NDA 20—732, NDA 20-733
`Page 12
`
`The following is a list of action items.
`
`ACTION:
`
`ACTION:
`
`ACTION:
`
`ACTION:
`
`ACTION:
`
`ACTION:
`
`ACTION:
`
`ACTION:
`
`ACTION:
`
`ACTION:
`
`ACTION:
`
`The Sponsor will submit the information about the characterization of the
`impurities to the Division.
`
`The Sponsor will clarify the COA listed in the meeting package for the
`Suboxone extract used in the pre-clinical studies on impurities.
`
`The Sponsor agreed to send in a request for another meeting prior to the
`next submission.
`
`The Sponsor will provide the appropriate data for acceptance criteria for
`the drug product tests.
`
`The Sponsor will provide the appropriate data on individual degradation
`products.
`
`The Sponsor will provide the acceptance criteria for individual
`degradation products. The Sponsor has improved their identification and
`monitoring process.
`
`The Sponsor will provide the test and acceptance criteria for individual
`tablet dissolution. In the submission the data were reported as mean data
`but the individual tablet data are available.
`
`The Sponsor will provide data to cross correlate the different degradation
`products found in Subutex and Suboxone.
`
`The Sponsor will provide identification of the site of packaging used for
`drug product stability batches and the proposed commercial drug product
`packaging site.
`
`No agreement was reached on a PK study design and this issue will need
`to be resolved by telecon or another meeting.
`
`The Sponsor will submit a summary of all the stability studies conducted
`on the drug product (manufacturing site, packaging, formulation, storage
`conditions, etc.).
`
`The meeting adjourned at ~12230 PM
`
`NOTE: The Sponsor provided a package of their overheads used during the meeting.
`
`APPEARS nus w
`0M ORIGINAL M
`
`

`

`Sara Shepherd
`3/13/01 08:57:35 AM
`
`APPEARS THIS WAY
`0N ORRGINAL
`
`APPEARS THIS WAY
`0N ORIGINAL
`
`

`

`M E M O R A N D U M
`
`DEPARTMENT OFHEALTII AND HUMAN SERVICES
`FOOD AND DRUG ADMINISTRATION
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`Date:
`
`January 25, 2001
`
`To:
`
`Director, Division of Anesthetic, Critical Care, and Addiction Drug Products
`(HFD-l70)
`
`Through:
`
`Deborah B. Leiderman, MD, MA
`Director, Controlled Substance Staff (HFD-009)
`
`From:
`
`Michael Klein, PhD.
`
`Controlled Substance Staff (HFD-009)
`
`Subject:
`
`Controlled Substance Staff Proposals on Scheduling and Risk Management for
`Buprenorphine and Buprenorphine-Naloxone Sublingual Tablets (NDA #20-732
`& 20-733)
`
`The purpose of this memo is to summarize the basis for the proposal to reschedule
`buprenorphine under the Controlled Substances Act (CSA) to Schedule III and to reschedule the
`combination products of buprenorphine-naloxone to Schedule IV. Rescheduling will occur soon
`after approval of NDAs 20-732 and 20.733, and prior to marketing. For the purposes of CSA
`scheduling, buprenorphine is defined as the drug substance and all possible products, mixtures
`and combinations, except for approved drug products that contain buprenorphine and naloxone.
`CSS additionally proposes that a Risk Management Program be developed to ensure safe use of
`the buprenorphine-containing drugs.
`
`DRUG SCHEDULING & RISK MANAGEMENT PROPOSALS
`
`The criteria for listing a drug in a CSA schedule derive from an assessment of its relative abuse
`and dependence potential properties. A drug listed in Schedule III must have a potential for
`abuse less than drugs in Schedules I and II and must produce moderate or low physical
`dependence or high psychological dependence. A drug in Schedule IV has a lower potential for
`abuse than drugs in Schedule III and produces limited physical or psychological dependence.
`Sublingual buprenorphine tablets produce predominantly opiate agonist effects with little or no
`contributing antagonist effect of naloxone. By contrast, buprenorphine combined with naloxone
`and parenterally administered to opioid-dependent individuals may precipitate a withdrawal
`syndrome. Actual abuse documented from France, New Zealand, and other countries largely
`involves opiate addicts extracting and injecting the active ingredient of the buprenorphine
`tablets. Therefore, if this pattern repeats in the United States, the addition of antagonist to
`buprenorphine would be expected to reduce its intravenous abuse, although other routes for the
`"street addict" to abuse the drug would not be significantly affected.
`
`

`

`Page 2
`
`Buprenorphine & Buprenorphine—NaloxoneSublingual Tablets
`NDAs #20-732 and #20—733
`
`In addition to listing buprenorphine in more restrictive CSA schedules, a Risk Management
`Program (RMP) is needed and needs to be part of the NDAs. Such a program will ensure safe
`use of buprenorphine and prevent abuse by other at-risk populations, including the drug nai've
`individual and non-dependent intravenous opioid abuser. Features of the Program should
`include the following:
`
`1. A post—marketing surveillance plan for diversion and safety
`2. Development of
`~
`3. Voluntary restriction of take-home medication
`4. An
`__.
`
`5. Educational material to be distributed to patients, doctors, pharmacies
`6. A plan to monitor signals for off-label use
`7.
`1-800 number to report diversion
`8. A Dear Pharmacy/Healthcare letter
`9. A plan for physician/pharmacist interaction
`10. Monitoring of existing databases to provide periodic updates to FDA
`
`ABUSE AND DEPENDENCE POTENTIAL
`
`The evaluation of buprenorphine considers the profile of effects related to (l) abuse potential and
`(2) physical dependence capability.
`
`Buprenorphine has high affinity for, and slow dissociation from, the mu-opioid receptor.
`Buprenorphine produces a typical opioid-like spectrum of effects. These include euphoria, drug
`liking, pupillary constriction, respiratory depression and sedation. In both preclinical and
`clinical studies, buprenorphine manifests a shallower dose response curve and “ceiling effect”
`for many actions compared to pure agonists such as morphine (OH) and hydromorphone (C-H).
`Buprenorphine is thus considered a partial opioid agonist.
`
`The withdrawal syndrome that develops afier continued use is typical of opioids and is evidence
`of the capacity of buprenorphine to produce physical dependence. The intensity of the
`withdrawal syndrome has been evaluated by clinical investigators to vary from moderately
`severe to moderate to mild. Drug craving has been reported afler discontinuing use of
`buprenorphine, which has in some patients resulted in the need to resume use of heroin. This
`craving is indicative of psychophysiological dependence. Individuals dependent on
`buprenorphine can easily retum to heroin use and vice versa. Twenty percent of newborns born
`to mothers in treatment with buprenorphine substitution for opiate dependence have exhibited a
`narcotic abstinence syndrome (NAS) severe enough to require treatment. For mothers maintained
`on methadone (C-II), 60-80% NAS of varying severity was reported.
`
`The presence of the opiate antagonist, naloxone, in the combination product is expected to
`reduce its abuse. The antagonist may diminish the euphoria produced by buprenorphine.
`Withdrawal in opiate dependent individuals may be precipitated, if the drug combination is
`
`

`

`Page 3
`
`Buprenorphine & Buprenorphine—NaloxoneSublingual Tablets
`NDAs #20-732 and #20-733
`
`parenterally administered. Dependence production is thus limited in this at-risk population.
`Naloxone administered by the sublingual route is not bioavailable.
`
`MORBIDITY AND MORTALITY
`
`In France, sublingual buprenorphine has been available by prescription. During the first three
`years of marketing, approximately ’-
`individuals were treated with the drug for heroin
`addiction. More than 100 buprenorphine-related deaths were reported. The deaths involved
`individuals who were not in treatment for addiction, but who obtained the drug through
`diversion. Most cases involved diverted medication and concomitant use of other psychoactive
`drugs, especially benzodiazepines. Risks associated with misuse of the tablet form of
`buprenorphine were primarily by intravenous injection.
`'
`
`Benzodiazepines ranked first in association, (present in 9] observations, of which 64 were
`nordiazepam). There were 37 cases involving neuroleptics, of which 26 were with
`cyamemazine. Eighteen cases (8 with tricyclics and 10 SSRI’s) were with antidepressants.
`Concomitant use of other narcotics was observed with morphine (12 cases), codeine (2 cases),
`methadone (4 cases), meperidine (1 case) and dextro-propoxyphene (4 cases). There were 4
`reported fatalities involving ethanol and buprenorphine.
`
`ACTUAL ABUSE
`
`Numerous articles have been published in the scientific literature on buprenorphine abuse. Thus
`far, in the United States, buprenorphine has been marketed as a Schedule V, injectable product
`(0.3 mg/mL). Abuse of the injectable formulation has been low, because of limited marketing
`and availability. Parenteral formulations are not available to patient populations to the same
`extent as are oral, sublingual, or transdemial formulations. Many national governments have
`increased the regulatory controls on buprenorphine as a result of abuse and diversion. The
`reports from other countries need to be examined in relation to how the new drug products will
`be marketed in the United States. The proposed additional CSA restrictions and Risk
`Management Program will offer deterrents to abuse, diversion, overdose, and deaths, which
`differ from the manner in which buprenorphine has been marketed elsewhere after approval.
`
`Buprenorphine was first marketed in France in 1987 as an analgesic. Its approval for treatment
`of opiate addiction followed in 1996. Abuse and diversion was identified soon after it first
`became available. Due to misuse of the sublingual form, special narcotic restrictions on the
`prescribing and dispensing of buprenorphine in treating pain were instituted in December 1992.
`Prescriptions had to be written on a voucher taken from a counterfoil prescription book that was
`specifically designed for narcotic drugs and monitored by the French Medical Association.
`Records had to be retained by the pharmacist for 3 years. The prescription could be filled by any
`pharmacy. As of 1996, general practitioners were permitted to prescribe the buprenorphine
`tablets for treating opiate dependence for up to 28 days per prescription, by use of the counterfoil
`prescription book. Doses prescribed were in the range of 4 to 16 mg/day. In September 20,
`
`

`

`Page 4
`
`Buprenorphine & Buprenorphine-NaloxoneSublingual Tablets
`NDAs #20-732 and #20-733
`
`1999, because of continuing reports of abuse and diversion, dispensing was restricted to a 7—day
`supply at one time from the prescription.
`
`In New Zealand, buprenorphine was launched as a noncontrolled drug in April 1982. Within 2
`months, the first report of intravenous abuse appeared. Opioid users described using 4-5 tablets
`intravenously twice daily to produce euphoria lasting for hours. Buprenorphine was reported as
`the drug of choice during heroin shortages. Data from the
`—
`indicated that,
`of l 10 new patients in 1983, S6 (51%) reported buprenorphine abuse. Escalating abuse, theft,
`and forged prescriptions led to control of buprenorphine in September 1983. Nevertheless, abuse
`continued to rise in 1984. In 1986, more than 50% of drug abusers in New Zealand were abusing
`buprenorphine.
`
`In March 199], because of a continuing iv drug abuse problem, buprenorphine was reformulated
`with naloxone. Abuse of the naloxone combination product was compared to abuse of the single
`ingredient drug product. In 1990, 81% of the subjects reported buprenorphine abuse in the 4-
`week period prior to intake and 65% had buprenorphine in their urine. In 1991, after
`introduction of the combination product, 57% reported abuse of products containing
`buprenorphine, and 43% had buprenorphine in their urine. One-third of the patients abusing the
`buprenorphine-naloxone product intravenously reported withdrawal symptoms and felt that it
`was less appealing as a drug of abuse. Users reported injecting three tablets of the single entity
`product versus two tablets of the combination product. The illicit importation of buprenorphine
`single entity product was documented, as large seizures of the drug occurred at New Zealand
`airports.
`
`Thus, it appears that the combination of buprenorphine with naloxone reduced abuse and
`diversion of buprenorphine in the country where both products are available. We anticipate that
`in the United States the likelihood of abuse of the combination product by the "street addict" will
`be less than that of the single ingredient product afier approval. The institution of an adequate
`Risk Management Program, the features of which are described above, with the rescheduling of
`buprenorphine are expected to be significant deterrents to abuse, diversion, overdoses, and
`deaths resulting from the buprenorphine-containing products.
`
`CC:
`
`Orig NDA #20-732
`Orig NDA #20-733
`HFD—009/ KleinM/LeidermanD/MoodyC/LocklearD
`HFD- l 70/McCormickC/WinchellC/ShepherdS
`
`APPEARS THIS WAY
`0N ORIGINAL
`
`

`

`Michael Klein
`
`1/25/01 11:56:50 AM
`CHEMIST
`
`This is the same memo, however it is for the combo NDA.
`
`Deborah Leiderman
`1/25/01 12:10:46 PM
`MEDICAL OFFICER
`
`APPEARS IHIS WAY
`0N ORIGINAL
`
`

`

`5m
`
`FDA CENTER FOR DRUG EVALUATION AND RESEARCH
`MM"
`DIVISION OF ANES'I‘IIETIC, CRITICAL CARE, AND ADDICTION DRUG PRODUCTS
`RFD-170, Room 93-45, 5600 Fishers Lane, Rockville MD 20857
`
`Tel:(301)443-‘3741
`
`MEMORANDUM
`
`To: File, NDA 20-732
`NDA 20-733 V
`
`From: Celia Winchell, M.D., Medical Team Leader, Addiction Drug Products
`Through: Cynthia G. McCormick, M.D., Director, HFD—l70
`Date: 1/22/01
`Re: Pediatric Studies for Subutex (Buprenorphine HCl) Sublingual Tablets
`
`I believe that pediatric studies for Subutex (Buprenorphine HCI) Sublingual Tablets
`- at this time for the following reasons:
`
`"‘
`
`1. The drug substance, buprenorphine, is already known to be safe in children, and the
`injectable product is labeled for pediatric use. The doses for children 13 and over are the
`same as for adults.
`
`Although
`_
`‘
`2. The indication for this product is
`the rates are reported to be increasing, opiate addiction in teenagers remains relatively
`rare. Opiate maintenance treatment of children under age 16 has been prohibited under
`the methadone treatment regulations, and treatment of patients between 16 and 18 has
`been permitted only under limited circumstances; therefore maintenance treatment in
`adolescents is not a common part of clinical practice. Given what is known about the
`drug substance, based on experience with the injectable formulation, it is reasonable to
`expect that those few patients between the ages of 16 and 18 who require maintenance
`therapy can be treated with the doses used in adults.
`
`3. Should the epidemiology of this disorder change so that extensive use in patients under
`age 16 becomes more common, pediatric studies may be indicated in the future.
`—-—-
`
`/
`
`__
`
`APPEARS THIS WAY
`0N ORIGINAL 7
`
`

`

`v
`Celia Winchell
`1/22/01 03:05:33 PM
`MEDICAL OFFICER
`
`Cynthia McCormick
`1/24/01 10:20:28 AM
`MEDICAL OFFICER
`
`”u.\
`
`

`

`“With.
`0'
`
`9"
`
`’3 f
`
`9%"
`
`FDA CENTER FOR DRUG EVALUATION AND RESEARCH
`
`DIVISION OF ANESTHETIC, CRITICAL CARE, AND ADDICTION DRUG PRODUCTS
`RFD-170, Room 93-45, 5600 Fishers Lane, Rockville MD 20857 (301) 827-7410
`
`ADDENDUM TO REVIEW AND EVALUATION OF CLINICAL AND
`STATISTICAL DATA
`
`NDA #:
`
`p
`
`Supplement #2
`
`Sponsor:
`
`Generic Name:
`
`Proprietary Name:
`
`Pharmacologic Class:
`
`Proposed Indication:
`
`Submission Date:
`
`Dosage forms:
`
`Route:
`
`20-733
`
`Response to Approvable
`
`Reckitt & Colman Pharmaceuticals
`
`Buprenorphine HCl/Naloxone Sublingual
`Tablets
`
`Suboxone (TBD)
`
`Opioid
`
`Treatment of Opioid Dependence
`
`7/28/00
`
`Buprenorphine 2 mg/Naloxone 0.5 mg
`sublingual tablet;
`Buprenorphine 8 mg/Naloxone 2 mg
`sublingual tablet
`Sublingual
`
`Clinical Reviewer:
`
`Celia Jaffe Winchell, MD.
`
`Date:
`
`1/22/01
`
`Financial Disclosure:
`
`The sponsor submitted financial disclosure information for studies cited in the NDA. The
`studies were primarily sponsored by NIDA, but Reckitt & Colman, Schering—Plough, and
`various other entities provided financial support for some studies.
`
`Form FDA 3454 was submitted for 42 studies cited in the NDA, including the three
`studies deemed pivotal to the demonstration of safety and efficacy of buprenorphine for
`treatment of opiate addiction.
`
`

`

`Celia Winchell
`
`1/22/01 03:15:09 PM
`MEDICAL OFFICER
`
`Cynthia McCormick
`1/24/01 10:22:48 AM
`MEDICAL OFFICER
`
`APPEARS THIS WAY
`
`ON ORIGINAL
`
`

`

`NDA 20-733
`Reckitt & Colman
`Suboxone
`
`sfl‘mm‘”.
`42‘
`
`E2 /c
`
`"m.
`"a
`
`FDA CENTER FOR DRUG EVALUATION AND RESEARCH
`
`DIVISION OF ANESTHETIC, CRITICAL CARE, AND ADDICTION DRUG PRODUCTS
`RFD-170, Room 9M5, 5600 Fishers Lane, Rockville MD 20857 Tel:(301)827-7410
`
`Division Director Review of NDA and Basis for Action
`
`Drug:
`
`Buprenorphine HCl/Naloxone, Sublingual Tablets
`
`Sponsor.
`
`Reckitt & Colman Pharmaceuticals, Inc.
`
`NDA:
`
`#20—733
`
`Review Cycle:
`
`2, Response to approvable action
`
`Received:
`
`July 28, 2000
`
`Indication:
`
`Treatment of _ . —'
`
`This review summarizes the basis for the action to be taken on the New Drug Application
`for Suboxone, buprenorphine and naloxone sublingual tablet, for the treatment of opiate
`dependence. The previous review (memorandum) dated December 7, 1999 summarized
`the basis for the findings of safety and efficacy for this application, but delineated a
`number of significant deficiencies which were to have been corrected before the
`application could be approved. These deficiencies were explained in the approvable letter
`of December 7, 1999. This application represents a response to that letter and each of
`these deficiencies will be discussed. The previous findings that were not in dispute will
`not be reviewed at this time. Additional related problems identified during this review
`cycle will also be noted.
`
`Chemistry, Manufacturing, and Controls
`The stability of naloxone in Suboxone was a significant issue that arose during the review
`of this NDA. During the previous review cycle it was learned that the product was
`unable to meet the naloxone content specifications at room temperature storage of 25
`C/60%RH beyond - " , The approvable letter stated that
`
`The stability data are not sufficient to assess a reasonable expiry datefor the product.
`Information on any new packaging material should be provided Provide information
`demonstrating compliance with USP standards, including
`’—
`f _
`e data. Submit a written stability protocol prior to
`conducting the stability studies that includes, but is not limited to, the following items
`
`

`

`
`
`a.
`
`b.
`
`'——
`lots ofthe packagedproduct based an accelerated.
`long-term stability testing per ICH QIA&B guidance conditions
`testing time stations; i. e.,
`~—-
`, for accelerated and ’ M
`
`and
`
`NDA 20-733
`Reckitt & Colman
`Suboxone
`
`Provide thefirst 3 months ofdata at time ofresubmission and the additional data as
`they become available.
`
`The sponsor has responded by submitting data for the NDA stability batches, which failed
`under ICH conditions. The sponsor writes “ICH storage conditions are not ideal for
`Suboxone, since the proposed pack is
`«—
`"
`..Results from the first llCH study of 7“ batches
`of 2 mg and “batches of 8 mg Suboxone tablets were presented to the Division in an
`Amendment dated October 5,1999. This study was terminated after
`V‘—
`.” The
`sponsor also stated, however, that additional studies conducted showed that
`""
`,
`_ aid not help the stability of naloxone. Two additional
`developments are in progress, however thereis insufficient information1n the NDA to
`review these
`r/
`
`The determination of approvability
`1—".
`must be made on the data that are present in this NDA, not those that are anticipated.
`Therefore the data provided for the NDA stability batches using the initially proposed
`formulation do not support even a
`"‘
`shelf life. There is a
`“a
`
`-
`
`the individual dissolution data have not been provided. It has been noted
`that the use of " rpm for dissolution testing rather than the recommended -‘ rpm may
`in addition be delivering a falsely optimistic result. Due to the trends on stability, the
`more discriminating method should have been employed.
`
`The stability problems with this formulation must be satisfactorily resolved
`before this drug is placed on the market.
`
`The degradation of naloxone in this formulation had previously raised two additional
`specific concerns. The first was the potential for toxicity of the breakdown products
`when taken under conditions directed. The degradation products of naloxone had not
`been identified and the toxicity of these degradation products has not been determined.
`Identification of all degradation products occurring at or above I . of the active
`ingredient, naloxone, should have been provided. The degradation products should have
`been qualified with respect to safety in accordance with the ICH Q3 A and Q33 guidance.
`The approvable letter stated
`
`

`

`NDA 20-733
`Reckitt & Colman
`Suboxone
`
`The identity and toxicity ofthe degradation products have not been determined.
`Provide identification ofall degradation products occurring at or abOVe "'" of
`the active ingredient, naloxone. You mustfbllow ICH Q33 guidancefor
`qualification ofdegradation products.
`
`In response, the sponsor provided some data on the identity of naloxone degradation
`products, but a complete impurity profile was not provided. Of those that were identified,
`#occurred in clinical batches in quantities that exceeded the — threshold for
`individual impurities requiring safety qualification. Furthermore, the preclinical testing
`submitted to this NDA did not expose animals to these breakdown products, since the
`relevant formulation was not used in those studies. These impurities have, therefore, not
`been safety qualified as required. The sponsor has indicated that nonclinical studies are
`underway, but that the histopathology has not yet been completed. These data have not
`been submitted. This deficiency has not been corrected.
`
`The sponsor was further required to
`
`(2) Develop and validate analytical methods and specifications to provide afidl
`accountingfor all degradation products ofnaloxone. Additionally provide
`linkage between the analytical methods used by the “Nor generating the
`
`data at
`and the regulatory methods that are suitablefor
`detecting and quantifiling the degradation products ofnaloxone Without
`
`confirmation ofthts determination, the
`stability data may not be
`considered to support the expiration dating ofthe product.
`
`Dr. Al-Hakim has reviewed these materials and has found them unsatisfactory. These
`materials were not stored under [CH conditions. The shelf life of the product must be
`based on stability data generated using the [CH guidelines.
`~__-—.
`
`A second and greater concern with the
`
`is that the product may
`/
`not be an adequate deterrent for abuse as purported. This has important implications for
`the justification for including naloxone. The stability of naloxone:n this product15
`critical to its approval under 21CFR300.50(a)(2) (See Abuse Liability in Fixed
`Combination Prescription Drug Regulation). It was reasoned that if the presence and
`stability of naloxone could not be assured, there would be no basis for approving this
`product The approvable letter stated:
`
`(5) The stability ofnaloxone in this product is critical to its approval under
`21CFR300. 50(a)(2), in which it is stated that two or more drugs may be combined
`in a single dosage form when each component makes a contribution to the
`claimed eflects and the dosage ofeach component is such that the combination is
`safe and effective. It is permissible that a component is added to minimize the
`potentialfor abuse ofthe principal active component. Therefore in order to
`
`

`

`NDA 20-733
`Reckitt & Colman
`Suboxone
`
`satisfy the requirements ofthe combination policy, the naloxone component of
`Suboxone must be shown to minimize the abuse potential ofthe buprenorphine
`component. Ifthe presence and stability ofnaloxone cannot be assured, there is
`no basisfor approving the product with the addition ofnaloxone. In order to
`evaluate the integrity ofthe unpackagedproduct under conditions ofintentional
`degradation, additional testing is required. The tablets should be stressed under
`- forced degradation conditionsfor sufi‘icient time to predict extent ofdegradation
`under abuse conditions.
`
`In response, the sponsor provided stability testing under stressed conditions. Under the
`conditions tested,
`‘
`a
`_
`.here was no selective
`degradation. Testing from two independent FDA laboratories, however, was able to
`demonstrate nearly 100% extraction of buprenorphine from Suboxone using readily
`available methods and inexpensive equipment. This information will be considered in
`the overall plan to increase the schedule ofbuprenorphine under the CSA.
`
`——
`The product packaging finally also did not provide adequate
`__
`id did not comply with the child resistance provisions of the Poison Prevention
`Packaging Act as an oral dosage form of a controlled substance. The approvable letter
`stated
`
`#—
`(3)Prowde packaging that afiords adequate protectionfrom
`andis compliance with 16CFR 1 700. I4(a)(4) for controlled drugs.
`
`In response, the sponsor did provide child resistant packaging, but it was learned that the
`_,,..———-——:—— could not be readily opened
`Additional
`testing is underway but the results have not yet been submitted to the FDA. As the
`package stands, however, the current solution to child resistant packagingis
`unsatisfactory in that the integrity of the dosage form, and therefore, likely, its
`bioavailability and its efficacy, cannot be ensured.
`
`Control ofbuprenorphine under the CSA (Controlled Substances Act)
`An Eight-Factor Analysis was conducted and a recommendation for a higher schedule for
`buprenorphine and buprenorphine with naloxone was developed based on new data on
`comparative binding at the opiate receptors, information about the product’s ability to
`cause physical dependence, including reports of neonatal withdrawal syndrome, and
`reports of actual abuse worldwide using the sublingual formulations by intranasal,
`sublingual and intravenous routes. The stability of naloxone continues to be an issue in
`the scheduling of Suboxone, as it may prove less of a deterrent to abuse than was
`anticipated.
`
`APPEARS THIS WAY
`
`0N ORIGINAL
`
`

`

`NDA 20—733
`Reckitt & Colman
`Suboxone
`
`Pharmacokinetim
`
`.
`
`Pharmacokinetic studies to determine the appropriate method of delivering doses of more
`than two tablets still have not been submitted. These have been requested throughout the
`review cycles for Subutex and Suboxone by telecon and discussions with the sponsor.
`Studies were formally requested in the text of the Subutex NDA approvable letter and
`was irnplied in the labeling which was to have been adopted with the Suboxone AE letter
`also. Clearly, instructions for use cannot be written without these data, which should
`ultimately provide the regimen for dosing and the corresponding pharmacokinetic profile
`for multiple tablet delivery. This continues to remain a deficiency plaguing both
`applications. This will be requested again.
`
`Treatment under the Drug Addiction Treatment Act of2000
`The Drug Addiction Treatment Act of 2000 was passed during the review of
`buprenorphine and amends the Controlled Substances Act (CSA) to provide a system for
`physicians to prescribe drugs in schedules III, IV, and V in the setting of a doctor’s office
`rather than dispensed in a specialized clinic setting. As a new addiction medication
`about to be approved in a new health care system for delivery ample care should be taken
`to minimize the risks anticipated with this new treatment, based on European experience.
`Discussions have been initiated with the sponsor who will be expected to develop a risk
`management program to assess the success of this new treatment. The sponsor will be
`asked to develop a plan for postmarketing surveillance to assess the extent abuse and
`diversion, the effectiveness of naloxone as a deterrent to intravenous abuse, and the
`
`extent of abuse by other routes, particularly as it relates to the appropriate control of this
`drug substance.
`
`Action: Approvable pending satisfactory resolution of the stability issues, appropriate
`revisions in the package insert in accordance with previous recommendations, and
`development of a satisfactory program of Risk Management and Postrnarketing
`Surveillance in conjunction with the appropriate government agencies.
`
`{I}
`
`Cynthia G. McCormick, MD,
`Director,
`
`Division of Anesthetics, Critical Care, and
`
`Addiciton Drug Products
`
`January 24, 2001
`
`f
`
`_
`
`APPEARS THIS WAY
`0N ORIGINAL
`
`

`

`Cynthia McCormick
`1/24/01 11:29:35 AM
`MEDICAL OFFICER
`
`APPEARS THIS WAY
`0N ORIGINAL
`
`

`

`Electronic Mail Message
`
`Date:
`From:
`To:
`Subject:
`
`1/17/01 2:11:53 PM
`Bona, James
`Shepherd, Sara
`Re: ORPHAN DRUG QUESTION
`
`JBonaGOC.FDA.GOV )
`(
`( ShepherdS@A1 )
`
`Sara:
`
`Sorry I took so long to answer but I wanted to be certain of our position.
`
`Orphan designation for a single product does NOT cover a combination of the
`designated product and one or more other active ingredients. A separate
`designation application would have to be submitted and approved for the
`combination.
`
`However. in this case, buphrenorphine was designated on 6/15/94 (application
`~—-—
`and the combination w/naloxone designated on 10/27/94 (application
`\ , 80 both products appear to be covered by orphan designations.
`However, the firm should have provided a copy of the oombination's
`designation before the User Fees were waived.
`
`You should ask to have that submitted for completion sake. Hope this helps.
`
`ll Cathie I said hi!
`
`Jim
`
`-——-On'ginal Message-«-
`From:
`Sara Shepherd FAX t- [SMTP:SHEPHERDS@cder.fda.gov]
`Sent:
`Tuesday, January 16, 2001 11:36 AM
`To:
`JBONA@OC.FDA.GOV
`Subject: ORPHAN DRUG QUESTION
`Sensitivity:
`Confidential
`
`Cathie Schumaker suggested 1 talk to you about the orphan drug
`
`Subutex (buprenorphine HCl, NDA 20-732) and Suboxone
`(buprenorphine/naloxone, NDA 20-733). The letter we have on file
`
`status of
`
`(dated
`
`June 15, 1994) stated that "it is buprenorphine and not its
`formulation
`
`that has received orphan designation". The company submitted this
`letter to both NDAs (listed above). Does this orphan drug status
`
`the buprenorphine/naloxone product?? Both NDAs have gone thru
`
`cover
`
`several
`
`review cycles and the next PDUFA date is Jan 26, 2001. Thanks
`
`Sara Shepherd
`Project Manager
`Division of Anesthetic, Critical Care and Addiction Drug Products.
`827-7430
`
`

`

`saw:
`It.”
`('
`
`fit
`53*
`é;
`2%.,"
`
`.
`.
`DEPARTMENT OF HEALTH & HUMAN
`Public Health Semce
`SERVICES
`
`
`Food and Drug Administration
`Rockville, MD 20857
`
`NDA 20-732
`NDA 20-733
`
`Reckitt & Colman Pharmaceuticals, Inc.
`
`1909 Huguenot Road
`Richmond, VA 23235
`
`Attention: Alan Young
`Director, Regulatory Affairs
`
`Dear Mr. Young:
`
`Please refer to the teleconference between representatives of your firm and the FDA on
`December 14, 2000. The purpose of the telecon was to discuss the development of a risk
`management plan, and chemistry issues for Subutex and Suboxone.
`
`A copy of our minutes of that meeting is enclosed. These minutes are the official minutes of the
`meeting. You are responsible for notifying us of any significant differences in understanding
`you have regarding the meeting outcomes.
`
`If you have any questions, contact Sara Shepherd, Project Manager, at (301) 827-7430.
`
`’
`
`Sincerely,
`
`f3!
`
`,
`
`Sara E. Shepherd
`Regulatory Project Manager
`Division of Anesthetic, Critical Care,
`and AddictionDrug Products
`Office of Drug" Evaluation H
`Center for Drug Evaluation and Research
`
`APPEARS THIS WAY
`0N ORIGINAL
`
`

`

`NDA 20-732, NDA 20-733
`
`Page 2
`
`MEMORANDUM OF TELECON
`
`DATE: December 14, 2000
`
`APPLICATION NUMBER: NDA 20-732, NDA 20-733
`
`DRUGS: Subutex and Suboxone
`
`BETWEEN: Reckitt & Colman (waiting for list)
`Name:
`Charles O'Keeffe, President Reckitt & Colman Pharmaceuticals, Inc
`Alan Young, Director, Regulatory Affairs
`Chris Chapleo, Director, Buprenorphine Business Group
`Don Walter, Buprenorphine Development Manager
`Sharon James, Director R&D for Buprenorphine
`Paul Field, Formulation Development Manager
`Neil Hyde, Buprenorphine Project Manager
`Tim Baxter, Medical Director
`
`Name:
`
`Division of Anesthetic, Critical Care, and Addiction Drug Products
`Cynthia McCormick, M.D., Director
`Celia Winchell, M.D., Medical Team Leader
`
`Ali Al-Hakim, Ph.D., Chemistry Reviewer
`Sara E. Shepherd, Project Manager
`Controlled Substance Staff
`
`Corrine Moody, Project Manager,
`Michael Klein, Ph.D., Senior Interdisciplinary Scientist,
`Deborah Leiderman, M.D., Director
`
`SUBJECT: To discuss chemistry issues and the development of a risk management plan
`
`91mm
`1.
`The Division is still reviewing the chemistry issues for Subutex and Suboxone and has
`the following concerns:
`The instability of Suboxone under ICH guidelines.
`The limited shelf-life (12 months or less) based on submit