CENTER FOR DRUG EVALUATION AND
`
`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`RESEARCH
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`
`
`APPLICATION NUMBER:
`22-272
`22-272
`
`
`
`APPLICA TION NUMBER:
`
`CLINICAL PHARMACOLOGY AND
`
`CLINICAL PHARMACOLOGY AND
`BIOPHARMACEUTICS REVIEW(S)
`BIOPHARMACEUTICS REVIEW! S 2
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`

`

` PRE-IND
`ANIMAL to HUMAN SCALING
` IN-VITRO METABOLISM
` PROTOCOL
` PHASE II PROTOCOL
` PHASE III PROTOCOL
` DOSING REGIMEN CONSULT
` PK/PD- POPPK ISSUES
` PHASE IV RELATED
`
`
`
`
`
`
`
`
`
` NAI (No action indicated)
` E-mail comments to:
`Medical Chemist
`Pharm-Tox
`Micro
`Pharmacometrics Others
`(Check as appropriate and attach e-mail)
`
`
` DISSOLUTION/IN-VITRO RELEASE
` BIOAVAILABILITY STUDIES
` IN-VIVO WAIVER REQUEST
` SUPAC RELATED
` CMC RELATED
` PROGRESS REPORT
` SCIENTIFIC INVESTIGATIONS
` MEETING PACKAGE (EOP2/Pre-
`NDA/CMC/Pharmacometrics/Others)
`
` FINAL PRINTED LABELING
` LABELING REVISION
` CORRESPONDENCE
` DRUG ADVERTISING
` ADVERSE REACTION REPORT
` ANNUAL REPORTS
` FAX SUBMISSION
` OTHER (SPECIFY BELOW):
`DDI study protocol employing Oxycontin 10
`mg (ER) with 200 mg bid ketoconazole
`
`
`
`REVIEW ACTION
` Oral communication with
`Name: [ ]
` Comments communicated in
`meeting/Telecon. see meeting minutes
`dated: [ ]
`
`
`
` Formal Review/Memo (attached)
`See comments below
`See submission cover letter
` OTHER (SPECIFY BELOW):
` [ ]
`
`
`
`DEPARTMENT OF HEALTH AND
`HUMAN SERVICES
`PUBLIC HEALTH SERVICE
`FOOD AND DRUG ADMINISTRATION
`
`
`From: Sheetal Agarwal, Ph.D.
`
`
`DATE: 04/29/09
`
`
`IND No.: 29,038
`SDN.:687
`
`
`NAME OF DRUG: Oxycontin
`
`NAME OF THE SPONSOR: Purdue Pharma
`
`
`
`Related NDA Nos.
`20-553 (SDN 351),
`22-272 (SDN 60)
`
`PRIORITY CONSIDERATION
`
`Clinical Pharmacology
`Tracking/Action Sheet for Formal/Informal Consults
`
`To: DOCUMENT ROOM (LOG-IN and LOG-OUT)
`Please log-in this consult and review action for the specified
`IND/NDA submission
`
`Submission Date: 04/16/2010
`
`
`
`
`
`Date of informal/Formal Consult:
`
`
`
`
`TYPE OF SUBMISSION
`
`CLINICAL PHARMACOLOGY/BIOPHARMACEUTICS RELATED ISSUE
`
`
`
`REVIEW COMMENT(S)
` NEED TO BE COMMUNICATED TO THE SPONSOR
` HAVE BEEN COMMUNICATED TO THE SPONSOR
`
`
`
`
`COMMENTS/SPECIAL INSTRUCTIONS:
`
`The submitted study protocol OTR1023 for a drug-drug interaction study employing Oxycontin and
`ketoconazole as a Phase 4 post marketing commitment for approval of Oxycontin is acceptable from a
`Clinical Pharmacology perspective. No further action is indicated at this time.
`
`BACKGROUND:
`
`This review pertains to the final drug-drug interaction protocol # OTR1023 submitted to the Agency on
`04/16/2010. This DDI study is designed to fulfill the Post Marketing Commitment outlined in the Agency’s
`letter dated September 2, 2009 in reference to the approval of supplement # S-060 that was submitted
`on December 13, 2007. A draft of protocol OTR1023 was submitted on September 11, 2009 (NDA
`20533/SDN 340) and reviewed by Dr. Sayed Al Habet (see review in DARRTS dated 09/30/00).
`
`
`
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`

`

`
`
`The following Clinical Pharmacology related comment was conveyed to the sponsor at the time of initial
`review of the draft protocol:
`
`“Although, a drug interaction is expected between ketoconazole and oxycontin, the magnitude of
`resulting increase in oxycodone exposure is unknown. In order to protect the healthy volunteers
`participating in this study from the opioid side effects resulting from a potential interaction, we advice that
`you provide naltrexone blockade to the participating volunteers. We recommend that naltrexone at a
`dose of 50 mg be administered during the study at the following time points in relation to oxycontin
`dosing: 12 hours pre-dose, 12 hours, 24 and 36 hours post-dose.”
`
`It should be noted that the final protocol does not contain any major amendments to the study design
`reviewed by Dr. Al Habet which would materially affect the clinical pharmacology assessments.
`
`
`Purdue did not include naltrexone blockade in their final protocol but provided an acceptable rationale to
`the Agency via email on April 27, 2010 to the project manager, Ms. Lisa Basham. Dosing in this study
`was planned to be started on April 28, 2010. Attachment 1 is an extract of Purdue’s rationale, while
`attachment 2 contains the final protocol synopsis.
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`ATTACHMENT 1: RATIONALE PROVIDED BY PURDUE PHARMA FOR NOT INCLUDING
`ATTACHMENT 1: RATIONALE PROVIDED BY PURDUE PHARMA FOR NOT INCLUDING
`NALTREXONE BLOCKADE IN THE DRUG-DRUG INTERACTION STUDY
`NALTREXONE BLOCKADE IN THE DRUG-DRUG INTERACTION STUDY
`
`
`
`jApril26,2fl1flj FDA Comment on proposed studv OTR1U23:
`
`“Aithough, a drug interaction is expected between hetoconazoie and vaflontin, the magnitude of
`
`resulting increase in oxvcodone exposure is unknown. in order to protect the healthy voiunteers
`
`participating in this studvfrom the opioid side effects resuiting Jfrom a potentiai interaction, we advise
`
`that you provide naltrexone blockade to the participating volunteers. We recommend that naitrexone at
`
`a dose of Eli] ma be administered during the study at the Jfoiiowingr time points in reiation to OxvContin
`
`dosing: 1.2 hours pre—dose, 12 hours. 2:11 anaI 35 hours post—dose.”
`
`April 2? 2pm PPLP Response:
`
`OTR1023 is a drug—drug interaction studv in which 10 mg OxvContin (oxvcodone hvdrochloride
`
`controlled—release [CR]]I tablets will be administered to subjects with and without concomitant
`
`ketoconazole administration to assess the impact of this potent azole CYP3A4 inhibitor on oxvcodone
`
`pharmacokinetics. We considered inclusion of naltrexone blockade in protocol DTR1D23 but elected not
`
`to include it based upon the considerations summarized below.
`
`In a published report, Hagelberg et al (Euri Clin Pharmacol. 20¢]?! Mar:65{3}:263-?1 attached in email]
`
`examined the interaction between oxvcodone and the potent azole CYPSAA inhibitor voriconazole in 12
`
`healthv subjects. vacodone was administered as single 10 mg immediate-release {le capsule
`
`{Oxvnormj doses. In the presence of voriconazole. mean peak oxvcodone (Cmaxj increased from 18.1 to
`
`3&5 ngimL. This corresponds to a 12-fold increase in Cmax on average {range 1.4 —2.4x). Mean total
`
`oxvcodone exposure {AUCinfj increased from 1:32 to 363 ng.himL. This corresponds to a 16—fold
`
`increase in AUCinf on average [range 2.? — 5.6x].
`
`Adverse events were described bv Hagelberg et al as follows:
`
`r’AII subjects completed the studv. Eight of the 12 subjects experienced adverse
`
`events on dav 3. Adverse events were headache (n=5]. nausea {n=3]I, vomiting
`
`{n21}. dizziness {n22}. extremefatigue [n21] and itch {n21}. Three subjects
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`received paracetamol [1,0130 mg} for headache 12 h after oxvcodone dosing. and
`
`one received tropisetrone 2 mg iv for nausea 5 h after dosing. All cases of nausea
`
`or vomiting were reported during the voriconazole phase. Number of reports of
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`headache did not differ between voriconazole and control phases.”
`
`PPLP concluded that although the increase in oxvcodone exposure following co-administration with
`
`voriconazole was associated with more AEs, there were no significant safetv concerns raised bv the
`
`observed AEs following the administration of 10 mg IR oxvcodone under CYP3A4 inhibition, bevond
`
`those applicable whenever an opioid is administered under experimental conditions.
`
`We hvpothesize that since ketoconazole and voriconazole are both potent azole CYP3A4 inhibitors. thev
`
`will have similar effects on oxvcodone pharmacokinetics. We further hvpothesize that the magnitudes of
`
`the increases in Cmax and AUC. noted bv Hagelberg et al are the best available predictions of the
`
`magnitude of effect likelv to be characterized in OTR1023. These hvpotheses are supported bv observed
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`
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`effects of these C‘r’P3fit4 inhibitors on sirolimus exposure in healthy subjects. ‘y'oriconazole produced
`
`increases in sirolimus exposure of 2—fold and 11—fold for Cmax and AUC, respectiyely jyfend Package
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`Insert attaached in email]. Ketoconazole produced increases in sirolimus exposure of 4.4—fold and 11—
`
`fold for Cmax and fiUC, respectiyely [Floren et al. Clin Pharm Ther [1999] 65, 159—159 attached in
`
`email].
`
`In OTR1923, oxycodone is administered in CR form as a 19 mg nyContin dose. In the absence of
`
`CYP3A4 inhibition, this dose is expected to produce a mean Cmax of approximately 9.4 ngme and an
`
`EUCinf of approximately 198 ng.h;'mL. It should be noted that this expected peak exposure [Cmax] is
`
`approximately 59% of that expected for a 19 mg IR oxycodone dose, while total oxycodone exposure
`
`{fiUCinfl is similar for ER and IR formulations. Thus, use of a CR dosage form [OxyContin] proyides a 2—
`
`fold reduction in expected Cmax, with and without CYP3A4 inhibition. Since the intensity of opioid AEs is
`
`typically related to lEmax, this margin is releyant to the safety and tolerability of oxycodone closing in
`9T91923.
`
`In a prior PPLP single—dose crossoyer study DC93—9891 [submitted to IND 29,938 on October 2, 1994,
`
`Serial Number 188]], both 29 and 49 mg nyContin doses and 29 mg IR oxycodone doses were
`
`administered to healthy subjects {n=24] without naltrexone blockade. Mean oxycodone Cmax and EU:
`
`following 49 mg nyContin administration were 39.3 ngme {range 23.9 — 92.5] and 421 ng.h;'mL {range
`
`244 — 921], respectiyely. The l9993—9891 study report states that most .4Es were mild or moderate in
`
`intensity and that there were no discontinuations due to adyerse experiences. It further states that a
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`dose—response was obseryed between 29 mg {n=22] and 49 mg {n=24] lEixyilontin doses, with 9? and
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`19? AEs reported, respectiyely, for the two treatments.
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`The prior safety and tolerability experience in l9993—9891 with 49 mg nyContin administered without
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`naltrexone represents the safety and tolerability that is expected in l9TH1923 assuming ketoconazole
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`were to produce approximately a 4-fold increase in Cmax fits. the 1.?-fold increase noted with
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`yoriconazolej and AUC jys. the 3.6—fold increase noted with yoriconatole].
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`fidministration of 59 mg naltrexone blockade is belieyed by our inyestigators to be associated with
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`tolerability issues, reflected by reported AEs, and can eyen lead to subject discontinuations in rare
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`instances.
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`While exclusion of naltrexone is adyantageous in permitting a “cleaner” assessment of the effect of
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`ketoconazole on oxycodone pharmacokinetics, this consideration only applies if the conclusion is
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`reached that naltrexone blockade is not required to minimise the opioid agonist effects anticipated in
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`this study. Based upon the considerations summarised aboye, we concluded that naltrexone blockade is
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`not required in this study. Therefore co—administration of naltrexone was not included in protocol
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`[2991923.
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`ATTACHMENT 2: FINAL PROTOCOL SYNOPSIS
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`(b) (4)
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`

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`Treatments, Doses, and Modes of Administration:
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`OTR 10 mg tablet, Ketoconazole 288 mg oral tablet, and placebo tablet {administered o12h]. All treatments
`
`will be administered orally with 8 oz. {248 mL] water.
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`Treatments will be administered in an open-label fashion. Subjects will be dosed in an upright position, and
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`will remain upright for4 hours afterwards. Treatment administrations will be separated by a 14 day
`
`washout period.
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`Concomitant Medication:
`
`placebo or upon discontinuing from the study.
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`Naloxone HCI challenge test (administered on Day —1, Period 1 check-in].
`
`The use of concomitant medications during this trial is discouraged, unless necessary to treat adverse
`events or unless approved on a case—by—case basis prior to randomization leg, hormonal contraceptives].
`The use of any concomitant medications should be approved by the sponsor in advance, in writing, when
`possible.
`
`Duration of Treatment and Study Duration:
`
`Screening and baseline period will be up to 28 days prior to administration of study medication (in this case
`either ketoconazole or placebo administration).
`
`In Period 1 subjects will be administered ketoconazole or placebo in a randomized fashion on days 1-4.
`On day 3, the subjects will receive a single oral dose of OTR. This will be followed by a washout period
`lasting 14 days {days 5 to 18}. In Period 2 subjects will be administered ketoconazole or placebo in a
`crossover fashion on days 18—22. On day 21, the subjects will receive a single oral dose of OTR.
`
`Subjects will be confined to the study facility during Periods 1 and 2.
`
`Subjects will have end of study procedures fEOS} performed T—1 8 days after last dose of ketoconazole or
`
`The total duration ofthe study is approximately 88 days.
`
`Treatment Schedule:
`
`Pro-Randomization Phase:
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`Screening: Subjects will be screened within 28 days of Period 1 check—in. Drug and alcohol screens,
`physical exam, 12— lead ECO, vital signs (systolic blood pressure, diastolic blood pressure, pulse rate,
`respiration rate and oral temperature), SpOg, medical and medication history, clinical laboratory testing and
`inclusion-“exclusion criteria will be evaluated. Subjects are not allowed to consume applejuice, orange juice
`or grapefruit juice during the treatment period.
`
`Randomization Phase:
`
`On Day -1, Period 1 Check-in only, subjects will receive a Naloxone HOI challenge test. Vital signs and
`SpOg will be measured prior to and following the Naloxone HCI challenge test.
`
`For each Period, subjects will check into the unit the day prior to dosing. At check—In, subjects will have
`chemistry (fasting for at least 4 hours}, hematology and urinalysis tests performed. Urine pregnancy test
`{for women of childbearing potential], vital signs, SpOE, and alcohol and urine drug screens will be
`performed.
`
`Period 1 (Days 1 to 5}
`
`Ketoconazole {288 mg} or placebo administration will begin on Day 1 and will be given twice a day at
`approximately 8 Alt-1 and approximately 8 Plvl through Day 4. Throughout Period 1, vital signs, SpOg and
`HDYF? will be performed as per study flow chart.
`
`On Day 3 at approximately 8 AM, OTR 18 mg tablet will be administered following an overnight fast.
`Subjects will continue fasting until 4 hours post—dose. Blood samples for PK analysis will be drawn at pre-
`dose, and at ore-determined time points through 48 hours post—dose.
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`On Day Ll: blood samples for the determination of ketoconazole levels will be drawn at approximately 8 Alvl,
`prior to ketoconazole or placebo administration.
`
`On Day 5: vital signs, SpOg and HDYF? will be performed as per study flow chart and the subject will then
`be discharged with instructions to return on Day ‘I S.
`
`Wash-out Period {Days 5 to 13}
`
`Baseline 2 [Day 181
`
`During this period, the investigator will ensure that provisions are made for the subjects to contact the study
`site in case of adverse events during the washout period. Such reporting ofadverse events and the
`investigators response will be accurately documented, and the Purdue Pharma L.P. study monitor will be
`notified immediately.
`
`analysis set will be documented in the Statistical Analysis Plan.
`
`‘v’ital sign evaluation, safety laboratory tests {serum
`On Day 13, subjects will be confined to the study unit.
`chemistries including liver function tests, hematology, and urinalysis}; urine pregnancy testing (if female],
`urine drug screening: and alcohol testing will be performed.
`
`Period 2 (Days 19 to 23)
`
`On Day '19, the subjects will be crossed over to the opposite treatment schedule. Subjects who were given
`ketoconazole during Period 1 will be given placebo in Period 2, and those given placebo in Period "i will be
`given ketoconazole during Period 2.
`
`Ketoconazole {200 mg) or placebo administration will begin on Day 19 and will be given twice a day at
`approximately 8 AM and approximately 8 PM through Day 22. Throughout Period 2, vital signs, SpOg and
`HDYF? will be performed as per study flow chart.
`
`On Day 21 at approximately 8 Alvl, OTR 113 mg tablet will be administered following an overnight fast.
`Subjects will continue fasting until 4 hours post—dose. Blood samples for PK analysis will be drawn at pre-
`dose: and at ore-determined time points through 48 hours post—dose.
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`On Day 22, blood samples for the determination of ketoconazole levels will be drawn at approximately 8
`AM, prior to OTR and ketoconazole administration.
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`On Day 23. vital signs: SpO2 and HDYF‘? will be performed as per study flow chart and the subject will then
`be discharged with instructions to return for End of Study procedures.
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`Adverse events {AEs} and concomitant medications will be recorded throughout the study.
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`Note: for clarity: OTR is assigned as the study drug for determination of adverse event causality.
`Ketoconazole and placebo are considered distinct from study drug in this determination.
`
`End of Study Visit: Subjects will return to the unit T to it} days after receiving their last dose of
`ketoconazole or placebo or upon discontinuation from the study for their end of study {EOS} procedures.
`EOS procedures will include a physical exam, ’12- lead ECG. vital signs, SpOg: and laboratory tests.
`
`Criteria and Methods for Evaluation:
`
`Analysis Pogulations:
`
`The enrolled gogulation is the group of subjects who provide informed consent.
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`The randomized safety gogulation is the group of subjects who are randomized, receive study drug. and
`have at least one post dose safety assessment.
`
`The full analysis gopulation for PK metrics will be the group of subjects who are randomized, receive study
`drug, and have at least one valid PK metric for that treatment. Subjects experiencing emesis within 12
`hours after dosing may be excluded from PK analysis. Subjects and profiles-"metrics excluded from the
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`

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`Oxycodone Concentration Measurements: Ellood samples for determining the concentrations of oxycodone
`and its metabolites {noroxycodone oxymorphone, and noroxymorphonej in plasma, will be obtained for
`each subject at predose and at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 16,24, 28, 32, 38, and 48 hours
`post study drug administration during each ofthe study Periods.
`
`Elioanalytical methods:
`
`Plasma oxycodone and its metabolites (noroxycodone, oxymorphone, and noroxymorphoneji
`concentrations will be quantified using a validated liquid chromatography tandem mass spectrometric
`method.
`
`Safety Assessments: Safety will be assessed using recorded adverse events, clinical laboratory test
`results, vital signs, SpCrg, physical examinations, and electrocardiograms (ECG).
`
`Statistical Methods:
`
`
`
`Su bjects‘ AEs will be categorized into preferred terms and associated system organ class using the
`Medical Dictionary for Regulatory Activities (h-ledDRA}. Treatment—emergent AEs will be defined as AEs
`that start after, or increase in severity after, a dose of study drug. Treatment—emergent AEs that occur
`during the washout period up to the point of dosing the next study drug will be assigned to the previous
`treatment dosed. Treatment—emergent AEs will be summarized by presenting the incidence ofAEs for each
`treatment group by the MedDRA preferred term, nested within System Organ Class for the safety
`population.
`
`Pharmacokinetic Metrics: Plasma concentrations of oxycodone and its metabolites (noroxycodone,
`oxymorphone, and noroxymorphone} will be analyzed to determine the following pharmacokinetic metrics:
`AUCt, AUCinf, Cmax, tmax, tlag, t‘|.-’22, and LambdaZ. Descriptive statistics will be tabulated by treatment,
`as applicable, for all pharmacoltinetic metrics.
`
`Safety Analysis:
`
`All safety data (AEs, clinical laboratory results, vital signs, SpClg and ECGs) will be listed for subjects in the
`enrolled and safety populations. Results of clinical laboratory evaluations that lie outside the normal range
`will be flagged on the listings as high or low.
`
`Laboratory, vital signs and 8pc}; will be summarized by treatment and time—point for the safety population.
`
`Sample Size Rationale:
`
`No formal sample-size calculations were performed. A sufficient number of subjects {up to 3D) will be
`randomized to complete approximately 20 subjects.
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`

`Application
`Type/Number
`--------------------
`NDA-22272
`
`Submission
`Type/Number
`--------------------
`PMR/PMC-1
`
`Submitter Name
`
`Product Name
`
`--------------------
`PURDUE PHARMA
`INC
`
`------------------------------------------
`OXYCONTIN
`
`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`SHEETAL S AGARWAL
`04/30/2010
`
`SURESH DODDAPANENI
`04/30/2010
`
`

`

` PRE-IND
`ANIMAL to HUMAN SCALING
` IN-VITRO METABOLISM
` PROTOCOL
` PHASE II PROTOCOL
` PHASE III PROTOCOL
` DOSING REGIMEN CONSULT
` PK/PD- POPPK ISSUES
` PHASE IV RELATED
`
`
`
`
`
`
`
`
`
` NAI (No action indicated)
` E-mail comments to:
`Medical Chemist Pharm-Tox
` Micro Pharmacometrics Others
`(Check as appropriate and attach e-
`mail)
`
`
` DISSOLUTION/IN-VITRO
`RELEASE
` BIOAVAILABILITY STUDIES
` IN-VIVO WAIVER REQUEST
` SUPAC RELATED
` CMC RELATED
` PROGRESS REPORT
` SCIENTIFIC INVESTIGATIONS
` MEETING PACKAGE (EOP2/Pre-
`NDA/CMC/Pharmacometrics/Others)
`REVIEW ACTION
` Oral communication with
`Name: [ ]
` Comments communicated in
`meeting/Telecon. see meeting minutes
`dated: [ ]
`
`
`
` FINAL PRINTED LABELING
` LABELING REVISION
` CORRESPONDENCE
` DRUG ADVERTISING
` ADVERSE REACTION REPORT
` ANNUAL REPORTS
` FAX SUBMISSION
` OTHER (SPECIFY BELOW):
`Labeling changes related to drug-drug
`interactions following published reports
`
`
`
` Formal Review/Memo (attached)
`See comments below
`See submission cover letter
` OTHER (SPECIFY BELOW):
` [ ]
`
`
`
`DEPARTMENT OF HEALTH AND
`HUMAN SERVICES
`PUBLIC HEALTH SERVICE
`FOOD AND DRUG ADMINISTRATION
`
`
`From: Sheetal Agarwal, Ph.D.
`
`
`IND No.:
`Serial No.:
`
`
`DATE: 03/15/10
`
`
`NAME OF DRUG
`Oxycontin®
`
`NAME OF THE SPONSOR: Purdue Pharma
`
`
`Clinical Pharmacology
`Tracking/Action Sheet for Formal/Informal Consults
`
`To: DOCUMENT ROOM (LOG-IN and LOG-OUT)
`Please log-in this consult and review action for the
`specified IND/NDA submission
`
`Submission Date: 02/05/10
`
`
`
`
`
`PRIORITY
`CONSIDERATION
`
`
`
`Date of informal/Formal
`Consult:
`
`
`
`
`
`NDA No. 22-272
`SDN: 50
`
`TYPE OF SUBMISSION
`CLINICAL PHARMACOLOGY/BIOPHARMACEUTICS RELATED ISSUE
`
`
`
`REVIEW COMMENT(S)
` NEED TO BE COMMUNICATED TO THE SPONSOR
` HAVE BEEN COMMUNICATED TO THE SPONSOR
`BACKGROUND:
`
`This is a Class I resubmission of NDA 22272 pertaining to reformulated oxycontin formulation. The original
`NDA submission and the complete response submission were previously reviewed by Dr. Sayed Al Habet
`(see reviews dated 5/23/2008 and 9/1/2009 for complete details regarding clinical pharmacology aspects of
`this product). Pertinent Clinical Pharmacology relevant labeling language was negotiated with the sponsor in
`the last previous cycle. However, subsequent to this, Drug-Drug interaction data between coadministration of
`oxycodone and rifampin from the following publication came to light; Nieminen TH et al. Rifampin greatly
`reduces the plasma concentrations of intravenous and oral oxycodone. Anesthesiology.
`2009;110:1371-1378.
`
`This review captures the labeling changes related to this interaction and other minor appropriate
`modifications suggested by this reviewer. Attachment contains the proposed labeling changes (additions
`indicated by underlined text and deletions indicated by strikethrough text).
`
`Following is a discussion of the rifampin and oxycodone interaction study. In this four-session, paired,
`crossover study, twelve volunteers were given 600 mg oral rifampin or placebo once daily for 7 days.
`
`

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`Oxycodone was given on day 6. In the first part of the study, 0.1 mg/kg oxycodone hydrochloride was given
`intravenously. In the second part of the study, 15 mg oxycodone hydrochloride was given orally.
`Concentrations of oxycodone and its metabolites noroxycodone, oxymorphone, and noroxymorphone were
`determined for 48 h. Psychomotor effects were characterized for 12 h by several visual analog scales.
`Analgesic effects were characterized by measuring the heat pain threshold and cold pain sensitivity.
`
`Plasma profiles and PK parameters are listed in Figure 1 and Tables 1 and 2 extracted from the publication.
`
`Rifampin decreased the AUC of intravenous oxycodone by 53%, increased the mean plasma Cl by 2.2-fold,
`and decreased its t½ from 3.7 to 2.4 h. Rifampin decreased the mean AUC and Cmax of oral oxycodone by
`86% and 63%, respectively. The mean oral bioavailability of oxycodone was decreased from 69% to 21% by
`rifampin. Rifampin increased the Cmax of noroxycodone by 2.7-fold after intravenous oxycodone and by 2.0-
`fold after oral oxycodone compared with the control values. The corresponding metabolite–to–parent drug
`AUC ratios (AUCm/AUCp) were increased 2.4-fold and 7.6-fold, respectively. Rifampin reduced the AUC of
`oxymorphone to approximately 5–10% of the corresponding control value after intravenous and oral
`administration of oxycodone. Intravenous oxycodone produced no detectable oxymorphone concentrations in
`two subjects after placebo and in eight subjects after rifampin. After rifampin and oral oxycodone, five of the
`subjects had every measured oxymorphone concentration below the lower limit of quantification. Rifampin
`increased the Cmax of noroxymorphone more than twofold in both the intravenous and the oral part of the
`study. The corresponding metabolite– to–parent drug AUC ratios increased 2.4-fold after intravenous and
`9.6-fold after oral oxycodone. In addition, pharmacologic effects of oral oxycodone were attenuated.
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`Figure 1: Plasma concentrations (mean - SD) of oxycodone and its metabolites in 12 volunteers following
`intravenous administration of 0.1 mg/kg and oral administration of 15 mg oxycodone hydrochloride
`after placebo or rifampin. The volunteers were given in randomized order either 600 mg oral rifampin or
`placebo once daily at 8 PM for 7 days. Oxycodone was given on day 6 at 8 AM, 12 h after the fifth dose
`of rifampin or placebo. Two more doses of rifampin or placebo were given on days 6 and 7. The
`oxycodone concentrations are shown both on arithmetic and on a semilogarithmic plot (inset).
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`Table 1: Pharmacokinetic Parameters of Oxycodone and Its Metabolites in Volunteers after Intravenous
`Administration of Oxycodone Following Placebo (Control) or Oral Rifampin
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`Table 2: Pharmacokinetic Parameters of Oxycodone and Its Metabolites in Volunteers after Oral
`Administration of Oxycodone Following Placebo (Control) or Oral Rifampin
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`5 WARNINGS AND PRECAUTIONS
`
`5.8 Cytochrome P450 3A4 Inhibitors and Inducers
`
`Since the CYP3A4 isoenzyme plays a major role in the metabolism of OxyContin, drugs
`that alter
` CYP3A4 activity may cause changes in
` clearance of
`oxycodone which could lead to an increase or decrease in oxycodone plasma
`concentrations. The expected clinical results with CYP450 inhibitors would be increased
`or prolonged opioid effects. If co-administration with OxyContin is necessary, caution is
`advised when initiating therapy in patients, currently taking, or discontinuing CYP3A4
`inhibitors. Evaluate these patients at frequent intervals and consider dose adjustments
`until stable drug effects are achieved. The expected clinical results with CYP450 inducers
`would be decrease in oxycodone plasma concentrations, lack of efficacy or, possibly,
`development of abstinence syndrome in a patient who had developed physical
`dependence to oxycodone. Evaluate these patients at frequent intervals and consider dose
`adjustments until stable drug effects are achieved. [see Drug Interactions (7.2) and
`Clinical Pharmacology (12)]
`
`
`7.1 Neuromuscular Junction Blocking Agents
`
`OxyContin may enhance the neuromuscular blocking action of true skeletal muscle
`relaxants (such as pancuronium) and produce an increased degree and/or duration of
`respiratory depression.
`
`7.2 Agents Affecting Cytochrome P450 Isoenzymes
`
`Inhibitors of CYP3A4:
`Since the CYP3A4 isoenzyme plays a major role in the metabolism of OxyContin, drugs
`that inhibit CYP3A4 activity, such as macrolide antibiotics (e.g., erythromycin), azole-
`antifungal agents (e.g., ketoconazole), and protease inhibitors (e.g., ritonavir), may cause
`decreased clearance of oxycodone which could lead to an increase in oxycodone plasma
`concentrations. A published study showed that the co-administration of the antifungal
`drug, voriconazole, increased oxycodone AUC and Cmax by 3.6 and 1.7 fold, respectively.
`Although clinical studies have not been conducted with other CYP3A4 inhibitors, the
`expected clinical results would be increased or prolonged opioid effects. If co-
`administration with OxyContin is necessary, caution is advised when initiating therapy
`with, currently taking, or discontinuing CYP450 inhibitors. Evaluate these patients at
`frequent intervals and consider dose adjustments until stable drug effects are achieved.
`[see Clinical Pharmacology (12.3)]
`
`Inducers of CYP3A4:
`
` 7
`
` DRUG INTERACTIONS
`
`(b) (4)
`
`(b) (4)
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`(b) (4)
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`CYP450 inducers, such as rifampin, carbamazepine, and phenytoin, may induce the
`metabolism of oxycodone and, therefore, may cause increased clearance of the drug
`which could lead to a decrease in oxycodone plasma concentrations, lack of efficacy or,
`possibly, development of abstinence syndrome in a patient who had developed physical
`dependence to oxycodone. A published study showed that the co-administration of
`rifampin, a drug metabolizing enzyme inducer, decreased oxycodone (oral) AUC and
`Cmax by 86% and 63% respectively. If co-administration with PERCODAN is
`necessary, caution is advised when initiating therapy with, currently taking, or
`discontinuing CYPP450 inducers. Evaluate these patients at frequent intervals and
`consider dose adjustments until stable drug effects are achieved.
`
`Inhibitors of CYP2D6:
`Oxycodone is metabolized in part to oxymorphone via cytochrome CYP2D6. While this
`pathway may be blocked by a variety of drugs (e.g., certain cardiovascular drugs
`including amiodarone and quinidine as well as polycyclic antidepressants), such blockade
`has not been shown to be of clinical significance during oxycodone treatment.
`
`12.3 Pharmacokinetics
`
`
`Drug-Drug Interactions
`
`
`Oxycodone is extensively metabolized by multiple metabolic pathways. CYP3A4 is the
`major enzyme involved in noroxycodone formation followed by CYP2B6, CYP2C9/19
`and CYP2D6. Drugs that inhibit CYP3A4 activity, such as macrolide antibiotics (e.g.,
`erythromycin), azole-antifungal agents (e.g., ketoconazole), and protease inhibitors (e.g.,
`ritonavir), may cause decreased clearance of oxycodone which could lead to an increase
`in oxycodone plasma concentrations. For example, a published study showed that the co-
`administration of the antifungal drug, voriconazole, increased oxycodone AUC and Cmax
`by 3.6 and 1.7 fold, respectively. Similarly, CYP450 inducers, such as rifampin,
`carbamazepine, and phenytoin, may induce the metabolism of oxycodone and, therefore,
`may cause increased clearance of the drug which could lead to a decrease in oxycodone
`plasma concentrations, lack of efficacy or, possibly, development of abstinence syndrome
`in a patient who had developed physical dependence to oxycodone. For example, a
`published study showed that the co-administration of rifampin, a drug metabolizing
`enzyme inducer, decreased oxycodone (oral) AUC and Cmax by 86% and 63%
`respectively.
`
`Oxymorphone is a minor metabolite, its formation is catalyzed primarily by CYP2D6 and
`to a small extent by CYP2C19. The formation of oxymorphone may be blocked by a
`
`(b) (4)
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`

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`variety of drugs (such as antipsychotics, beta blockers, antidepressants, etc.) that inhibit
`these enzymes. However, in a study involving ten subjects using quinidine, a known
`inhibitor of CYP2D6, the pharmacodynamic effects of oxycodone were unchanged. The
`genetic expression of CYP2D6 may have some influence in the pharmacokinetic
`properties of oxycodone.
`
`The in vitro drug-drug interaction studies with noroxymorphone using human liver
`microsomes showed no significant inhibition of CYP2D6 and CYP3A4 activities which
`suggests that noroxymorphone may not alter the metabolism of other drugs that