CENTER FOR DRUG EVALUATION AND
`
`RESEARCH
`
`APPLICA TION NUMBER:
`
`75028
`
`APPROVAL LETTER
`
`

`

`ANDA 75-028
`
`JUL 20 1998
`
`Keller and Heckman
`Attention:
`John Dubeck
`U.S. Agent for: Biovail Laboratories,
`1001 G Street N.W., Suite 500 West
`Washington, DC
`20001
`
`Inc.
`
`Dear Sir:
`
`This is in reference to your abbreviated new drug application
`dated December 16, 1996, submitted pursuant
`to Section 505(j) of
`the Federal Food, Drug, and Cosmetic Act, for Pentoxifylline
`Extended-release Tablets, 400 mg.
`
`Reference is also made to your amendments dated October 29, 1997;
`and February 12, April 9, June 15, June 17, and July 10, 1998.
`
`We have completed the review of this abbreviated application and
`have concluded that the drug is safe and effective for use as
`recommended in the submitted labeling. Accordingly,
`the
`application is approved.
`The Division of Bioequivalence has
`determined your Pentoxifylline Extended—release Tablets, 400 mg
`to be bioequivalent and,
`therefore,
`therapeutically equivalent to
`the listed drug (Trental® Tablets, 400 mg, of Hoechst Marion
`Roussel, Inc.). Your dissolution testing should be incorporated
`into the stability and quality control program using the same
`method proposed in your application.
`
`Under 21 CFR 314.70, certain changes in the conditions described
`in this abbreviated application require an approved supplemental
`application before the change may be made.
`
`Post-marketing reporting requirements for this abbreviated
`The
`application are set forth in 21 CFR 314.80-81 and 314.98.
`Office of Generic Drugs should be advised of any change in the
`marketing status of this drug.
`
`in duplicate, any proposed
`We request that you submit,
`advertising or promotional copy which you intend to use in your
`initial advertising or promotional campaigns. Please submit all
`proposed materials in draft or mock-up form, not final print.
`
`

`

`Page 2
`
`Submit both copies together with a copy of the proposed or final
`printed labeling to the Division of Drug Marketing, Advertising,
`and Communications (HFD—40). Please do not use Form FD—2253
`(Transmittal of Advertisements and Promotional Labeling for Drugs
`for Human Use)
`for this initial submission.
`
`We call your attention to 21 CFR 314.81(b)(3) which requires that
`materials for any subsequent advertising or promotional campaign
`be submitted to our Division of Drug Marketing, Advertising, and
`Communications
`(HFD—40) with a completed Form FD—2253 at the time
`of their initial use.
`
`Sincerely yours,
`/7
`.
`
`/S/
`//
`Douglas L. SpSEh
`7-2.5 ~93.
`Director
`Office of Generic Drugs
`Center for Drug Evaluation and Research
`
`,
`
`6/
`
`

`

`CENTER FOR DRUG EVALUATION AND
`
`RESEARCH
`
`APPLICA TION NUMBER:
`
`75 02 8
`
`DRAFT FINAL PRINTED LABELING
`
`

`

`Pe‘ntoxitylline”
`
`Extended-release Tablets, ‘00 mg
`
`Discfilfllfltl
`Pentoxitylline Extendederelease Tablets tor oral administration. contains 400 m?
`at the active drug and the Mowing inactive ingredients: tiydroiryeth
`cellulose N .
`povidone USP, talc USP. magnesrum stearate NF, isopropyl also ol USP_ in an
`extended-release lorrnulation. Panto '
`ine is a tri-substitoted xanthine derivative
`desr hated chemically as 3.74ihydro-3J-dime
`l-l-[5-oxohexyI)-tH-puririe-
`2,6 tone that, unlike ttieoptiylline. is a hemormeo ogic agent. i.e. an agent that
`attests blood viscosity. Pentoxitylline is lreely soluble in chlorolorm, soluble In
`water and soluble in methanol
`The structural formula is:
`
`i“
`o
`it
`NW
`CH;CCH;CH,CH;CH7\N ll
`l
`I
`1\
`04 N I"
`lCH;
`
`Molecular weight. 278,31
`Molecular lormula: Culluflim
`culthAL PHARMACOtOGY
`
`Mode at Action. Pentoxilylline and its metabolites improve the flow properties oi
`blood by decreasing its viscosrty In
`tients With chronic peripheral arterial dis-
`ease, this increases blood flow tot e attected microcirculation and enhances
`tissue oxygenation. The precise mode at action ol pentoxitylline and the sequence
`ot events lead-no to clinical improvement are still to be defined. Pentoxiaélcme
`administration tias been shown to produce dose related hemorrheolopic e
`s,
`lowering blood viscosity. and improving erythrocyte llexrbility. Leukocyte proper
`ties ol hemorrheologic importance have
`een modilied in animal and in vitro
`human studies. Pentoxitylline has been shown to Increase leuk
`e delormabiiily
`and to inhibit neutrophil adhesion and activation. Tissue oxyoen evels have been
`shown to be significantly increased by therapeutic doses ol pentoirilylline in
`patients with peripheral arterial disease.
`Hiannaooliinetir: and Metabolism. After oral administration in aqueous solu-
`tion pentoxitylline IS almost completely absorbed It undergoes a first<pass ellect
`and the various metabolites appear in plasma very soon atter dosing Peak
`asrna levels at the parent compound and its metabolites are reached within t
`ur. The rnaior metabolites are Metabolite l (l-[S—hydroxyhexyl ~3,7-dimettiylx-
`anthine] and Metabolite V (1-[3<carboxypro yttIlJ-dimethy xanthine), and
`plasma levels at these metabolites are 5 and
`times greater, respectively. than
`penloxilylline,
`
`Following oral administration ol aqueous solutions containing 100 to 400 mg ot
`pentoxitylline, the pharmaookinetics ol the parent compound and Metabolite l are
`dose-related and not proportional (non-linear), with halt-lite and area under the
`blood-level time curve (AUC) increasi
`with dose. The elimination kinetics ol
`Metabolite V are not dose-
`ndent.
`apparent plasma battalile ol pentoiii-
`fylline vanes trom 0 4 to 0. hours and the apparent plasma hall-lives ol its
`metabolites vary trom t to 1.6 hours. There is no evidence at accumulation or
`enzyme induction (mochrome Pm) lollowmg multiple oral doses.
`Excretion is almost totally urinary; the main biotranslormation roduct is
`Metabolite V. Essentially no parent drug is round in the urine. Despite
`rue varia-
`tions in plasma levels of parent compound and its metabolites, the urinary
`recovery of Metabolite V is consistent and shows dose proportionality Less than
`4% ot the administered dose is recovered in feces, Food intake shortl before
`dosing delays absorption ol an immediate-release dosage term but oes not
`attest total absorption The pharmaeolrinetics and metabolism ol Pentoxitytline
`Extended-release Tablets have not been studied in patients with renal and/or
`hepatic dystunction, but AUC was increased and elimination rate decreased in an
`older population (60-68 years] compared to younger indiwduals (22% years),
`After administration at the 400 mg extendedrelease pentoxlly‘iline tablet~ plasma
`levels at the parent compound and its metabolites reach their rriaxmta within 2 to
`4 hours and remain constant over an extended period at time, Coadministration
`ol Pentoxilylline extended-release tablets with meals resulted in an increase in
`mean (2m and AUC by about 28% and l3% lor pentoxrlylline, respectively, Cw
`tor metabolite M1 also increased by about 20% The controlled release or pentox—
`ilylline lrom the tablet eliminates peaks and troughs in plasma levels tor improved
`gastrointestinal tolerance
`
`
`
`

`

`INDICATIONS "In USAGE
`
`.
`
`Pentoxilylline mended—release Tablets are indicated tor the treatment of patterns
`wrth intermittent claudrcabon on the basis 0! chronic occlusive arterial disease at
`the limbs. Pen onlyllme Extended-release Tablets can improve tunction and
`lh
`.
`
`CONTRAINDICATIONS
`
`Pentoxilyttine Extended-release Tablets should not be used in patients with recent
`cerebral and/or retinal hemorrhage or in patients who have previously exhibited
`ammo.
`intolfince to this product or methytxanthmes such as caffeine. theoohytline, and
`
`inhibitors..Patientsvon warfann should have more frequent monitoring 0 our
`nto ‘
`line
`
`closely monitore
`'
`'
`evels and theoplylline toxicity in some individuals. Such patient shou d be
`
`have been observed in some patients tmted with periton'lylline; periodic sys-
`temic blood pressure monitoring is recommended tor patients receiving
`agents should be reduced.
`concomitant antihypenensive therapy. It indicated. dosage ol the antihypertensive
`Carcinogenesis. Intermix. lmpalnnant at Fertility: Lonqtenn studies or the
`carcrnogemc potentia ot bentoxilyiline were conducted In mice and rats by
`dietary administration at the data at doses up to 450 mg/kq (approximately 19
`times the maximum recommended human dail dose (MRHD) in both species
`
`Pregnancy Teratogenic Ettects: Pregnancy Category [2. Teratooenicity studies
`have been performed in rats and rabbits. using oral doses up to 576 and 264
`mqr‘ko. respectivel . On a weight basis, these doses are 24 and 11 times the max
`imum recommend; human dai
`dose MRHD. On a hody-surtacearea basis.
`they are 4.2 and 3.5 times the
`RHD.
`o evi ence oi fetal malformation was
`observed. increased resorption was seen in rats of the 576 mg/lio rouprhere
`are no adequate and well controlled studies in ore nant women.
`entoxilylhne
`ris
`to the etus.
`shguld he used dunhg pregnancy onty it the poten
`heneiit iustilies the potential
`Nursing Mothers. Pentoio'lyiline and its metabolites are excreted in human mint.
`Bemuse ol the potenbal tor tumongenicity shown Ior pemoerline In rats, a decr-
`sion should be made whether to discontinue nursing or discontinue the drug.
`taking into account the importance ol the dmg to the mother.
`fished.
`Pediatric Use: Safety and effectiveness in pediatric oahents have not been estatr
`\
`
`

`

`ADVERSE REACHOIIS
`
`Clinical trials were conducted using either emnded-release oentodmline tablets
`tor up to 60 weeks or immediate-release pentoxiiyiline capsules
`r up to 24
`weeirs.Dosaperanpesinttielabletstudiesweremnigbidtotidandinttieeap—
`sule studies. 200 to 4(1)
`lid. The table summarizes the incidence (In percent)
`of adverse reactions consi ered drug related, as well as the numbers at patients
`who received unaided-release pentoxity‘line tablets, irnmediaterelease pentoxi-
`tylline capsules, or the corresponding placebos. The incidence at adverse
`reactions was higher in the capsule studies (where dose related increases were
`seen in digestive and nervous system side eltects) than in the tablet studies.
`Studies with the capsule include domestic experience. whereas studies with the
`encoded-rem tablets were conducted outsrde the US. The table indicates that
`in the tablet studies tew patients discontinued because ol adverse eflects.
`
`INCIDENCE l'l-l Of SIDE EFFECTS
`Hunted-Helene humane-Helene
`Toilets
`Caps-In
`til-Ion tor
`humility comm llnleu
`Trials
`billable
`Ml line
`lino
`Pent“
`Emmd
`d
`Release
`Release
`Ilttllts Flam. Glpuln Placebo
`
`0.3
`—
`—
`
`-—
`0.6
`—
`2.8
`2.2
`1.2
`
`(321)
`[Nos.otPa1ierrtsatrisk)
`Discontinued tor Side Eltect 3.1
`CARDIOVASCULAR SYSTEM
`'na/Chest Pain
`A
`mia/Palpitation
`Hus ing
`DIGESTIVE SYSTEM
`Abdominal Discomtort
`Belohingr‘Flatus/Bloating
`Diarrhea
`Dyspepsia
`Nausea
`Vomiting
`NERVOUS SVSTEM
`Agitation/Nervousness
`Dizziness
`Drowsiness
`Headache
`Insomnia
`Tremor
`Blurred Vision
`
`——
`1.9
`—
`1.2
`——
`0,3
`—
`
`[128)
`0
`
`(177)
`9.6
`
`(138)
`7.2
`
`—
`—
`
`-—
`—
`—
`4.7
`0 8
`—
`
`——
`3.1
`—
`1.6
`—
`0.8
`—
`
`1.1
`t 7
`2.3
`
`4.0
`9.0
`3.4
`9.6
`28 B
`4.5
`
`1.7
`11.9
`1.1
`6.2
`2.3
`—
`2.3
`
`2.2
`0.7
`0.7
`
`1.4
`3.6
`2.9
`2.9
`B]
`0.7
`
`0.7
`4.3
`5.8
`5 8
`2.2
`—
`1.4
`
`Pentoxityitrne Extended—release Tablet has been marketed in Europe and else»
`where srnce 1972. in addition to the above symptoms. the following have been
`reported spontaneous
`since marketing or occurred in other clinical trials with an
`incrdenoe oi less than “lo; the causal relationship was uncertain:
`Cardiovascular. Dyspnea. edema. hypotension
`Digestive. Anorexia. cholecystitis. constipation, dry mouth/thirst.
`Nervous. Anxiety. contusion. depression. seizures,
`Respiratory. Epistaxis, nutrke symptoms, laryngitis, nasal congestion.
`Skin Ind Appendices Brittle fingernails, pruntus. rash. urticaria angioedema.
`Special Senses. Blurred Vision. coniunctivitis, earache. scotoma.
`Miscellaneous. Bad taste. excessive salivahon. leukopenia, malaise. sore
`throat/swollen neck glands. weight change.
`A law rare events have been reported spontaneously worldwide since marketing
`in 1972. Amougtt they occurred under oircumstames in which a causal relation-
`ship with pentrmtytline could not be established. they are listed to serve as
`intormation tor physicians, Cardiovascular — angina, arrhythmia, tachycardia,
`anaphytactoid reactions. 'Dioestive — hepatitis. iaundice, increased liver enzymes:
`and Heroic and Lymphatic - decreased serum hbrlnooen. pancytopenia, aptastic
`anemia. leukemia, purpura. thrombocytopenia.
`
`

`

`OVERDOSAGE
`Overdosage with Pentoxitylline Extended-release Tablet has been reported in
`pediatric patients and adults. Symptoms appear to be dose related. A report trom
`a porson control center on 44 patients taking overdoses or enteric~coated pentox-
`ilylline tablets noted that s mptoms usually occurred 4-5 hours alter ingestion
`and lasted about 12 hours. he tii hest amount ingested was 30 mglkt]; flushing.
`hypotensiori. convulsions. sent
`me. loss or consciousness. lever, and agita-
`n’on occurred All patients recovered,
`In add'nion to symptomatic treatment and gastric lavage. special attentim must
`be given to supporting respiration. maintaining systemic blood pressure. and
`controlling convulsions. Activated charcoal has been used to absorb pentoxra
`lylline in pan’eots who have overdosed.
`DOSAGE AND IDHIHLSTMTION
`The usual dosage oi pentoau'tylline in mended-release tablet lorrn is one tablet
`(#00 mg) three times a day with meals.
`While the etlect ot pentoxilylline may be seen within 2 to 4 weeks. it is record-
`mended that treatment he continued tor at least B weelrs Etlicacy has been
`demonstrated in double-blind clinical studies ol 6 months duration
`ll patients
`Digestive and central nervous system side eltects are dose related.
`develop these eftects it is recommended that the dosage be lowered to one tablet
`twice a
`(300 rug/day). It side ellects persist at this lower dosage. the admin-
`istration o Pentoxitylline Extended-release Tablets should be discontinued.
`HOW SUPPLIED
`
`Penlox'rlylline Extended-release Tablets. are available tor oral administration as
`400 mg white. oblonu. compressed tabets. engraved with WP on one side and
`31967;)?the other,tablets are unscored; supplied in bottles at 100 (NBC 0093-
`l
`Store at controlled room temperature l5°<3l)"c (SQ-86"?)
`Dispense in well-closed. tight~resistanl containers with salety closures
`Caution. Federal (U SM law protiib'os dispensing without prescription
`Manutactured lor:
`TEVA PHARMACEUHCALS USA
`Se1lersville, PA
`18960
`Manutactured W
`Biovail Corporation International
`Mississauga, Ontario
`Canada LSL 1J9
`Rev: W98
`
`,
`
`Lil-000300
`
`

`

`PRINTED CONTAINER LABELS
`
`«
`
`1
`
`.8on2.an23202:2=on:s:on
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`.535m_E;2:832:8=3:8:8
`
`mm
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`
`£2.35".$55:2:B:8225.8:4.:E:2.:$5.
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`
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`43.3.mm.9.8.9SBEKEE:823:92.50522m
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`
`
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`
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`
`.5395m_3823202:3n3:E:on
`
`
`

`

`CENTER FOR DRUG EVALUATION AND
`
`RESEARCH
`
`APPLICA TION NUMBER:
`
`75 02 8
`
`CHEMISTRY REVIEW; S!
`
`

`

`CHEMIST'S REVIEW NO.
`
`3
`
`ANDA # 75-028
`
`NAME AND ADDRESS OF APPLICANT
`Biovail Laboratories Inc.
`
`#34 Iturregui Avenue
`Carolina, Puerto Rico 00983
`
`Patent Exclusivity
`The Referenced Listed Drug is TrentalE Extended-release
`tablets 400 mg, by Hoechst-Roussel Pharmaceuticals,
`Inc.
`The drug is not entitled to a period of marketing
`exclusivity.
`It is covered by two U.S. patents that expired
`on February 2, 1997 and April 3, 1997, respectively.
`
`PROPRIETARY NAME
`N/A
`
`7. NONPROPRIETARY NAME
`Pentoxifylline Extended—release Tablets
`
`AMENDMENTS AND OTHER DATES:
`Firm
`
`Original Submission
`Correspondence
`Amendment
`Amendment
`Amendment
`Amendment
`Amendment
`Amendment
`
`(Major)
`(bio)
`
`(bio)
`
`FDA
`
`N/A Letter
`Date filed
`Label review w/defic.
`Chemistry def. Letter
`Bio def. Letter
`Chem & label def. Fax
`Methods acceptable
`Bio review acceptable
`
`12/16/96
`2/12/97
`2/14/97
`9/22/97
`10/29/97
`2/12/98
`4/9/98
`6/15/98
`
`2/10/97
`2/18/97
`4/3/97
`7/31/97
`10/14/97
`1/22/98
`2/28/98
`4/28/98
`
`10.
`
`12.
`
`PHARMACOLOGICAL CATEGORY
`Vasodilator
`
`11. Rx or OTC
`Rx
`
`RELATED IND/NDA/DMFQS)
`
`

`

`13.
`
`DOSAGE FORM
`
`14.
`
`POTENCY
`
`Ext. release tablet
`
`400 mg
`
`15.
`
`CHEMICAL NAME AND STRUCTURE
`
`Pentoxifylline
`C13H18N4O3; M.W.
`= 278.31
`0
`H
`//\\\///\\\//A\\
`
`H36
`
`0
`H
`
`Nk I
`
`6;;
`
`CH3
`
`/
`N
`/>
`
`N
`
`3,7—Dihydro-3,7—dimethyl—1—(5—oxohexy1)—1H—purine—2,6—dione.
`CAS
`[6493-05—6]
`
`17.
`
`COMMENTS
`
`Label review satisfactory dated 6/24/98.
`EER acceptable dated 7/1/97 and 2/18/98.
`Method verification results are acceptable.
`Bio review satisfactory.
`Firm withdrew the additional two new sources for NDS.
`
`18.
`
`CONCLUSIONS AND RECOMMENDATIONS
`
`No outstanding chemistry issues; ANDA can be approved!
`
`19.
`
`REVIEWER
`
`DATE COMPLETED
`
`Radhika Rajagopalan Ph.D.
`
`5/15/98
`
`

`

`DIVISION APPROVAL SUMMARY
`
`ANDA
`
`#: 75—028
`
`DRUG PRODUCT: Pentoxifylline Extended-release
`Tablets
`
`FIRM: Biovail Laboratories,
`
`Inc.
`
`DOSAGE: Extended—release Tablets
`
`STRENGTH: 400 mg
`
`CGMP STATEMENT/EIR UPDATE STATUS:
`
`(Page 8442).
`CGMP: GMP Certification is enclosed.
`EER: Acceptable dated 7/1/97 and 2/18/98.
`
`BIO STUDY(ies)/BIOEQUIVALENCE STATUS:
`On 4/28/98 the Division of Bioequivalence issued a letter with
`dissolution specifications to the firm.
`The recommended
`specifications are already in place.
`
`METHODS VALIDATION (Including dosage form description):
`Drug substance and drug product are verified by the field labs and
`found satisfactory. Results filed in volume 1.1.
`
`STABILITY(Conditions, Containers, methods): The product will be
`distributed in 100 count only.
`
`Evaluation of stability indicating methods: Satisfactory
`
`Stability Assays
`
`Appearance
`
`White, oblong compressed
`tablet with ‘BVF’ on one side
`and ‘0117' on the other
`
`%
`
`
`
`Impurities
`
`Theobromine
`Other individual
`Total
`
`
`Dissolution
` 1 hour NMT
`8 hours NMT
`
`24 hours NLT
`
`
`
`
`Moisture content
`
`NMT
`
`%
`
`

`

`LABELING REVIEW STATUS: Satisfactory.
`
`See review dated 6/23/98.
`
`STERILIZATION VALIDATION (If Applicable): Not applicable for this
`product.
`’
`
`BATCH SIZES:
`
`BIO BATCH: Supplier:
`
`STABILITY BATCHES (different from BIO BATCH, manuf.
`
`site, process)
`Stability batch is the same as the bio—batch
`
`PROPOSED PRODUCTION BATCH
`
`is the proposed production batch size.
`
`Process is the same as the demonstration batch.
`
`COMMENTS: Approvable
`
`CHEMISTRY REVIEWER:
`
`DATE:
`
`Radhika Rajagopalan, Ph.D.
`
`May 15, 1998
`
`11L44A4J' Kalllac 4L£24£47C3
`~4/¢4A4)
`1
`-
`.
`
`

`

`CENTER FOR DRUG EVALUATION AND
`
`RESEARCH
`
`APPLICA TION NUMBER:
`
`7502 8
`
`BIOE UIVALENCY REVIEW S
`
`

`

`OFFICE OF GENERIC DRUGS
`
`DIVISION OF BIOEQUIVALENCE
`
`ANDA: #75-028
`
`SPONSOR: Biovail Corporation International
`
`Drug: Pentoxifylline
`DOSAGE FORM: Extended-Release Tablets
`
`STRENGTH: 400 mg
`
`TYPE OF STUDIES: Single-dose(Fasting, Non—fasting), Multiple—dose
`CLINICAL SITE: Biovail Corporation International
`ANALYTICAL SITE:
`
`_______________________________________________________________
`STUDIES SUMMARY:
`
`The single-dose and multiple—dose bioequivalence studies
`conducted under fasting conditions, and single-dose food effect
`study have been found acceptable by the Division of
`Bioequivalence.
`
`
`DISSOLUTION:
`
`The dissolution testing has been found acceptable.
`
`
`PRIMARY REVIEWER: F. Nouravarsani
`
`BRANCH:
`
`III
`
`SIGNITURE;
`
`[8/
`
`DATE:
`
`ff[211.9313
`
`0 A
`
`cting Team Leader: M. Makary
`
`BRANCH:
`
`III
`
`SIGNITURE:_
`
`c1,
`/ a
`
`/
`
`DATE:
`
`4 (lg Z! Z!
`_
`
`
`
`DIRECTOR: Dale P. Conner
`
`DIVISION OF BIOEQUIVALENCE:
`/7
`
`SIGNITURE :
`
`lg]
`
`_ DATE: ZZZSZ/ig
`
`
`
`DIRECTOR: Doug Sporn
`
`OFFICE OF GENERIC DRUGS:
`
`SIGNITURE:
`
`DATE
`
`

`

`BIOEQUIVALENCY COMMENTS TO BE PROVIDED TO THE APPLICANT
`
`ANDA: #75—028
`
`APPLICANT: Biovail Corporation International
`
`DRUG PRODUCT: Pentoxifylline Extended-Release Tablets, 400 mg
`
`The Division of Bioequivalence has completed its review and has
`no further questions at this time.
`
`The following dissolution testing will need to be incorporated
`into your stability and quality control programs:
`
`The dissolution testing should be conducted in 900 mL
`of water at 37° C using USP 23 Apparatus 2
`(paddle)
`at 50 rpm.
`The test product should meet the following
`tentative specifications:
`
`WWW
`
`1 hour
`
`8 hours
`
`Not More Than
`
`%
`
`24 hours
`
`Not Less Than
`
`%
`
`%
`
`Please note that the bioequivalency comments provided in this
`communication are preliminary. These comments are subject to
`revision after review of the entire application, upon
`consideration of the chemistry, manufacturing and controls,
`microbiology,
`labeling, or other scientific or regulatory issues.
`Please be advised that these reviews may result in the need for
`additional bioequivalency information and/or studies, or may
`result in a conclusion that the proposed formulation is not
`approvable.
`
`Sincerely yours,
`/3/
`
`’7
`
`Dale P. Conner, Pharm. D.
`Director
`
`Division of Bioequivalence
`
`Office of Generic Drugs
`
`Center for Drug Evaluation and Research
`
`

`

`2.!
`
`BIOEQUIVALENCY COMMENTS TO BE PROVIDED TO THE APPLICANT
`
`ANDA: #75—028
`
`APPLICANT: Biovail Corporation International
`
`DRUG PRODUCT: Pentoxifylline Extended—Release Tablets, 400 mg
`
`The Division of Bioequivalence has completed its review and has
`
`no further questions at this time.
`
`The following dissolution testing will need to be incorporated
`into your stability and quality control programs:
`
`The dissolution testing should be conducted in 900 mL
`of water at 37° C using USP 23 Apparatus 2
`(paddle)
`
`The test product should meet
`at 50 rpm.
`tentative specifications:
`
`the following
`
`1'
`
`1
`
`E
`
`E
`
`J
`
`i
`
`of:
`
`1 hour
`
`8 hours
`
`Not More Than
`
`‘%
`
`24 hours
`
`Not Less Than
`
`%
`
`%
`
`Please note that the bioequivalency comments provided in this
`communication are preliminary. These comments are subject to
`revision after review of the entire application, upon
`consideration of the chemistry, manufacturing and controls,
`microbiology,
`labeling, or other scientific or regulatory issues.
`Please be advised that these reviews may result in the need for
`additional bioequivalency information and/or studies, or may
`result in a conclusion that the proposed formulation is not
`approvable.
`
`Sincerely yours,
`
`/3/’”
`
`Dale P. Conner, Pharm. D.
`Director
`
`Division of Bioequivalence
`
`Office of Generic Drugs
`
`Center for Drug Evaluation and Research
`
`

`

`Pentoxifylline
`Extended—Release Tablets
`
`Biovail Corporation International
`Ontario, Canada
`
`400 mg
`
`ANDA #75—028
`Reviewer: F. Nouravarsani
`750288DA.097
`
`Submission Dates:
`
`October 29, 1997
`April 09, 1998
`
`
`
`Biovail Corporation International had previously submitted three
`bioequivalence studies (two single—dose studies conducted under
`fasting and nonfasting conditions, and one multiple—dose study
`conducted under fasting conditions) and dissolution testing on
`its test product, Pentoxifylline Extended—Release Tablets, 400 mg
`and the listed reference product, Trental, 400 mg Pentoxifylline
`Extended-Release Tablets manufactured by Hoechst Marion Roussel
`Pharmaceuticals,
`Inc.
`in USA (NDA #18631, August 30, 1984).
`
`The firm has responded to the deficiencies of the above studies
`as follows:
`
`Dgfiigigngy fll:
`
`It was stated that, results from rejected batches, if any, were
`not
`included in the report.
`The rejected runs (if any) and the
`reasons for their rejection were required.
`
`13
`
`LE"
`
`II:
`
`The firm responded that there was one rejected run for study
`#1775—1.
`Run FKR-29 was rejected for metabolite V [1—(3—
`Carboxypropyl)—3,7—Dimethylxanthine], because of “unacceptable
`deviation of both QC samples".
`The samples were re-analyzed on
`run FKR—39. There were no rejected runs for study #1773-1 and
`#1774-1.
`
`Went:
`
`Results from the rejected run FKR—29 were not submitted for
`review.
`The firm was contacted by phone call from the DBE to
`submit
`the results of this run.
`
`

`

`The firm submitted results of the rejected run on April 09, 1998.
`Both high Quality Control samples deviated more than
`% from the
`nominal concentration.
`
`2
`
`The firm’s response is acceptable.
`
`Deficien§¥_£2:
`
`The Y-scale for the Semi-log Plots was not correct.
`
`E
`
`L E'
`
`.
`
`H2:
`
`the
`The firm responded that “After careful review of the reports,
`semi—logarithmic plots for the fasting study (Study #1773—1) and
`the food—effect study (Study #1775-1) were found to be correct.
`Typically,
`the y—scale in a semi-log plot is presented as a
`logarithmic scale ranging from 1 to 100. Similarly,
`the semi—log
`plots in both Study #1773-1 and Study #1775-1 had logarithmic y~
`scales. However,
`the ranges of the y—scale in these plots were
`more specific and related to the study data.
`For example,
`in
`Study #1773-1,
`the y-scale of the mean semi—log plot ranged from
`0.125 to 64.000, with equal tick intervals, and with values
`
`doubling per major tick".
`
`The firm has further stated that “the
`
`semi-log plots for both studies were drawn so that the details of
`
`the distribution of the data points for both studies could be
`seen graphically”.
`A copy of the plot was attached (Attachment
`1).
`
`Wt:
`
`The firm’s explanation is acceptable.
`
`I E'
`
`.
`
`H
`
`:
`
`the curve code FKQ41 was missing from
`In the Multiple-Dose Study,
`the tables summarizing the quality controls' values and standard
`concentrations.
`The firm was requested to clarify.
`
`E'
`
`.
`
`Hi:
`
`The firm responded that Curve FKQ-41 was re-injected on Curve
`FKQ-43 due to system problems.
`
`

`

`v' w r
`
`nt:
`
`The response is acceptable.
`
`Dgfiigigngy #3:
`
`The ranges and coefficient of variations (CV%) for all
`
`dissolution testing data for each medium were requested to be
`submitted for both test and reference products at each time
`point; a dissolution testing method was requested to be
`
`suggested; and tentative specifications to be proposed.
`
`Response LQ Deficiency #5:
`
`ranges, and standard deviation (SD) for
`The firm submitted mean,
`the dissolution testing data using media of phosphate buffer
`solutions pH 1.5, 4.5, 6.5, and 7.5 (Iable_lA;D) and water
`(Table_2).
`The method conditions were as follows:
`
`Volume: 900 mL
`
`Apparatus: paddle
`
`Stirring Speed: 50 rpm
`Sampling Times: 1, 4, 8, 12, 18, and 24 hours.
`
`The proposed tentative Specifications using water as the medium
`are as follows:
`
`limes—hr
`
`_%_11r_us_Es_l_e_a.se_._
`
`1
`
`8
`
`24
`
`Not More Than
`
`%
`
`Not Less Than
`
`%
`
`%
`
`W:
`
`a. The percentages of Coefficient of Variations (CV%) were
`
`calculated by the reviewer
`
`(Iabl§_1A;D) and (Iable_z).
`
`b. Results of the dissolution testing in buffer solutions show
`similarity between the test and reference products (Iable_lA;D)
`
`0. Results of the mean and individual data demonstrate that
`
`

`

`release of the drug is similar in buffer solutions of pH 1.3 to
`pH 7.5.
`
`d. The mean and individual data points at pH 1.5, 4.5, 6.5, and
`
`7.5 show more than 80% release for both,
`
`the test and reference
`
`products at 24 hours (Iable_;A;D).
`
`e. Results of the dissolution testing in water show similarity
`between the test and reference products (Iahl§_2).
`
`f. The mean and individual data points for water show more than
`
`80% release for the test product at 24 hours, and for the
`
`reference product at 18 hours (Ighle_2).
`
`g. The percentages of the labeled amount of Pentoxifylline
`released in water at l, 8, and 24 hours fall in the USP
`
`“Acceptance Table 1" under Drug Release <724>.
`
`h. The test and reference products used in the dissolution
`testing and bio—studies were from the same bulk lot #96H020 (test
`
`The manufacturing
`product), and lot 0780446 (reference product).
`date for the test product was August 1996.
`The expiration date
`for the reference product was February 1998.
`The dissolution
`testing was conducted prior to its expiration.
`
`i. The response is acceptable.
`
`DEIIQlENQX_QE_IEE_QHBEENI_EHEMI§§IQNS= None.
`
`BEQQMMEHDAIIQNS:
`
`1. The fasting single—dose, fasting multiple-dose, and
`nonfasting single—dose bioequivalence studies conducted by
`Biovail Corporation International on its Pentoxifylline Extended—
`Release Tablets, 400 mg,
`lot #96H023 (Bulk lot #96H020) comparing
`it to Trental Extended-Release Tablets, 400 mg,
`lot #0780446 have
`been found acceptable by the Division of Bioequivalence.
`
`The studies demonstrate that Biovail’s Pentoxifylline Extended-
`Release Tablets, 400 mg is bioequivalent to the reference
`product, Trental, 400 mg Pentoxifylline Extended—Release Tablets
`manufactured by Hoechst Marion Roussel Pharmaceuticals,
`Inc.
`
`

`

`2. The dissolution testings conducted by Biovail Corporation
`International on its Pentoxifylline Extended—Release Tablets,
`
`400 mg (Bulk lot #96H020) have been found acceptable by the
`Division of Bioequivalence.
`
`3. The dissolution testing should be incorporated into the firm's
`
`The dissolution
`manufacturing controls and stability program.
`testing should be conducted in 900 mL of water at 37° C using USP
`23 apparatus 2
`(paddle) at 50 rpm.
`The test product should meet
`the following tentative specifications:
`
`WW
`
`1 hour
`
`8 hours
`
`24 hours
`
`Not More Than
`
`%
`
`Not Less Than
`
`%
`
`%
`
`4. From the bioequivalence point of view the firm has met the
`requirements of in vivg bioequivalency and in 21119 dissolution
`
`/S/
`
`Farahnaz Nouravarsani, Ph.D.
`
`Division of Bioequivalence
`Review Branch III
`
`RD
`INITIALED MMAKARY
`FT
`INITIALED MMAKARY_'
`Concur.‘
`v
`V
`_/S/
`
`/S/
`
`_
`
`/
`
`Dale P. Conner, Pharm.D.
`Director
`
`Division of Bioequivalence
`
`Date: ggzgg’zg
`
`FNouravarsani/O4-22—98/750288DA.O97
`
`CC: ANDA #75—028 (Original, Duplicate), HFD—650 (Director),
`
`HFD-658 (Nouravarsani), Drug File, Division File
`
`

`

`Iablo_;:
`
`In Vitro Dissolution Testing
`
`Drug (Generic Name): Pentoxifylline Extended—Release Tablets
`
`Dose Strength: 400 mg
`ANDA: #75-028
`
`Firm: Biovail Corporation International
`Submission Date: October, 29, 1997
`
`I. Conditions for Dissolution floating:
`
`USP XXIII
`
`Basket
`
`Paddle
`
`3
`
`RPM 5Q
`
`No. Units Tested
`
`12
`
`Medium: Phosphato onffior 93 1,5, 51,5. 5,5. and 7,5 a; 37° 9 Volume: 299 mL
`
`Reference Drug:
`
`jljzontal
`
`Assay Methodology: _
`
`II.
`
`BmaQLaJfi_Lilutnilu§aflatnxleadng:
`
`Sampling
`Times
`hr
`
`Test Product:
`LOt#96H020 (bulk)
`Strength (mg)J_o_Q_
`
`Reference Product:
`Lot #0780446
`Strength (mg)__4_Q_Q_
`
`Mean’:
`
`Range%
`
`(CV‘k)
`
`Mean%
`
`Range%
`
`(CV%)
`
`4.
`
`.L}...Q_
`
`_ (4.7)
`
`_13_._0_ _
`
`_4_
`
`.3.l_._0_
`
`‘
`
`_ (4-6)
`
`_3_1_‘_0__ _
`
`_3_ M .
`
`_ (3.8) 42L _
`
`(1.2)
`
`(2.0)
`
`(1.8)
`
`_l_2__
`
`_6_5_._Q_
`
`.
`
`- (3.1) ALA?— ..
`
`. (1.4)
`
`JL M .
`
`- (2-5)
`
`J2_._Q_.
`
`_
`
`_ZA__
`
`.2AIQ_
`
`.
`
`_(2.1)
`
`.21lg_ -
`
`. (0.95)
`
`_(o.7m
`
`

`

`Sampling
`Times
`
`hr
`
`Test Product:
`Lot#96H020
`
`Strength (mg) ALL
`
`Reference Product:
`Lot #0780446
`
`Strength (mg) JQ_O_
`
`Meanfis
`
`Range 1:
`
`(CV%)
`
`Mean%
`
`Range 1:
`
`(CV’r)
`
`J.—
`
`_ll_._0_
`
`.
`
`_ (14.0)
`
`.1.Z_._Q_
`
`.'
`
`_ (14.7)
`
`4..
`
`_21..£_
`
`_ ( 8.0)
`
`_2§_._0_
`
`.
`
`-
`
`( 6.8)
`
`4...
`
`ALL ,
`
`‘12—
`
`_5_6_._Q_
`
`_L8_
`
`_13_._0_.
`
`.
`
`.
`
`_
`
`_
`
`_
`
`( 5.9)
`
`JA...0_ _
`
`( 4.7)
`
`J14)— _
`
`( 3.3)
`
`JAIL _
`
`.
`
`.
`
`( 4-7)
`
`( 3.6)
`
`( 2.5)
`
`_ZL_.
`
`Jig—9— .
`
`_ (2.7)
`
`_8§_._O_ _
`
`__
`
`( 1.8)
`
`Reference Product:
`Lot #0780446
`
`Sampling
`Times
`
`hr
`
`Test Product:
`Lot#96H020
`
`Strength (mg)__g_9_0_
`
`Strength (mg)_igg_
`
`Mean%
`
`Ranges‘s
`
`(CV%)
`
`Mean%
`
`Rangefi;
`
`(CV95)
`
`_1_
`
`4.1.0— .
`
`_‘1_
`
`_29_._0_
`
`-
`
`__8_
`
`ALL -
`
`42_
`
`_6_l_._Q.
`
`_l§__.
`
`__lB_._Q_
`
`_
`
`_
`
`_
`
`_
`
`_
`
`,
`
`( 3.8)
`
`_l.2.._0_.
`
`( 3.4)
`
`.39....Q_
`
`( 3.1)
`
`_4_8_._Q_
`
`.
`
`.
`
`-
`
`( 2.8) M -
`
`( 2.3)
`
`_8_0_._0_
`
`_
`
`.23—
`
`_9_LJL__
`
`_(2.1)_9_2_.9__
`
`_ ( 2.7)
`
`_
`
`-
`
`_
`
`_
`
`( 3.2)
`
`( 2-9)
`
`( 2.3)
`
`( 1.7)
`
`.(l.6)
`
`

`

`Sampling
`Times
`
`Test Product:
`Lot#96H020
`
`hr
`
`Strength (mg)_&22.
`
`Reference Product:
`Lot #0780446
`
`Strength (mg) 399
`
`Mean%
`
`Range%
`
`(CV%)
`
`Mean?
`
`Range% (CV%)
`
`__l._
`
`.12.2.
`
`_
`
`. (6.1)
`
`_ll.Q_
`
`..£_.
`
`.22.Q_ _
`
`,(4.1)
`
`__§._.
`
`_$§.Q_ _
`
`_12..
`
`_§l.2_ _
`
`.l&._
`
`_1§.Q_ _
`
`.21..
`
`.22.2_ _
`
`(3.4)
`
`(2.6)
`
`(1.9)
`
`(1.7)
`
`(1.
`
`6)
`
`(2.
`
`8)
`
`(2
`
`.2)
`
`(1.
`
`6)
`
`(1.
`
`1)
`
`(0.
`
`89)
`
`

`

`Iable_2:
`
`In Vitro Dissolution Testing
`
`Drug (Generic Name): Pentoxifylline Extended—Release Tablets
`
`Dose Strength: 400 mg
`ANDA: #75-028
`
`Firm: Biovail Corporation International
`Submission Date: October 29, 1997
`
`1- WWW:
`
`'
`
`USP XXIII
`
`Basket
`
`Paddle
`
`K
`
`RPM 59
`
`No. Units Tested
`
`12
`
`Medium: Wage; a; 31° 9
`
`Volume: 299 mL
`
`Reference Drug:
`
`Irental
`
`__
`
`Assay Methodology:
`
`Proposed Specifications:
`
`1 hr:
`8 hr:
`24 hr:
`
`NMT
`
`NLT
`
`%
`
`%