of action are different from other classes of oral antihyperglycemic agents.
`Metformin decreases hepatic glucose production, decreases intestinal absorption of glucose, and
`improves insulin sensitivity by increasing peripheral glucose uptake and utilization.
`
`Unlike sulfonylureas, metformin does not produce hypoglycemia in either patients with
`type 2 diabetes or normal subjects (except in special circumstances, see PRECAUTIONS) and
`does not cause hyperinsulinemia. With metformin therapy, insulin secretion remains unchanged
`while fasting plasmainsulin levels and day-long plasma insulin response may actually decrease.
`
`.
`
`What is the proposed dosage and route of administration?
`
`The firm has proposed two strengths, 500 mg and 1000 mg tablets for extended release
`formulation. The drug is recommended to start with 1000 mg once a day and titrate up to 2500
`mg once a day based on blood glucose levels. The drug is instructed to take with food after
`evening dinner.
`
`4.2
`
`GENERAL CLINICAL PHARMACOLOGY
`
`o
`
`What is bioavailability of FortametTM relative to Glucophage® after a single dose?
`
`The firm has conducted 4 single dose and 2 multiple dose relative bioavailability studies
`in comparison with Glucophage®.
`
`Study 155-002 (Lot No. P98231) was an open-label, single-dose, randomized, three—
`period crossover design with a one-week washout period between treatments and was conducted
`to compare the extended—release dosage form of metformin (FortametTM) with Glucophage® in
`healthy subjects in terms of safety and plasma profile of metformin.
`In each study period, either a
`'single oral dose of FortametT'“I or BID doses of Glucophage® was administered according to the
`following scheme: Group A received Metformin XT (4 x 500 mg tablets) immediately after
`breakfast; Group 8 received Metformin XT (4 x 500 mg tablets) immediately after dinner; and
`Group C received Glucophage® (2 x 500 mg tablets)
`at approximately 8 am, immediately
`following breakfast, and at immediately after dinner. Five male and seven female adult subjects
`enrolled and completed the study. Results are summarized in the Table 3.
`
`
`Table 3. Human. charmacokinetics and bioavailability
`Geometric Mean Ratio
`Mean 1 SD (N=12)
`
`(Metformin XT/Glucophage)
`
`
`FortametTM
`Fortamet‘"ll
`Glucophage
`FortametTM
`FortametTM
`
`
`after dinner
`after breakfast
`BID
`after dinner
`after breakfast
`
`1.12
`1814i302
`20535447
`21275545
`1.15
`
`
`16274 t 4607
`19670 t 3.983
`20196 i 4.24
`0.79
`
`
`
`20.34 t 4.36
`21.22 i 4.50
`17.25 i 4.96
`0.80
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`_
`Parameter
`
`AUC 0.24 hr
`n - .hrImL
`
`AUC am
`
`
`
`
`
`
`NDA21—574 Fortamet ER -121702.doc
`
`7
`
`

`

`Figure 1. Mean plasma concentration-time profiles of metformin, based on dosing
`time after oral administration of FortametTM (4 x 500 mg) or Glucophage® (2 X 500 mg for
`one day)
`
`NaS
`
`—.— Mutant-in NT .nm- Ilrnlkllxl
`-o-— Medan-in x'I' after u
`» -.. GLUCOI'IMCE bJ.-L ur an:
`
`a
`
`
`
`
`
`a.n
`.5
`
`5E
`
`a“-
`
` AdooeiQiSSOd#568
`
`FortametTM exhibited extended-release characteristics in terms of pharmacokinetic
`profiles of metformin when compared to Glucophage®. The relative bioavailability of FortametTM '
`given after dinner relative to Glucophage BID was approximately 98%. The bioavailability of
`FortametTM given after breakfast was lower than FortametTM given after dinner or Glucophage
`given BID (about 80%). The Cmax of the test drug dosing after breakfast and dinner was similar
`to that. after dosing with Glucophage BID for one day. The total exposure of Fortamet‘iWI given
`immediately after dinner was comparable to Glucophage BID dosing with the same dose.
`
`Three additional single dose relative bioavailability studies (Study 155—101, Study 155—
`102, and Study 155-103) were conducted with the doses of 1000 mg, 1500 mg and 2500 mg
`between FortametTM and Glucophage.
`In all three studies, FortametTM was given immediately
`after dinner. The relative bioavailability of FortametTM to Glucophage® at the doses of 1000 mg,
`1500 mg and 2500 mg were 1.02, 1.03 and 0.96, respectively.
`
`0
`
`What is bioavailability of FortametTM relative to Glucophage after multiple doses?
`
`The firm has conducted two multiple-dose bioavailability studies of FortametTM relative to
`Glucophage® during phase 2 clinical trials.
`
`Study 155-005 (Lot No. P99041) was a phase II safety, pharmacokinetic and
`pharmacodynamic study of FortametTM relative to Glucophage®in type 2 diabetic patients. The
`steady state pharmacokinetics of FortametTM 'was compared with Glucophage® after 4 weeks of
`treatment. This was a randomized, open—label, two-way crossover study. Eligible patients were
`randomized to one of the following treatment groups: Study Medication: A - FortametTM (2 x 1000
`mg tablets) taken orally immediately after dinner; or Study Medication B - Glucophage (1 x 1000
`mg tablet) taken orally immediately after breakfast, and immediately after dinner. Period l lasted
`for 4 weeks, at the completion of which patients received the alternate treatment for 4 weeks in
`Period II. There was no washout between treatment periods. 24 patients were randomized into
`Treatment Period. One patient withdrew during Treatment Period l for personal reasons. 23
`patients completed the study. The results are presented in Table 4 and Figure 2.
`
`NDA21—574 Fortamet ER -121702.doc
`
`8
`
`

`

`Table 4. Mean values of pharmacokinetic parameters and bioavailability after dinner
`relative to Gluco - ha e®
`
`Geometrlc
`
`
`
`
`mean who
`AUC 0.24 hr
`
`Treatment
`Cmax (ng/nL)
`
`
`(ng.hr/mL)
`AUC 11-24 hr
`
`
`
`2681 1 i 7055
`2849 i 797
`FortametTM
`
`
`
`27371 i 5781
`1820 i 370
`Glucophage®
`
`
`
`
`
`The AUCOQ.“1r for equivalent doses of FortametTM, administered qd and Glucophage,
`administered bid, was similar, confirming the extended release nature of FortametTM. FortametTM,
`dosed at 2000 mg qd at 6 PM, was as effective as Glucophage, dosed at 1000 mg bid, for the
`control of, blood sugar in patients diagnosed with NlDDM.
`
`Figure 2. Pharmacokinetic profiles of FortametTM and Glucophage after 4 weeks
`treatment.
`nu- Sandy-cm nun- c-umuu4m m: {Wu-ill In mum run-y I—u)
`nl‘IuM-llipltonllh—‘N-‘ormhlfflx [Mc‘1‘lfilmu
`clummanulm-‘uqh4w‘.
`
`4500
`
`
`a J
`
`6’
`Q?
`I
`
`O
`(5‘
`.S‘ '
`[6
`49
`
`:00
`
`J’
`
`m
`J5“)
`A m
`i
`2900
`I
`E 1“”
`: moo
`I
`I000
`
`. 5
`
`Study 155—106 was an identical study except that FortametTM was given immediately
`after breakfast. The relative bioavailability of FortametTM to the same dose of Glucophage was
`0.84. ThisIs consistent with the resultIn Study 155-002, in which the relative bioavailability of
`FortametTM after breakfast was lower than that after dinner.
`
`0
`
`What is the dose-concentration relationship for Fortametm?
`
`A dose proportionality study of FortametTM at the dosage levels of 1000,1500, 2000, and
`2500 mg in healthy male volunteers was conducted under fed conditions (after dinner) (Study
`155-106 (Lot No. 271R002 for 1000 mg and Lot No. 266R003 for 500 mg). The pharmacokinetic
`summary is presente