'
`
`1llllllllllllllllllllllllllll1
`
`*’l51966*
`
`'*'A *
`
`151966
`
`A
`
`Glucophage 500 and 850 mg Tablets (Lipha
`Pharmaceuticals) 12/29/1994 Approval: Approval
`Letter, Pediatric Studies, Labeling
`
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`AURO — EXHIBIT 1012
`0001
`
`

`
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`
`FS.
`
`JAN 0 8 1998
`
`December 30. 19tr7
`
`In Response Refer to File : P97-41306
`
`FOI Services, Inc.
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`
`Dear Requestor:
`
`Public Health Service
`Center for Drug Evaluai ion and Research
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`B !I-;
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`
`Z 1S966
`
`This is in response to your request of December 11, 1997, your control number 151966, in
`which you requested documents for the drug METFORMIN. Your request was received in the
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`
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`
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`IIVZXDati ar 1311011113LTION =MT
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`(cid:9)
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`FOOD & DRUG ADMINISTRATION
`FREEDOM OF INFORMATION STAFF
`5600 FISHERS LANE
`ROCKVILLE, MD 20857
`
`12/11/97
`
`CONTROL NUMBER 151966
`
`p B
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`PURSUANT TO THE PROVISIONS OF THE FREEDOM OF INFORMATION ACT, PLEASE
`PROVIDE US WITH A PAPER COPY (PREFERABLY NOT MICROFICHE) OF THE
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`COPY OF ALL CORRESPONDENCE DONE TN THE CENTER FOR DRUG EVALUATION AND
`RESEARCH FOR THE APPROVAL OF METFORMIN HCL (TABLETS).
`
`Hf-L.D-b5
`
`COte*ORMa 5795
`
`0005
`
`(cid:9)
`(cid:9)
`

`
`ovtu )nTD
`LS.Qt' 4011
`
`0006
`
`

`
`410)
`d7V404deDiaq
`
`0007
`
`

`
`NDA 20-357
`
`Lipha Pharmaceuticals Inc.
`Attention: Gerard L Daniel, M.D.
`Chairman, President & Chief Executive Officer
`9 West 57th Street, Suite 3825
`New York, NY 10019-2701
`
`Dear Dr. Daniel:
`
`DEC 2 9 1994
`
`Please refer to your September 29, 1993, new drug application submitted under section 505(b)
`of the Federal Food, Drui, and Cosmetic Act for Glucophage (metformin hydrochloride
`tablets) 500 and 850 mg Tablets.
`
`We acknowledge receipt of your amendments dated September 29, November 12, 16, 18,
`19, and 23, and December 1, 6, 13, and 15, 1993; and January 11 (2), February 2, 3, 4, 7, 11, 15,
`and 23, March 4, 7, 11, and 12 (2), May 12, 13, 19, 20, and 27, June 15 and 22, August 19, 30,
`and 31, October 19 and 28, November 8, 11, 21, 22, and 29, and December 28 and 29 (2), 1994.
`Your major amendment of August 19, 1994, extended the Goal Date fcr this NDA to
`December 29, 1994.
`
`This new drug application provides for the use of Glucophage as an adjunct to diet to lower
`blood glucose in patients with non-insulin-dependent diabetes mellitus (NIDDM; type II
`diabetes), whose hyperglycemia cannot be satisfactorily managed on diet alone.
`
`We have completed the review of this application as amended, including the submitted draft
`labeling, and have concluded that adequate information has been presented to demonstrate
`that the drug product is safe and effective for use as recommended in the draft labeling
`submitted September 29, 1993 (bottle labels), November 11 (blister packaging), and
`December 29, 1994 (package insert). Accordingly, the application is approved, effective on the
`date of„thisjetter.
`
`Please submit 15 copies of the final printed labeling (FPI) as soon as available, in no case more
`than 30 days after it is printed. The FPL must be identical to the draft labeling submitted
`September 29, 1993 (bottle labels), November 11 (blister packaging), and December 29, 1994
`(package insert). Marketing the product with FPL that is not identical to this draft labeling
`may render the product misbranded and an unapproved new drug. Please individually mount
`10 of the copies on heavy-weight paper or similar material. For administrative purposes, this
`submission should be designated "FINAL PRINTED LABELING" for approved NDA 20-357.
`Approval of this labeling by FDA is not required before it is used.
`
`We refer to your communication dated December 28, 1994, proposing a patient package insert
`(PPI). Although we have not completed our review of the PM, we will do so in the near
`future. We also refer to your communication of December 29, 1994, in which you committed
`not to market Glucophage without an accompanying PPI containing mutually agreeable
`language. You also stated in the latter submission that each bottle of 100 tablets will include a
`
`0008
`
`

`
`NDA 20-357 (cid:9)
`
`Page 2
`
`copy of the approved PPI, and if larger bulk containers are proposed in the future, an
`appropriate mechanism for distributing the PPI to each patient will be developed in
`consultation with FDA.
`
`In addition, please submit three copies of the introductory promotional material that you
`propose to use for this product. All proposed materials should be submitted in draft or
`mock-up form, not final print. Please submit one copy to the Division of Metabolism and
`Endocrine Drug Products and two copies of both the promotional material and the package
`insert directly to:
`
`'Food and Drug Administration
`Division of Drug Marketing, Advertising and Communications, HFD-240
`5600 Fishers Lane
`Rockville, Maryland 20857
`
`Please include the MedWatch telephone number in all your advertising and promotional
`materials (1-800-FDA-eV- 11/4- (cid:9)
`A0
`iv
`Validation of the regulatory methods has not been completed. At the present time, it is the
`policy of the Center not to withhold approval because the methods are being validated.
`Nevertheless, we expect your continued cooperation to resolve any deficiencies that may occur.
`
`Your communications of May 27 and August 31, 1994, commit to performing Phase 4 studies
`as follows:
`
`1)
`
`2)
`
`Your May 27 submission contains a draft of a dose-ranging protocol (No. 94-02-6023)
`entitled "Dose Response Stbdy of Various Dose Levels of Metformin v. Placebo in Non-
`Insulin-Dependent Diabetic Outpatients." et final protocol should be submitted to
`your IND to conduct this study.
`
`Your August 31 submission includes a draft proposal (in response to our letter dated
`June '9, 1994) for a prospective, randomized, controlled clinical trial involving 10,000
`patient's with NIDDM to focus on detection, confirmation, and evaluation of the
`incidence of lactic acidosis while taking Glucophage. Further, you have submitted a
`on December 8, 1994. We will now solicit a written
`detailed protocol to IND (cid:9)
`review of the protocol by several consultants. Their comments will be provided to you
`so that you can refine the protocol and submit a final version to the IND prior to
`initiation of the study.
`
`Prominently identify all communications regarding these Phase 4 studies as such.
`
`Your communication of August 31 also provides an overview of the type of medical education
`program to be conducted by Bristol-Myers Squibb for various health professionals. You
`indicate that it will primarily emphasize preventing the occurrence of lactic acidosis with
`proper Glucophage usage.
`
`0009
`
`

`
`NDA 20-357 (cid:9)
`
`Page 3
`
`Please note that we will very likely convene an Endocrinologic and Metabolic Drugs Advisory
`Committee meeting after Glucophage has been marketed for one year to assess the implemen-
`tation of the Phase 4 commitment in regard to the large cohort study and the completion of
`the Phase 4 commitment of the dose-response study.
`
`Regarding the carton and blister-pack labels used for Glucophage Tablets, the "tablet"
`designation should appear as part of the established name, i.e., "metformin hydrochlorick
`tablets" rather than "metformin hydrochloride." This change can be made some time after
`introduction of the drug and reported in the first annual report.
`
`Please submit one market package of the drug product when it is available.
`
`Under section 736(a)(1)(BXii) of the Prescription Drug User Fee Act of 1992, this letter triggers
`the remaining 50% of the fee assessed for this application. You will receive an invoice for the
`amount due within the next month. Payment will be due within 30 days of the date of the
`invoice.
`
`We remind you that you must comply with the requirements for an approved NDA set forth
`under 21 CFR 314.80 and 314.81.
`
`If you have any questions, please contact:
`
`Mr. John R. Short
`Consumer Safety Officer
`(301) 443-3510
`
`Sincerely yours,
`
`, (cid:9)
`
`James Bilstad, M.D.
`Director
`Office of Drug Evaluation H
`Center for Drug Evaluation and Research
`
`0010
`
`

`
`ODE I/11 ORIGINAL NDA/NDA EFFICACY SUPPLEMENT
`ACTION PACKAGE CHECKUST
`'1 4 (7
`L C.-doh A-5
`I Drug (cid:9)
`4.7K/17 /9C 4 t 11 e/1-1.5CSO )1 (cid:9)
`
`NDA (cid:9)
`
`Applicant (cid:9)
`
`(."'"71-ZVECar 1,7/ I.L7) —14-101-e-4:r
`
`3r'phone /C4 :357 c,
`
`Arrange package in the following order: (cid:9)
`
`Check or comment
`
`ACTION LETTER with supervisory signatures (cid:9)
`
`AP ' (cid:9)
`
`AE __ . NA__
`
`AG-TieN-PlIteitAr3E-TroteteNS-FORM. N E ta .. ) z (". tiC4 it
`
`Completed copy of this CHECKLIST in package (cid:9)
`
`LABELING (package insert And labels). (If final or revised (cid:9)
`draft. include copy of previous version with ODE's comments (cid:9)
`and state where in action package the Division's review is
`located. If Rx-lo-OTC switch, include current Rx PI and
`HFD-2I0 review of OTC insert.)
`
`Chern/Ther Types__
`
`Types__ P
`
`Draft X (cid:9)
`Final (cid:9)
`Revised Dratl (cid:9)
`
`
`
`
`
`SUMMARY BASIS OF APPROVAL. (Copy of previous version (cid:9)
`with ODE's comment as well as disk. FPL and sign.olf sheet (cid:9)
`must accompany revised or final version. If no SBA. include (cid:9)
`memo stating what reviews will be used as SBA equivalent)
`
`SBA
`
`Revised SBA (cid:9)
`SBA Equivalent
`
`X
`
`PATENT INFORMATION (cid:9) V/". (cid:9)
`
`EXCLUSIVITY CHECKLIST V7
`
`Debarment Certification (Copy of applicant's certification for
`all NDAs submitted on or alter June 1. 1992)
`
`III more than I review
`DIVISION DIRECTORS MEMO
`for any I discipline.
`GROUP LEADERS MEMO
`!separate reviews with
`PEDIATRIC PAGE
`la sheet of colored paper.
`MEDICAL REVIEW
`!Any conflicts between
`SAFETY UPDATE REVIEW
`!reviews must have
`STATISTICAL REVIEW
`BIOPHARMACEUTICS REVIEW trosolubon documented
`PHARMACOLOGY REVIEW (Include pertinent IND reviews)
`Statistical Review 01 Carcinogenicity Sludy(ies)
`CHEMISTRY REVIEW
`
`Date EER completed pit.;/ (cid:9)
`
`.ri (cid:9)
`CIRTS printout); FUR n (cid:9)
`Have the methods been validated?
`Environmental Assessment Review
`MICROBIOLOGY REVIEW
`Has the monograph been approved?
`
`(attach signed for
`requested
`
`OlLer.... No__
`
`Yer(a1tach)__ No_t
`
`-e/s4 (cid:9)
`
`No
`
`1. (cid:9)
`
`2. (cid:9)
`
`3. (cid:9)
`
`4.
`
`5.
`
`6.
`
`7.
`
`8.
`
`9.
`
`10.
`
`1 t. (cid:9)
`
`12.
`
`13.
`
`14 (cid:9)
`
`Statement on status el DSIS AUDIT OF PIVOTAL CLINICAL STUDIES
`. 4f 4E or AP IV. explain it not satisfactorily completed.
`Attach a COMIS printout or DM status
`
`CORRESECNDEKCEaxi MB/1050F TREOCNS
`
`minkirF_GOFMEEINGS
`Dabs of End-of-Phase It Meeting
`Dale of pre-NDA Meeting
`
`ADVISORY COMMITTEE MEETING MINUTES or, it nol available.
`48-Hour Info Alert or pertinent section of transcript
`
`Minutes (cid:9)
`Transcript (cid:9)
`
`FEDERAL REGISTER NOTICES: OTC or DESI DOCUMENTS
`
`; •//511./
`ffigpe
`Info
`No m19_
`
`II approval letter, has ADVERTISING MATERIAL been reviewed?
`II no and this is an AP with drall labeling letter, has
`advertising material already bean requested?
`
`No__X____
`Yes.. (cid:9)
`Yes, documentation attached.
`No. included in AP Itr_X,
`
`15 (cid:9)
`
`Have all disciplines Completed !heir reviews!
`II no, what review(s) rsraie shit pending',
`
`16 (cid:9)
`
`Integrated Summary of Safety
`
`NDA (especially MedicallSiatimic.30 Summary
`17, (cid:9)
`9/9/92
`
`Yes X_ _ Nu__
`
`0011
`
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`

`
`NDA 20357
`
`SBA EQUIVALENT
`
`Medical Officer Reviews/Memos dated: /
`
`1/27/94 (Dr. Stadel)
`3/22/94 (Dr. Gueriguian)
`5/17/94 (Dr. Innerfield)
`5/18/94 (Dr. Stadel)
`5/20/94 (Dr. Innerfield)
`7/18/94 (Dr. Innerfield)
`9/9/94 (Dr. Stadel)
`11/29/94 (Dr. Gueriguian)
`11/29/94 (Div. Dir.'s Memo)
`12/16/94 (Group Leader's Memo)
`12/29/94 (Dr. O'Neill's Memo)
`
`Statistical Review dated:
`
`3/1/94
`
`Biopharmaceutics Review dated:
`
`7/3/94
`12/22/94
`
`Pharmacology 'Reviews dated:
`
`(Mr. 1-lertig)
`5/3/94 (cid:9)
`642/9.4. (Dr. Lin/Statistical Review of Carcinogenicity Studies)
`
`0012
`
`

`
`0013
`
`

`
`REVISED PACKAGE INSERT
`
`GLUCOPHAGE. (mettormln hydrochloride tablets) — 500 mg and 850 mg
`
`(2-12V914
`
`DESCRIPTION
`
`GLUCOPHAGE (metformin hydrochloride tablets) is an oral antihyperglycemic drug
`
`used in the management of non-insulin-dependent diabetes mellitus (NIDDM).
`
`Metformin hydrochloride (N,N-dimethylimidodicarbonirnidic diamide hydrochloride)
`
`is not chemically or pharmacologically related to the oral sulfonylureas. The
`
`structural formula is as shown:
`
`H3C
`
`N-C-NH-C-NH, HCl
`II (cid:9)
`H
`H,C NH NH
`
`Metformin hydrochloride is a white to off-white crystalline compound with a
`
`molecular formula of C.,H„Ns eHCI and a molecular weight of 165.83. Metformin
`
`hydrochloride is freely soluble in water and is practically insoluble in acetone,
`•
`...
`ether and chloroform. The plc of metformin is 12.4. The pH of a 1% aqueous
`
`solution of metformin hydrochloride is 6.68.
`
`GLUCOPHAGE Tablets contain 500 mg and 850 mg of metformin hydrochloride_
`
`In addition, each tablet contains the following inactive ingredients: povidone,
`
`magnesium stearate and hydroxypropyl methylcellulose (hypromellose) coating.
`
`Decamber 29. 1904 (cid:9)
`
`1
`
`0014
`
`

`
`REVISED PACKAGE INSERT
`
`GLUCOPHAGE• (metformin hydrochloride tablets) 500 mg and 850 mg
`
`CLINICAL PHARMACOLOGY:
`
`Antidlebetic Activity
`
`GLUCOPHAGE is an antihypergtycemic agent which improves glucose
`
`tolerance in NIDDM subjects, lowering both basal and postprandial plasma
`
`glucose. Its pharmacologic mechanisms of action are different from those
`
`of sutfonylureas. GLUCOPHAGE decreases hepatic glucose production,
`
`decreases intestinal absorption of glucose and improves insulin sensitivity
`
`(increases peripheral glucose uptake and utilization). Unlike sutfonylureas,
`
`GLUCOPHAGE does not produce hypoglycemia in either diabetic or
`
`nondiabetic subjects (except in special circumstances. see PRECAUTIONS)
`
`and does not cause hyperinsulinemia. With metformin therapy, insulin
`
`secretion remains unchanged while tasting insulin levels and day-long
`
`plasma insulin response may actually decrease.
`
`I
`
`In a double-blind. placebo-controlled. multicenter U.S. clinical trial involving
`
`obese NIDDM patients whose hyperglycemia was not adequately controlled
`
`with dietary management alone (baseline fasting plasma glucose [FPG] of
`
`approximately 240 mg/dL), treatment with GLUCOPHAGE (up to 2.55
`
`glday) for 29 weeks resulted in significant mean net reductions in fasting
`
`and postprandial plasma glucose (PPG) and HbA,„ of 59 mg/cll.., 83 mg/dl,
`
`and 1.5%, respectively. compared to placebo group (see Table 1).
`
`Dbcamber 29, 1994 (cid:9)
`
`2
`
`0015
`
`

`
`REVISED PACKAGE INSERT
`
`GLUCOPHAGE• (matformin hydrochloride tablets) 500 mg and 850 mg
`
`11••••
`(cid:9)4•16h. (cid:9)
`Table 1. GLUCOPHAGE vs Placebo
`Summary of Mean Changes from Baseline in Plasma Glucose
`HbA,. and Body Weight. at Final Visit (29-week 'study)
`
`GLUCOPHAGE
`(n •L, 141)
`
`Placebo
`(n -- 145)
`
`P-Value
`
`FPG (mg/dL)
`Baseline
`Change at FINAL VISIT
`
`Hemoglobin A„
`Baseline
`Chung° at FINAL VISIT
`
`Body Weight (the)
`Baseline
`Change at FINAL VISif
`
`741.5
`-53.0
`
`8.4
`1.4
`
`201_0
`-1A
`
`237.7
`63
`
`NS
`0.001**
`
`8 2
`
`04
`
`NS
`0.001**
`
`206.0
`2.4
`
`NS
`NS
`
`• - All patients on diet therapy at Baseline
`"- Statistically eigniric.unt
`
`Monotherapy with GLUCOPHAGE may be effective in patients who have
`
`not responded to sulfonylureas or who have only a partial response to
`
`ulfonylureas or who have ceased to respond to sulfonylureas. In such
`
`patients, if adequate glycemic control is not attained with GLUCOPHAGE
`
`monotherapy, the combination of GLUCOPHAGE and a sulfonylurea may
`
`have a synergistic effect, since both agents act to improve glucose
`
`tolerance by different but complementary mechanisms.
`
`December 29. 1994 (cid:9)
`
`3
`
`0016
`
`

`
`REVISED PACKAGE INSERT
`
`GLUCOPHAGE• (rnetformin hydrochloride tablets) — 500 mg and 850 mg
`
`A 29-week, double-blind, placebo-controlled study of GLUCOPHAGE and
`
`glyburide, alone and in combination, was conducted in obese NIDDM
`
`patients who had failed to achieve adequate glycemic control while on
`
`maximum doses of glyburide (baseline FPG of approximately 250 mg/dL)
`
`(see Table 2). Patients randomized to continue on glyburide experienced
`
`worsening of glycemic control, with mean increases in FPG. PPG and
`
`HbAIC of 14 mg/dL, 3 mg/dL and 0.2%, respectively. In contrast. those
`
`randomized to GLUCOPHAGE (up to 2.5 g/day) did not experience a (cid:9)
`
`./
`
`deterioration in glycemic conirol, but rather a slight improvement, with
`
`mean reductions in FPG. PPG and HbAIC of 1 mg/dL, 8 mg/dL and 0A%,
`
`respectively. The combination of GLUCOPHAGE and glyburide was
`
`synergistic in reducing FPG, PPG and fibAI, levels by 63 mg/dL, 65 mg/dL,
`
`and 1.7%. respectively. Compared to results of glyburide treatment alone,
`
`the net differences with combination treatment were -77 mg/dL, -68 mg/dL
`
`and -1.9%. respectively (see Table 2).
`
`4 (cid:9)
`
`4 I
`
`Docembar 29, 1904 (cid:9)
`
`- 4
`
`0017
`
`

`
`REVISED PACKAGE INSERT
`
`GLUCOPHAGE• (metformin hydrochloride tablets) — 500 mg and 850 mg
`
`Table 2. Combined GLUCOPHAGE/Glyburide (Comb) vs
`Glyburide (Glyb) or Glucophage (GLU) Monotherapy:
`Summary of Mean Changes from Baseline* In Plasma Glucose,
`HbA„ and Body Weight, at Final Visit (29-week study)
`
`P-Values
`
`Comb
`(n .7, 213)
`
`Glyb
`(n (cid:9)
`209)
`
`GLU
`(n (cid:9)
`210)
`
`Glyb vs
`Comb
`
`GLU vs
`Comb
`
`GLU Ira
`Glyb
`
`250.5
`-63.5
`
`2475
`13.7
`
`253.9' NS
`0.9
`0.0014°
`
`NS
`0.0016"
`
`NS
`0.075"•
`
`8.B
`-1.7
`
`B.5
`0.2
`
`t1.9
`-0.4
`
`NS
`0.001°-"
`
`NS
`0.001°°
`
`0.007"
`0.001"
`
`2022
`0.9
`
`203.0
`•0.7
`
`204.0
`-tI.4
`
`NS
`0.011°'
`
`NS
`0.001"
`
`NS
`0.001`"
`
`Fasting Plasma
`Glucose, (IttgfdL)
`Be10m
`Change at
`f INAL VISIT
`
`Hemoglobin A,, (%)
`Baseline
`Change at
`TINA' vtsrr
`
`Body Weight (lbs)
`Baseline
`Change at
`ANAL VISIT
`
`- Al! peewits on gtyburlde. 20 mg/day, at flasellne
`." - StellnerAlty eignWicent
`
`The magnitude of the decline in fasting blood glucose concentration
`
`• ' following the institution of GLUGOPHAGE therapy is proportional to the
`
`level of fasting hyperglycemia. Non-insulin-dependent diabetics with higher
`
`fasting glucose concentrations will experience greater declines in plasma
`
`glucose and glycosylated hemoglobin.
`
`December 29, 1994 (cid:9)
`
`5
`
`0018
`
`

`
`REVISED PACKAGE INSERT
`
`GLUCOPHAGE (metformin hydrochloride tablets) — 500 mg and 050 mg
`
`GLUCOPHAGE has a modest favorable effect on serum lipids. which are
`
`often abnormal in NIDDM patients. In clinical studies. particularly when
`
`baseline levels were abnormally elevated. GLUCOPHAGE, alone or in
`
`combination with a sulfonylurea, towered mean fasting serum triglycerides.
`
`total cholesterol and LDL cholesterol levels and had no adverse effects on
`
`other lipid levels (see Table 3).
`
`Table 3.
`Stenmary of Henn Percent Rsductkbr• at Major Serum Lipid
`Yertables at Final Vlsh (29-wssk siudy)
`
`•
`
`Glucaphage vs. Placebo
`(% Chung* from
`Beseline)
`
`r
`
`Combined Giucoptssue/Glyburkla
`VS. Monotherspy
`(% Change from Bassolina)
`i
`
`Glucopheip
`(n-141)
`
`Placebo
`(n.tas)
`
`Giocophage
`(n=210)
`
`GkicoPhocl ei
`
`
`G (cid:9)iliburids
`
`(nt'13)
`
`-4°6•"
`
`-2%
`
`-5%6
`
`16%
`
`-8%.
`
`1%
`
`1%
`
`1%
`
`Total
`Cholesterol
`
`t
`
`Total
`TrIceycerldes
`.
`LOU
`Cholesterol
`
`liDt..-
`Cholesterol
`
`-3%'•
`
`8%••
`
`4%••
`
`6%••
`
`2%
`
`-1%
`
`5%
`
`3%
`
`Glyburld•
`(n -209)
`
`1%
`
`4%
`
`3%
`
`t%
`
`•
`"o• - (cid:9)
`
`P <0.06 vs. Placebo
`P <0.05 vs. Glyburide
`
`In contrast to suitonylureas. body weight of individuals on GLUCOPHAGE
`
`tends to remain stable or may even decrease somewhat (see Tables i and
`
`2).
`
`December 29. 1994
`
`-8
`
`0019
`
`

`
`REVISED PACKAGE INSERT
`
`GLUCOPHAGE' (metformin hydrochloride tablets) — 500 mg and 850 mg
`
`In summary, metformin-treated patients showed significant improvement in
`
`all parameters of glycemic control (FPG, PPG and HbA,,), stabilization or
`
`decrease in body weight, and a tendency to improvement in the lipid
`
`profile, particularly when baseline values are abnormally elevated.
`
`Pharmacokinetics
`
`Absorption and Bioavallsbility:
`
`The absolute bioavailability of a 500 mg metformin hydrochloride tablet
`
`given under fasting conditions is approximately 50-60%. Studies using
`
`single oral doses of metformin tablets of 500 mg and 1500 mg, and 850
`
`mg to 2550 mg. indicate that there is a lack of dose proportionality with
`
`increasing doses, which is due to decreased absorption rather than an
`
`alteration in elimination. Food decreases the extent and slightly delays the
`
`absorption of metformin, as shown by approximately a 40% lower peak
`
`concentration and 25% lower AUC in plasma and a 35 minute prolongation
`
`of time to peak plasma concentration following administration of a single
`
`850 mg tablet of mefformin with food, compared to the same tablet
`
`strength administered fasting. The clinical relevance of these decreases is
`
`unknown.
`
`December 29. 1794 (cid:9)
`
`-
`
`0020
`
`

`
`REVISED PACKAGE INSERT
`
`GLUCCPHAGE• (metformin hydrochloride tablets) — 500 mg and 650 mg
`
`Distribution:
`
`The apparent volume of distribution (V/F) of metformin following single oral
`
`doses of 850 mg averaged 654 ± 3581. Metformin is negligibly bound to
`
`plasma proteins in contrast to sulfonylureas which are more than 90%
`
`protein bound. Metformin partitions into erythrocytes, most likely as a
`
`function of time. At usual clinical doses and dosing schedules of
`
`GLUCOPHAGE, steady state plasma concentrations of metformin are
`
`reached within 24-48 hours and are generally <1 pg/mL During controlled
`
`clinical trials, maximum metformin plasma levels did not exceed 5 pg/m1.,
`
`even at maximum doses.
`
`Metabolism and Elimination:
`
`Intravenous single-dose studies in normal subjects demonstrate that
`
`rretformin is excreted unchanged in the urine and does not undergo
`
`hepatic metabolism (no metabolites have been identified in humans) nor
`
`. (cid:9)
`
`• (cid:9)
`
`biliary excretion. Renal clearance (see Table 4)15 approximately 3.5 times
`
`I
`
`greater than creatinine clearance which indicates that tubular secretion is
`
`the major route of metformin elimination. Following oral administration,
`
`approximately 90% of the absorbed drug is eiminated via the renal route
`
`within the first 24 hours, with a plasma elimination half-rife of approximately
`
`6.2 hours. In blood, the elimination half-life is approximately 17.6 hours,
`
`suggesting that the erythrocyte mass may be a compartment of
`
`distribution.
`
`December 29. 1994 (cid:9)
`
`8
`
`0021
`
`

`
`REVISED PACKAGE INSERT
`
`GLUCOPHAGE0 (metformin hydrochloride tablets) — 500 mg and 850 mg
`
`Special Populations:
`
`. NIDDM Subjects:
`
`In the presence of normal renal function, there are no differences between
`
`single or multiple dose pharmacokinetics of metformin between diabetics
`
`and nondiabetics (see Table 4), nor is there any accumulation of metforrnin
`
`in either group at usual clinical doses.
`
`Renal Insufficiency:
`
`In subjects with decreased renal function (based on measured creatinine
`
`clearance), the plasma and blood half-life of metformin is prolonged and
`
`the renal clearance is decreased in proportion to the decrease in creatinine
`
`clearance (see Table 4).
`
`i Hepatic Insufficiency:
`
`No pharmacokinetic studies have been conducted in subjects with hepatic
`
`insufficiency.
`
`December 29. 1994
`
`- 9 -
`
`0022
`
`

`
`REVISED PACKAGE INSERT
`
`GLUCOPHAGE• (metformin hydrochloride tablets) — 500 mg and 850 mg
`
`Geriatrics:
`
`limited data from controlled pharmacokinetic studies of metformin in
`
`healthy elderly subjects suggest that total plasma clearance is decreased.
`
`the hall-life is prolonged and C is increased, compared to healthy young
`
`subjects. From these data, it appears that the change in metformin
`
`pharrnacokinetics with aging is primarily accounted for by a change in renal
`
`function (see Table 4).
`
`Pediatrics:
`
`No pharmacokinetic studies have been conducted in pediatric subjects.
`
`Gender.
`
`Metformin pharmacokinetic parameters did not differ significantly in diabetic
`
`and nondiabetic subjects when analyzed according to gender (males = 19,
`
`females (cid:9)
`
`16). Similarly. in controlled clinical studies in patients with
`
`, ,NIDDM, the antihyoerglycemic effect of GLUCOPHAGE was comparable in
`
`males and females.
`
`Rscs
`
`No studies of metformin pharmacokinetic parameters according to race
`
`have been performed. In controlled clinical studes of GLUCOPHAGE In
`
`patients with N1DDM, the antihyperglycemic effect was comparable in
`
`whites (n = 249), blacks (n. = 51) and hispanics (n = 24).
`
`December 29, 1994
`
`- 10 -
`
`0023
`
`

`
`REVISED PACKAGE INSERT
`
`GLUCOPHAGE• (mettorrnin hydrochloride tablets) — 500 mg and 850 mg
`
`Table 4. Select Mean (± S.D.) MeltOrmin Pharmacokinetic Parameters
`Following Single or Multiple Oral Doses of GLUCOPHAGE
`
`1
`
`Subject Groups: GLUCOPHAGE
`dose (number of subjects)
`
`Healthy, nondlabetic adults:
`
`C..2
`09/m 0
`
`t.: (has)
`
`Renal
`Clearance
`(m1/mln)
`
`ti
`
`500 mg Sir (24)
`
`B50 mg SO (74)'
`
`1.03. (±0.33)
`
`2.75 (±0.81)
`
`800 (;132)
`
`1.60 (±0.38)
`
`2.64 (±0.82)
`
`552 (1:139)
`
`650 mg t.i.d. for 19 dosed (9)
`
`2.01 (±0.42)
`
`1.79 (±0.94)
`
`642 (±173)
`
`Adults with NIDDPA:
`
`850 mg SD (23)
`
`1.48 (±0.5)
`
`322 (-1-1.08)
`
`491 (± 138)
`
`850 mg t.i.d. for 19 doses' (9)
`
`1.90 (±0.62)
`
`2.01 (±1.22) V 550 (±160) I
`
`Eldsily°,, healthy nondlabetic adults:
`
`850 mg SD (12)
`
`2A5 (±0.70)
`
`2.71 (±1.05)
`
`412 (±98)
`
`Rend-Impelred adults: 850 mg SD
`
`Mild (CI.: 61-90 ml/min) (5)
`
`1.86 (±0.52)
`
`320 (±0.45)
`
`384 (± 122)
`
`MaderaIs (Ci.c, 31-60 mlimin) (4)
`Sayers (CI„ 10-30 ml/min) (6)
`
`4.12 (-± 1.83)
`
`3.75 (±0.50)
`
`108 (±57)
`
`3.93 (±0.92)
`
`4.01 (± 1.10)
`
`130 (±90)
`
`4
`
`▪ - All donee given fasting except the ?instill doses of the mutUple dose studimn:
`Peek plasma concentration;
`- Time to peak plasma concentration;
`a SD — single close;
`• - C.emblried results (average means) of five studies: mean age 32 years (range 23-59 yrs).
`r - Kinetic study done following dose 19, given fasiing.
`▪ - Elderly subjects. mean ago 71 years (range 05-81 years).
`oreEdlnine vitalism* normalized 10 body surface area of 1.73
`▪ - (cid:9)
`
`December Z). 1994
`
`0024
`
`

`
`REVISED PACKAGE INSERT
`
`GLUCOPHAGE. (metformin hydrochloride tablets) — 500 mg and 850 mg
`
`INDICATIONS AND USE
`
`GLUCOPHAGE (metformin hydrochloride tablets), a5 monotherapy, is indicated
`
`as an adjunct to diet to lower blood glucose in patients with NIDDM whose
`
`hyperglycemia cannot be satisfactorily managed on diet alone.
`
`GLUCOPHAGE may be used concomitantly with a sulfonylurea when diet and
`
`GLUCOPHAGE or a sulfonylurea alone do not result in adequate glycemic control.
`
`In initiating treatment for NIDDM, diet should be emphasized as the primary form
`
`of treatment. Caloric restriction and weight loss are essential in the obese diabetic
`
`patient. Proper dietary management alone may be effective in controlling the
`
`blood glucose and symptoms of hyperglycemia. Loss of blood glucose control
`
`in diet-managed patients may be transient, thus requiring only short-term
`
`-pharmacologic therapy. The importance of regular physical activity should also
`
`be stressed, and cardiovascular risk factors should be identified and corrective
`
`4 (cid:9)
`
`•
`
`measures taken where possible. If this treatment program fails to reduce
`
`symptoms and/or blood glucose, the use of GLUCOPHAGE alone or
`
`GLUCOPHAGE plus a sulfonylurea should be considered.
`
`If. after a suitable trial of such treatments, glucose control still has not been
`
`achieved, consideration should be given to the use of insulin. Judgments should
`
`be based on regular clinical and laboratory evaluations.
`
`December 29, 1984
`
`- 12 -
`
`0025
`
`

`
`REVISED PACKAGE INSERT
`
`GLUCOPHAGE• (mefforrrain hydrochloride tablets) — 500 mg and WO mg
`
`CONTRAINDICATIONS:
`
`GLUCOPHAGE is contraindicated in patients with:
`
`1.
`
`Renal disease or renal dysfunction (e.g_ as suggested by serum creatinine
`
`levels a-1.5 mg/dt_ [males], a1.4 mg/cit. (females) or abnormal creatinine
`
`clearance) which may also result from conditions such as cardiovascular
`
`collapse (shock), acute myocardial infarction, and septicemia (see
`
`WARNINGS and PRECAUTIONS).
`
`2.
`
`GLUCOPHAGE should be temporarily withheld in patients undergoing
`
`radiologic studies involving parenteral administration of iodinated contrast
`
`materials, because use of such products may result in acute alteration of
`
`renal function_ (See also PRECAUTIONS).
`
`3.
`
`Known hypersensitivity to metformin hydrochloride_
`
`4.
`
`Acute or chronic metabolic acidosis, including diabetic ketoacidosis, with
`
`or without coma. Diabetic ketoacidosis should be treated with insulin.
`
`December 29, 1994 (cid:9)
`
`- 13 -
`
`0026
`
`

`
`REVISED PACKAGE INSERT
`
`GLUCOPHAGE• (metformin hydrochloride tablets) — 500 mg and 1150 mg
`
`WARNINGS
`
`Lactic Acidosis:
`Lactic acidosis is a rare, but serious, metabolic complication
`
`that can occur due to metformin accumulation during treatment
`
`with GLUCOPHAGE; when it occurs, it is fatal in approximately
`
`50% of cases.. Lactic acidosis may also occur in association
`with a number of pathophysiologic conditions, including
`
`diabetes mellitus, and whenever there is significant tissue
`hypoperfusion and hypoxemia. Lactic acidosis is characterized
`
`by elevated blood lactate levels (>5 mmol/L), decreased blood
`
`pH, electrolyte disturbances with an increased anion gap, and an
`
`increased lactate/pyruvate ratio. When metformin is implicated
`as the cause of lactic acidosis, metformin plasma levels >5
`
`pg/mL are generally found.
`
`The reported incidence of lactic acidosis in patients receiving
`metformin hydrochloride is very low (approximately 0.03
`cases/1,000 patient-years, with approximately 0.015 fatal
`cases/1,300 patient-years). Reported cases have occurred
`primarily In diabetic patients with significant ren