CENTER FOR DRUG EVALUATION AND RESEARCH

AIroval Package for:

APPLICATION NUMBER:

15-034 / S- 034

Trade Name: Ponstel

Generic Name: mefenamic acid capsules

Sponsor: Parke Davis

Approval Date: October 4, 2001

-"-I "

CENTER FOR DRUG EVALUATION AND RESEARCH

APPLICATION NUMBER:

15-034 / S- 034

CONTENTS

I Reviews / Information Included in this NDA Review. I

Approval Letter XApprovable LetterLabelin2 XMedical Review( s) XChemistry Review(s)

Pharmacology Review(s)Statistical Review(s)Microbiolo2Y Review(s)

Clinical Pharmacoloev/ Biopharmaceutics Review(s)Administrative/Correspondence Document(s)

(.

CENTER FOR DRUG EVALUATION AND RESEARCH

APPLICATION NUMBER:

15-034 / S- 034

APPROVAL LETTER

DEPARTMENT OF HEALTH & HUMAN SERVICES Public Health Service

Food and Drug AdministrationRockvile MD 20857

NDA 15-034/8-034

Parke-DavisAttention: James A. Parker, Jr.Director, Advertising and LabelingWorldwide Regulatory Affairs201 Tabor RoadMorris Plains, NJ 07950

Dear Mr. Parker:

Please refer to your supplemental new drug application dated August 14, 1998, received August 17,1998, submittedunder section 505(b) of the Federal Food, Drug, and Cosmetic Act for Ponstel(mefenamic acid) Capsules, 250 mg.

We acknowledge receipt of your submission dated August 14, 1998.

This supplemental new drug application provides for additions to the package insert to add a GeriatricUse subsection in accordance with 21 CFR 201.57(f)(1O).

We have completed the review of this supplemental application, as amended, and have concluded thatadequate information has been presented to demonstrate that the drug product is safe and effective for useas recommended in the agreed upon labeling text. Accordingly, the supplemental application isapproved effective on the date of this letter.

The final printed labeling (FPL) must be identical to the submitted draft labeling (package insertsubmitted August 14, 1998).

Please submit the copies of final printed labeling (FPL) electronically according to the guidance forindustry titled Providing Regulatory Submissions in Electronic Format - NDA (January 1999).Alternatively, you may submit 20 paper copies of the FPL as soon as it is available but no more than 30days after it is printed. Please individually mount ten of the copies on heavy-weight paper or similarmateriaL. For administrative purposes, this submission should be designated "FPL for approvedsupplement NDA 15-034/8-034." Approval of this submission by FDA is not required before thelabeling is used.

NDA l5-034/S-034Page 2

If a letter communicating important information about this drug product (i.e., a "Dear Health CareProfessional" letter) is issued to physicians and others responsible for patient oare, we request that yousubmita copy of the letter to this NDA and a copy to the following address:

MEDWATCH, HF-2FDA5600 Fishers LaneRockvile, MD 20857

We remind you that you must comply with the requirements for an approved NDA set forth Under 21 CFR314.80 and 314.81.

If you have any questions, call Carmen DeBellas, Regulatory Project Manager, at (301) 827-2090.

Sincerely,

(.S'ee appended electronic signature page)

Jonca Bull, M.D.Acting Director

Division of Anti-Inflammatory, Analgesic and OphthalmicDrug ProductsOffce of Drug Evaluation VCenter for Drug Evaluation and Research

--------------------------------------------------------------------------------------------------------This is a representation of an electronic record that was signed electronically andthis page is the manifestation of the electronic signature.--------------------------------------------------------------------------------------------------------

/s/Janca Bull10/4/01 10:34:52 AM

CENTER FOR DRUG EVALUATION AND RESEARCH

APPLICATION NUMBER:

15-034 / S- 034

LABELING

-'

4-4

Ponstel0540G152

I I1I11I1

'~,,""

~':4ïi,.;.t .-.

3.~

~

) . ~ .

PonstelC!(Mefenamic Acid) .

¡

DESCRIPTION

Ponstel (mefenamic acid) is N-(2,3-xylyl)-anthranilc acid. It is an analgesic agent fororal administration. Ponstel is available in cap-sules containing 250 mg of mefenamic acid.Each capsule also contains lactose, NF. Thecapsule shell and/or band contains citric acid,USP;D&C yellow No. 10; FD&C blue No.1;FD&C red No.3; FD&C yellow No.6; gelatin,NF; glycerol monooleate; silicon dioxide, NF;sodium benzoate, NF; sodium lauryl sùlfate,NF; titanium dioxide, USP. The structural for~mula of mefenamic acid is: '

O:::OH§ t

CH3 CH3

It is a white powder with a meiting point of230°-231°C, iìolecularweight 241.28,andwater solubility of 0.004% at pH 7.1.

CLINICAL PHARMACOLOGY

~~!EI' is_~ .n~r:~te.~~id~L a~D,t-.i!~.d~e.'!()ii.-

'. .,",

&t~~~~~,&~g~~~:$7~1f~~~f~%;,:£~, ;J¡CLINICAL PHARMACOLOGY

Ponste/is a nonsteroidal agent with demon-strated antiinflammatory, analgesic, andantipyretic activity in laboratoiyanimalsYThe mode of action is notknown.ln animalstudies,Ponstel wasJoûnd to inhibitprostaglandin synthesis arid to compete forbinding at the prostaglandin receptor site.'

Pharmacologic studies show Ponstel did notrelieve morphine abstinence signs in absti-nent, morphine-habituated monkeys.'

Following a single 1-gram oral dose, peakplasma levels of 10 IJg/mL occurred in 2 to 4hours with a half-life of 2 hours. Followingmultiple doses, plasma levels are proportion-al to dose with no evidence of drug accumu-lation. One gram of Ponstel given four timesdaily produces peak blood levels of 20 IJg/mLby the second day of administration;'

Following a single.dose, sixt-seven percentof the total dose is excreted in the urine asunchanged drug or as one of two metabo-lites. Twenty to twenty-five percent of thedose is excreted in the feces during the firstthree days.'

In controlled, double-blind, clinical trials,Ponstel was evaluated for the treatment ofprimary spasmodic dysmenorrhea. Theparam-eters used in determining efficacy includedpain assessment by both patient and investi-gator; the need for concurrent analgesic med-ication; and evaluation of change in frequen-cy and severity of symptoms characteristic ofspasmodic dysmenorrhea. Patients receivedeither Ponstel,500 mg(2 capsules) asan ini-tial dose of 250 mg every 6 hours, or placeboat onset of bleeding or of pain, whicheverbegan first. After three menstrual cycles,patients were crossed overto the alternatetreatment for an additional three cycles.Ponstel was significantly superior to placeboin all-parameters, and both treatments (drugand placebo) were equally tolerated.

'.

)

INDICATIONS AND USAGE r.

Ponstel is indicated for the relief of moderatepain' when therapy wil not exceed one week.Ponstel is also indicated for the treatment ofprimary dysmenorrhea....

Studies in children under 14 years (~agehave been inadequate to evaluate the safetyand effectiveness of Ponstel.

CONTRAINDICATIONS

Ponstel should not be used in patients whohave previously exhibited hypersensitivity toit.

Because the potential exists forcross-sensi-tivity to aspirin or other nonsteroidal antiin-flammatory drugs,Ponstelshould not begiven to patients in whom these drugs inducesymptoms of bronchospasm, allergic rhinitis,or urticaria.

Ponstel is contraindicated in patients withactive ulceration or chronic inflammation ofeither the upper or lower gastrointestinaltract.

Ponstel should be avoided in patients withpreexisting renal disease.

'-

-""""",,.;;""i'

WARNINGS

If diarrhea occurs, the dosage should bereduced or temporarily suspended (seeADVERSE REACTIONS and DOSAGE ANDADMINISTRATION). Certain patients whodevelop diarrhea may be unable to toleratethe drug because of recurrence of thesymp-toms on _ subsequent exposure,

Risk ofGI Ulceration, Bleeing andPerforation with NSAID Therapy: Seriousgastrointestinal toxicity, such as bleeding,ulceration, and perforation, can óccu':at anytime, with or without warning symptÒms, inpatients treated chronically with NSAID ther-apy. Although minor upper gastrointestinalproblems, such as dyspepsia! are common,usually developing early in therapy,(thysi-cians should remain alert for ulceration and

-- bleeding in patients treated chronically withNSAIDseven in the absence of previous GItract symptoms. In patients observed in clini-cal trials of several months to two years dura-tion, symptomatic upper GI ulcers, grossbleeding, or perforation appear to occur inapproximately 1% of patients treated for 3-6months, and in about 2-4% of patients treatedfor one year. Physicians should informpatients aboutthe signs and/or symptoms ofserious GI toxicity and what steps to take ifthey occur.Studies to date have not identified any subsetof patients not at risk of developing pepticulceration and bleeding. Except for a priorhistory of serious GI events and other riskfactors known to be associated with pepticulcer disease, such as alcoholism, smoking,etc, no risk factors (eg, age, sex) have beenassociated with increased risk. Elderly ordebiltated patients seem to tolerate ulcera-tion or bleeding less well than other individu-als and most spontaneous repprts offatal GIevents are in this population. Studies to dateare inconclusive concerning the relative riskof various NSAIDs in causing such reactions.High doses of any NSAID probably carry agreater risk ofthese reactions, although con-trolled clinical trials showing this do not existin most cases. In considering the use of rela-tively large doses (within the recommendeddosage range), sufficient benefit should be -anticipated to offset the potential increasedrisk of GI toxicity.

PRECAUTIONS

If rash occurs, administration of the drugshould be stopped.A false-positive reaction for urinary bile,using the diazo tablet test, may result aftermefenamic acid administration. If biluria issuspected, other diagnostic procedures, suchas the Harrison spot test, should be per-formed. -Renal Effec: As with other nonsteroidalantiinflammatory drugs, long.term adminis-tration of mefenamic acid to animals hasresulted in renal papilary necrosis and otherabnormal renal pathology. In humans, therehave been reports of acute interstitial nephri-tis with hematuria, proteinuria, and occasion-ally nephrotic syndrome.

")

",'

h_'_'_ ~ __~ _,~.-~__,-,_,~,-;~~,-":"..._,,,,.:-,;_,.:v._.:_~.,,..~_:.;,,.__

" -

~~~~;;~~~-J~~~~_1ier~~T;i"~¥ " .

A second form of renal toxicity has been seen .".'

in patients with prerenal conditions leadingto a reduction in renal blood flow or bloodvolume, where the renal prostaglandins have

a supportive role inthemaintenance of renalperfusion. In these patients administration ofan NSAID may cause a dose-dependentreduction in prostaglandin formation andmay precipitate overt renal decompensation.Patients at greatest risk of this reaction arethose with impaired renal function, heart fail-

" . ;

ure, liver dysfunction, those taking diuretics,and the elderly. Discontinuation of NSAIDtherapy is typically followed by recovery tothe pretreatment state.Since Ponstel is eliminated primarily by thekidneys, the drug should not be administeredto patients with significantly impaired renalfunctions. 'As with other nonsteroidal antiinflammatorydrugs, borderline elevations of one or moreliver tests may occur in some patients. Theseabnormalities may progress, may remainessentially unchanged, or may be transientwith continued therapy. The SGPT (AL T) test

,.

is probably the most sensitive indicator ofliver dysfunction. Meaningful (3 times theupper limit of normal) elevations of SGPT orSGOT (AST) occurred in controlled clinical tri-als in less than 1 % of patients. A patient withsymptoms and/or signs suggesting liver dys-function, or in whom an abnormal liver testhas occurred, should be evaluated for evi-

" .

dence of the development of more severehepatic reaction while on therapy withPonstel. Severe hepatic reactions, includingjaundice and cases of fatal hepatitis~.,avebeen reported with other nonsteroijJl antiin-flammatory drugs. Although such reactionsare rare, if abnormal liver tests persist orworsen, if clinical signs and symptoms con- ")

sistent with liver disease develop; or if sys-temic manifestations occur (eg, eosinophila, . "

rash, etc), Ponstel should be discontinued.Information for Patients: Patients should beadvised that if rash, diarrhea, or other diges-tive problems arise, they should stop thedrug and consult their physician.

Patients in whom aspirin or other non-steroidal antiinflammatory drugs inducesymptoms of bronchospasm, allergic rhinitis,or urticaria should be made aware that thepotential exists for cross-sensitivity toPonste!.

The long-term effects, if any, of intermittentPonstel therapy for dysmenorrhea are notknown. Women on such therapy should con-sult their physician if they should decide to

' . . . . .

become pregnant.

PARKE-DAVIS

Ponstel (Mefenamic Acid)

Ponstel,"1j;:ke other drugs of its class, is not

free ofs\~e effects: The side effects ofthesedrugs can cause discomfort and, rarely, thereare more serious side effects, such as gas-trointestinal bleeding, which may result inhospitaliz~tion and even fatal outcomes.

NSAIDs (nonsteroidal antiinflammatorydrugs) are often essential agents in the man-agement of arthritis and have a major role inthe treatment of pain, but they also may becommonly employed for conditions whichare less serious.

Physicians may wish to discuss with theirpatients the potentiaLrisks (see WARNINGS,PRECAUTIONS,and ADVERSE REACTIONSsections) and likely benefits of NSAID treat-ment, particularly when the drugs are usedfor less serious conditions where treatmentwithoutNSAIDs may represent an acceptablealternative to both the patient and physician~

Laboratory Tess: Because serious GI tractulceration and bleeding can'occur withoutwarning symptoms, physicians should followchronically treated patients for the signs andsymptoms ofulceration and bleeding andshould inform them of the importance of thisfollow-up (see Risk of GI Ulceration, Bleedingand Perforation with NSAID Therapy).

Drug Interact.ions: Ponstel may prolong pro-thrombin time.' Therefore, when the drug isadministered to patients receiving oral anti-coagulant drugs, frequent monitoring of pro-thrombin time is necessary.

Use in Pregnancy: Pregnancy Category C.Reproduction studies have been performedin rats, rabbits, and dogs. Rats given up to 10times the human dose showed decreased fer-tility, delay in parturition, and a decreasedrate of survival to weaning. Rabbits at 2.5times the human dose showed an increase inthe number of resorptions. There were nofetal anomalies observed in these studies norin dogs at up to 10 times thê human dose.'

There are no adequate and well-controlledstudies in pregnant women. 8ecauseanimalreproduction studies are not always predic-tive of huma.n response, this drug should beused only if clearly needed.

The use of Ponstelin late pregnancy is notrecommended because "of the effects on thefetal cardiovascúlar system of drugs of thisclass. .

")

',.' .

Nursing Mothers: Trace amounts of Ponstelmay be present in breast milk and transmit-ted to the nursing infant'; thus, Ponstel . .should not be taken by the nursingrnotherbecause of the effects on the infant cardio-vascular system of drugs of this class~

Use in Children: Sàfety and effectiveness inchildren below the age of 14 have not beenestablished.

ADVERSE REACTIONS

Gastrointesinal: The most frequently report-èd advèrse reactions assoCiated With the useof Ponstel involve the gastrointestinal tract. Incontrolled studies for up to eight months, thefollowing disturbances were reported indecreasing order of frequency: diarrhea(approximately 5% of patients), nausea withor without vomiting, other gastrointestinalsymptoms, and abdominal pain.

In certain patients, the diarrhea was of suffi-cient severity to require discontinuation ofmedication. The occurrence oHhediarrheaisusually dose related, generally subsides onreduction of dosage, and rapidly disappearson termination of therapy.

Other gastrointestinal reactions less frequent-ly reported were anorexia, pyrosis, flatulence,and constipation.

Gastrointestinal ulceration with and withouthemorrhage has been reported.

Hematopoietic: Cases ofautoimmunehemolytic anemia have beenassociated withthe continuous administration òf POhstel for12 months or longer. In slJch cases the .

Coombs test results are positive with evi-dence of ßoth accelerated RBC productionand RBC destruction. The process isreversiblë upon termination of Pónsteladministration. ")

Decreaslis in hematocrit have been noted in2%-5% clJpatients and primarily in those whohave received prolonged therapy. Leukopenia,

eosinophila, thrombocytopenic purpura,agranulocytosis, pancytopenia, and bonemarrow hypoplasia have also been reportedon occasion.

Nervous System: Drowsiness, dizziness, ner-vousness, headache, blurred vision, andinsomnia have occurred.Integumentary: Urticaria, rash, and facialedema have been reported.

Renal: Aswith other nonsteroidal antiinflam-matory agents, renal failure, including papil-lary necrosis, has been reported. In elderlypatients renal failure has occurred aftertak-ing Ponstel for 2-6 weeks. The renal damagemay not be completely reversible. Hematuriaand dysuria have also been reported with

Ponstel.

Other: Eye irritation, ear pain, perspiration,mild hepatic toxiCity, and increased need forinsulin in a diabetic have been reported.There have been rare reports of palpitation,dyspnea, and reve,rsible los50f coloryision.

" "

l\'¡X:':3:~"::-;':;'-"7:';'X-..""-l~~'"l¡~"'::::,,=S;'"7t_:- _.~",;q_ -"~"'"':. "._~,.--" -,

OVERDOSAGE'

AltilQUgl1 doses upto 6000 mg/day havebeen 'given, no specific information is avail-able on the management of acute massive

"overdosage. ShOüld accidentaloverdosageoccur, the stomach should be emptied byinduciniemesis or by careful gastric lavagefollowet.by the administration of activatedcharcoal.~ Laboratory studies indicate thatPonstel should be adsorbed from the gas-trointestinal tract by activated charcoaL.' Vital

funotionsshould be monitored and support-ed. Beca9se mefenamic acid and its metabo-lites are firmlybound to plasma proteins,hemodialysis and peritoneal dialysis may beof little value.'

DOSAGE AND ADMINISTRATION

,Administration is by the oral route, preferablywith food. .The recommended regimen in acute pain foradults and children over 14 years of age is500 mg as an initial dose followed by 250 mgevery six hours as needed, usually not toexceed one week.s

For the treatment of primary dysmenorrhea,the recommended dosage is 500 mg as aninitial dose followed by 250 mg every 6hours, starting with the onset of bleeding andassociated symptoms. Clinical studies indi-cate that effective treatment can be initiatedwith the start of menses and should not benecessary for more than 2 to 3 days."

HOW SUPPLIED

N 0071-0540-~4 (P-DS40) Ponstel (mefenamicaçid) is available as 250 mg capsules in bot-t1es of 100.

REFERENCES

1. WinderCV, et al: Antiinflammatory,antipyretic and antinociceptive properties ofN~(2,3-xylyl) anthranilic acid (mefenamicaCid). J Pharmacol Exp Ther 138: 405-413,1962.

2. Wax J, et al: Comparative aètivities, toler-ances and safety of nonsteroi(j.al antiinflam-matory agents in rats. J Pharmacol Exp Ther192: 172-178,1975.

3. Ferreira SH, Vane JR: Aspirin andprostaglandins, in The Prostaglandins,Ramwell PW Ed, Plenum Press, NY, vol. 2,1974, pp 1-47.

4. Glazko AJ:Experimental observati6ns offlufenamic, mefenamic, andmeclofenamicacids. Part Iii. Metabolic disposition, inFenamates in Medicine, A Symposium,London 1966; Annals of Physical Medicine,supplement, pp23-36; 1967.

Data on file, Mediçal Affairs Dept. Parkè-

)

'.

'..' .

m:~r~~5~:R;""''::'_~¡;;'';':f.:Iz:e:-',~,-''_-'_'''''_'~:V:d:~:;~~~~$"?Ì'd-"-'~~:,y-'i\,;;",;_"

6. Budoff PW:Use of mefenamic acid in thetreatment of primary dysmenorrhea. JAMA241: 2713-2716,1979.

7.BuchananRA et al: The breast milk excre-tion of mefenamic acid. Curr Ther Res 10:592,1968.

8. Corby DG. Decker WJ: Management ofacute poisoning with activated charcoaL.

Pediatrics 54:324, 1974.

Direct Medical Inquiries to: Parke-DavisDiv of Warner-Lambert Co. 201 Tabor RoadMorris Plains, NJ 07950An: Medical Affairs Department

Caution-Federal law prohibits dispensingwithout prescription.

~

.ii )

0540G152

Revised May 1995

(g 1995, Warner-Lambert Co.

PARKE-DAVISDiv of.Warner-Lambert CoMorris Plains, NJ 07950 USA

G9~ÐOv90-~.-~-------.. . 0' '

'... .

.'1:(0c:..(U

.

~~::~

..~ ~

.~.~,ct .,~ ~

'..rJ ..~"¡p-C

l/::,..~.,.....'.p'

/Q$..~

E.

0'.:9tn. u'~'--

!. .~

~..§i= i=

o~~

ij::'-

-*2\8 ';";~~_:',.i

, ii ~~

ii¡iili~iii¡i III ¡ hll

~ f~~"aJM

lS!OW

WO

Ji ioaiOJd "C

:o98-o6S)O

oOE

-..St. 8JnieJadwai W

,OO

Jpanoiiuoo i~ .uois'dsn Ð

lll u! pauuap SB JaU

IBlU

OO

l1I6ii B U

! a~uads!a

~rooi

IF~c:¿,..in9;:ooZ

.. '0

CU

.-.. ~ C'

0.2 E

C ~

O0$ inc. i C\

~.~12v

'" ¿'" 0

~:l~~~~-g.ju. co

g.~;'lf:i Q

.8:6

15~~~l~

Dose-A

dults and children over 14 years of age: 500 mg

as an initial dose, followed by 250 m

g at six-hour intervals.S

ee package insert.T

he blue bandon iVO

ly.capsule combination is a trdem

arKof W

arner-Lambert C

o.K

apseals-Registered tradem

ark.K

eep this and all drugs out of the reach of children.

Lot

Exp. date

0540G035

./

" ~

A

CENTER FOR DRUG EVALUATION AND RESEARCH

APPLICATION NUMBER:

15-034 / S- 034

ADMINISTRATIVE and CORRESPONDENCEDOCUMENTS

Labeling and Clinical Review of Supplemental Labeling Revisions (SLRs):

Sponsor: Parke-Davis Pharmaceutical

Products: Ponstelil (mefenamic acid) Capsule, 250mg

Materials Reviewed:

NDA 15-034 (Capsule):SLR Date submitted034 August 14, 1998 Date received

August 17, 1998Date completedSeptember 13, 2001

Background:On August 14, 1998, Parke-Davis Pharmaceuticals sent a letter to the agency stating thatthey had added the proper labeling for geriatric use as explained in 21 CFR 201.57(f)(10).The manufacture has complied with 21 CFR 20l.57(f)(10), which describes theappropriate use of drugs in the elderly. The manufactured also complied with subsectionsCFR 201.57(f)(lO)(ii)(A); CFR 201.57(f)(10)(iii)(B); CFR 201.57(f)(l0)(iv). Thesesubsections deal with what to state if there were not suffcient numbers of subjects aged65 and older, if the drug is excreted substantially in the kidney and if the drug causes aspecific hazard, respectively.

Conclusions/Recommendations:These labeling changes are acceptable. An approval letter should be sent advising the applicantthat these supplemental NDA submissions be approved.

Melanie Simmons Pharm D (C)University of Iowa

--------------------------------------------------------------------------------------------------------This is a representation of an electronic record that was signed electronically andthis page is the manifestation of the electronic signature.--------------------------------------------------------------------------------------------------------

/s/Mary Jane Waii ing10/3/01 12: 04: 30 PMCSO

Mary Jane Walling10/3/01 12: 05: 01 PMCSO