Ranjit B. Mani, MD, HFD-120 Medical Review
`NDA 21196 (N-BZ), Xyrem, Orphan Medical inc.
`
`Page 98 of 127
`3/4/02
`
`information regarding the proper handling of the drug with an outline of
`precautions to be taken against diversion
`If a patient has prescription drug coverage, “WM” ‘will then contact the
`patient’s insurance company to obtain coverage. mm will notify the
`patient of his/her approval status
`
`10. 1.1.3 Patient Services
`
`All patient assignment forms and registry information will need to be signed
`and sent back to the pharmacy before the initial prescription can be filled
`Comprehensive printed and video materials (see Xyrem® Patient Success
`Program below) that also contain information regarding the proper handling of
`the drug with an outline of precautions to be taken against diversion will be
`provided to the patient in advance of shipment.
`Once approval has been established, |\._—»—-—Wi” verify the patient’s
`home address and availability for shipping and arrange shipment through
`Federal Express RapidTrac or a similar carrier
`Receipt of the initial drug shipment will be ensured through the following
`. A phone call by the pharmacy to the patient, no more than 24 hours after
`the shipment is delivered, to verify that the medication and educational
`materials have been received
`
`. The courier service‘s own tracking system for shipments which requires a
`signature by the patient
`If the patient or their designee is unavailable to accept a shipment of Xyrem®
`and execute the required receipt after two delivery attempts, the package will
`be returned to the pharmacy.
`If a shipment is lost, an investigation will be launched to find it.
`If required by the patient’s insurance company the product may be shipped by
`“W to another pharmacy for patient pick-up. The sponsor anticipates
`that this will be an unusual occurrence and has a mechanism for verifying the
`second pharmacy’s ability to protect against diversion of sodium oxybate
`before shipping the drug there through NTlS and State Boards of Pharmacy
`
`101.1.4 Registry
`
`
`
`in
`Every patient and prescribing physician will be registered with
`a secure database The database will contain the physician’3 name, address,
`telephone and facsimile numbers, DEA and state license numbers and
`prescribing frequency. The database will be made available for review by the
`DEA as well as other federal and state agencies upon request. From this
`database it will be possible to obtain the following information
`o Prescriptions by physician specialty
`. Prescriptions by patient name
`. Prescriptions by volume (frequency)
`. Prescriptions by dose
`Prescription refills will be permitted in the number specified in the original
`prescription. In addition
`
`

`

`Ranjit B. Mani, MD, HFD—120 Medical Review
`NBA 21196 (N-BZ), Xyrem. Orphan Medical Inc.
`
`Page 99 of 127
`3/4/02
`
`lf a prescription refill is requested by the patient prior to the anticipated
`due date, such refills will be questioned by the pharmacist
`A lost, stolen, destroyed, or spilled prescription/supply will be documented
`and the prescription replaced to the extent necessary to honor the original
`prescription (e.g., a destroyed or spilled bottle will reduce the prescription
`refill amount). The pharmacist has the discretion to grant or not grant refill
`requests under those circumstances and at a minimum will contact the
`prescribing physician to determine if the physician has any special
`concerns in regard to that refill request. New supplies of Xyrem® will be
`sent to the patient only if the pharmacist and physician are in agreement.
`Repeat instances of lost, stolen, destroyed, or spilled
`prescriptions/supplies will be flagged formonitoring and future instances
`thoroughly questioned
`With the first prescription it is planned to provide the patient with only one
`month's supply of Xyrem®.
`Following further contact between the pharmacy and patient, and
`verification that the patient understands the material in the Xyrem® Patient
`Success Program, supplies of Xyrem® that are intended to last longer
`than a month may be shipped
`The quantity of drug shipped to the patient with each refill may also be
`regulated based on the requirements of the patient’s health insurance plan
`and the terms of the prescription itself
`It is anticipated that the majority of patients will receive only one month’s
`shipment at a time and never more than 3 months’ supply per shipment.
`
`A
`
`10. 1.2 Drug Product Kit
`
`The drug product kit will consist of
`
`The drug product, a clear solution, in a 180 mL amber bottle with a closure
`mechanism that is child-resistant
`
`The Press-ln—Bottle-Adapter (PIBA Well) which will be inserted into the bottle
`by the pharmacist
`An Exacta-Med Dispenser which allows the patient to withdraw the
`appropriate dose of drug
`Two child-resistant dosing cups, one for each of 2 nightly doses. The first
`dose will be consumed just prior to lying down at bedtime and the second
`dose will be placed at the bedside, and sealed with a childproof lid until
`consumed by the patient 2.5 to 4 hours later.
`A package insert which includes a Medication Guide
`
`Every box of Xyrem® shipped to the patient will contain all the above items
`
`10.1.3 Xyrem® Physician Success Program
`
`This program consists of a videotape and printed material(s) to educate
`physicians about the features of Xyrem®. When a physician prescribes the drug
`for the first time, he/she will be mailed the program; the mailing will be
`documented as will a follow-up phone call to the physician confirming receipt and
`
`

`

`Ranjit B. Mani, MD, HFD-120 Medical Review
`NBA 21196 (N-BZ), Xyrem, Orphan Medical lnc.
`
`Page 100 of 127
`3/4/02
`
`the physician must verify that they have read the materials before the medication
`will be sent to the patient
`
`10.1.4 Xyrem® Patient Success Program
`
`This program consists of a videotape and printed educational material. The
`patient will receive this material prior to the first shipment of drug.
`
`10.2 Proposed Physician Success Program
`
`The components of this section are as follows
`
`10. 2. 1 Dear Doctor Letter
`
`In this letter the following are outlined
`lndication for which Xyrem® is approved
`Active ingredient in Xyrem®
`Reason for Xyrem® being marketed under a restricted distribution program
`Patient responsibilities and requirements
`Physician responsibilities and requirements
`That monitoring patients for efficacy and safety is a condition for approval. For
`that purpose evaluation forms have been provided which the physician has
`been asked to fill in every 3 months for the first 6 months.
`. A toll—free number for the Xyrem® Physician Success Program
`
`10.2.2 Booklet
`
`The booklet has the following headings
`Prescribing Xyrem® - A Brief Guide
`Prescription and Enrollment Form
`Suggested Guidelines for Titrating Xyrem®
`Information You Need To Know About Xyrem®
`Contact Information
`
`Package lnsert (copied below)
`
`APPEARS THlS WAY
`0N ORIGIHAL
`
`

`

`Ranjit a. Mani, MD, HFD-tZO Medical Review
`NDA 21196 (N—BZ), Xyrem, Orphan Medical inc.
`
`Page 101 of 127
`3/4/02
`
`Prescription and Enrollment Form
`
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`
`[Juan-“nix
`
`. Medication Guide
`
`10.2. 3 Video
`
`The sponsor states that
`. A storyboard and proposed text has previously been submitted to the NDA
`. A prototype video has been submitted to the briefing booklet for the FDA
`Advisory Panel meeting
`0 A new video will be prepared once final labeling is arrived at and agreed upon
`
`

`

`Ranjit B: Mani, MD, HFD-120 Medical Review
`NBA 21196 (N-BZ), Xyrem. Orphan Medical inc.
`
`Page 102 of 127
`3/4/02
`
`10.2.4 Patient Evaluation Program
`
`This section contains the following components
`
`10.2.4.1 Dear Doctor Letter
`
`This explains
`. The purpose of the Program which is fulfil a commitment made as a condition
`for approval to provide data on the first 6 months of Xyrem® therapy for 1000
`patients to the FDA
`0 What the physician needs to do to fulfil this requirement: complete the
`Xyrem® Post-Marketing Evaluation Form at repeat visits every 6 months
`during the first 6 months of treatment (i.e., the form must be completed twice);
`and whenever any adverse event occurs
`.~
`
`10.2.4.2 Instructions For Completion Of Xyrem® Post-Marketing Evaluation
`Form
`
`10. 2 4. 3 Xyrem® Post—Marketing Evaluation Form
`This 2--page formIS copied below
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`

`

`Ranjit B. Mani, MD. HFD—120 Medical Review
`NDA 21196 (N—BZ). Xyrem. Orphan Medical lnc,
`
`SK'TION 3
`
`Page 103 of 127
`3/4/02
`
`PATIENY FOLLOWL‘P NARCOLEPSY St'MPtous AS‘ESSMENT
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`10.3 Proposed Patient Success Program
`
`The components of this section are as follows
`
`10.3.1 Dear Patient Letter
`
`This outlines
`
`. What Xyrem® is approved for
`. Distinctive features of the drug
`0 Purpose of the Patient Success Program
`. A toll-free number for the central pharmacy
`
`10.3.2 Booklet
`
`The main sections in this booklet are titled as follows
`
`0 How do I obtain Xyrem®?
`o How do I take Xyrem®?
`. Precautions needed for Xyrem® use
`. Other information (sources for information on Xyrem®, narcolepsy and other
`sleep disorders)
`0 My prescription record
`0 At home storage and safety tips
`. Traveling tips
`- Reimbursement information for patients
`. Medication guide
`. Wallet card
`
`

`

`Ranjit a. Mani, MD, HFD-120 Medical Review
`NDA 21196 (N-BZ), Xyrem, Orphan Medical Inc.
`
`Page 104 of 127
`3/4/02
`
`10.3.3 Video
`
`The sponsor states that
`. A storyboard and proposed text has previously been submitted to the NDA
`. A prototype video has been submitted to the briefing booklet for the FDA
`Advisory Panel meeting
`. A new video will be prepared once final labeling is arrived at and agreed upon
`
`10.4 Office Of Post-Marketing Drug Risk Assessment Comments On Risk
`Management Program
`
`This submission, including the comments made in the cover letter were reviewed
`by Lauren Lee, Pharm. D., of the Division of Drug Risk Evaluation 1. Her
`comments are contained in a memo dated 10/23/01 and are summarized below
`
`. Her Division is in agreement that the diagnosis of narcolepsy with cataplexy
`should be confirmed prior to the drug being dispensed. The sponsor’s
`counter-proposal (see Section 4.1.1) will not result in off—label use being
`restricted
`
`0 Her Division agrees that the pharmacist dispensing Xyrem® could obtain
`telephonic (as opposed to written) confirmation that the patient has read the
`educational materials. OPDRA does however recommend that the Risk
`
`Management Program explicitly states that this phone call be received and
`recorded by the pharmacist
`. The sponsor has proposed that “after completing the post-marketing
`surveillance program and review by the FDA any specific prescription be
`allowed to be extended to 6 months pursuant to normal Schedule III
`practices." OPDRA does not recommend that such an extension be given: the
`dispensing of 18 bottles of Xyrem® at a time raises safety concerns including
`those of secure storage of such a large quantity of Xyrem®
`0 According to the sponsor, Orphan Medical, Inc. has no legal right to access
`patient pharmacy records to actively monitor for abuse, misuse and diversion,
`and that the patient registry would be made available for review by the
`regulatory agencies charged with policing, abuse, and misuse. OPDRA
`recommends that a licensed pharmacist
`in the central pharmacy who has
`access to patient pharmacy records routinely monitors for over—prescribing or
`frequent refills
`‘
`
`.
`
`in addition to completing the Xyrem® Post—Marketing Evaluation Form and
`observing the standard Agency reporting requirements for deaths and serious
`adverse events physicians should be encouraged to report any adverse
`event, serious or not, to the FDA through MEDWATCH and/or the
`manufacturer using Form 3500 (since the Xyrem® Post-Marketing Evaluation
`Form is not intended to replace Form 3500). A copy of Form 3500 should be
`included in the Physician Success Program packet.
`. The registry created through the Xyrem® Post-Marketing Evaluation Forms
`should not be limited to 1000 patients or the first 6 months but should
`
`

`

`Ranjit B. Mani. MD, HFD-120 Medical Review
`NBA 21196 (N—BZ), Xyrem, Orphan Medical Inc.
`
`Page 105 of 127
`3/4/02
`
`a
`
`continue to accrue patients until sufficient safety data has been obtained and
`presented to the FDA. OPDRA also recommends that safety data from these
`forms should be submitted quarterly during the "initial” phase and the need for
`longer term reporting be reassessed.
`o The Post-Marketing Patient Evaluation Form does not provide for physician
`inquiry directed at evidence of abuse, misuse, or diversion of Xyrem®.
`OPDRA recommends revising the form to include a subsection where
`physicians are asked to record unusual refill requests and reports of loss/theft
`that would be suspicious of inappropriate drug use.
`In the column contained in the Post-Marketing Patient Evaluation Form that
`that records the severity of the adverse event it is unclear whether the
`severity is to be based on patient or physician assessment and what criteria
`are to be used to qualify an adverse event as mild, moderate or severe.
`OPDRA recommends clarifying these matters
`In the Column headed “Relationship to Xyrem®” it is unclear if the relationship
`of the adverse event to Xyrem® is to be based on patient or physician
`assessment; OPDRA feels that that requires clarification as well
`o The Response to Treatment section of the Post-Marketing Evaluation Form is
`designed to collect data on the efficacy of the drug and can be used for
`marketing purposes. One of the questions in this section requires assessment
`of the severity of daytime sleepiness and may encourage off-label use of the
`drug. OPDRA recommends that this section should be deleted since it does
`not address any safety—related issues
`. OPDRA recommends that the following statement be added to the section
`entitled “Information you need to know about Xyrem®” in the Physician
`Success Program booklet
`
`0
`
`‘
`
`“Educate your patients that Xyrem® should not be taken with alcohol and other medications
`that may cause drowsiness"
`. OPDRA recommends that the following be added to the section entitled
`“What do i do before taking Xyrem® each night" in the Patient Success
`Program booklet
`
`A statement specifying that the each dose should be diluted with 2 oz of water
`(currently the directions merely state that the each dose should be diluted
`with water)
`
`10.5 Reviewer’s Comments
`
`In making this summary l have also referred to the sponsor’s cover letter
`summarized in Section 4
`
`. The only significant change to the Risk Management Program summam
`outlined in the attachment to the Approvable letter is that the physician
`prescribing Xyrem® must verify that he/she has read the materials contained
`in the Xyrem® Physician Success Program prior the medication being sent to
`the patient.
`
`

`

`Ranjit B. Mani, MD, HFD-120 Medical Review
`NDA 21196 (N-BZ), Xyrem, Orphan Medical Inc,
`
`Page 106 of 127
`3/4/02
`
`Based on recommendations from the Office Of Post-Marketing Drug Risk
`Assessment, the following should be added to the detailed Risk Management
`Program
`
`0 The pharmacist who obtains telephone confirmation that the patient has read the
`educational materials should record this confirmation
`
`0 Even after completing the post-marketing safety assessment program, refills
`should continue to be limited to a maximum of 3 months
`
`in the central pharmacy who has access to patient
`. A licensed pharmacist
`pharmacy records should routinely monitor for over-prescribing or frequent refills
`. A copy of Form 3500 should be included in the Physician Success Program
`packet.
`o The registry created through the Xyrem® Post-Marketing Evaluation Forms
`should not be limited to 1000 patients or the first 6 months but should continue to
`accrue patients until sufficient safety data has been obtained and presented to
`the FDA as well as reviewed by the Agency.
`. The Post-Marketing Patient Evaluation should include a subsection where
`physicians are asked to record unusual refill requests and reports of loss/theft
`that would be suspicious of inappropriate drug use.
`0 The following statement be added to the section entitled “Information you need to
`know about Xyrem®" in the Physician Success Program booklet:
`
`“Educate your patients that Xyrem® should not be taken with alcohol and other medications that
`may cause drowsiness"
`o A statement specifying that the each nightly dose of Xyrem® should be diluted
`with 2 oz of water should be added to the section entitled “What do I do before
`
`taking Xyrem® each night” in the Patient Success Program booklet
`
`11. Interaction Of GHB With Human Hepatic Microsomal CYP450
`lsoenzymes
`
`This study is summarized below. Please see the Biopharmaceutics review for full
`details
`
`The purpose of the study was to evaluate the in-vitro inhibitory potential of
`GHB towards specific isoenzymes of human hepatic cytochrome P450 using
`selective probe substrates for each isoenzyme
`
`A mixed pool of human hepatic microsomes was used
`
`Each assay was performed at a single concentration of the probe substrate
`approximating the Km value for human hepatic microsomes. Each assay was
`performed in the presence and absence of GHB. GHB concentrations used
`were 300, 1000 and 3000 pM
`
`The substrates used, isoenzymes assessed and |C50 values for each assay
`are in the following table which I have copied from the submission.
`
`

`

`Ranjit B. Mani, MD, HFD—120 Medical Review
`NDA 21196 (N—BZ), Xyrem, Orphan Medical inc.
`
`Page 107 of 127
`3/4/02
`
`
`
`Assav
`
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`
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`
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`
`Alhdephenytoin 4'~h_\;droxyiase
`Dcxtromethorphan O-demethylase
`
`,n—Nitrophenol hydroxylzfie
`Li". [hroim cm N-dcmcthx lasc
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`
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`
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`
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`
`. The sponsor has concluded that GHB at concentrations of 300, 1000 and
`
`3000 uM did not inhibit the following CYP450 isoenzymes: 1A2, 2C9, 2C19,
`2D6, 2E1, and 3A
`
`12. Chemistry, Manufacturing And Controls
`
`l have confirmed with the Chemistry reviewer of this application, Dr Thomas
`Oliver, that _//T\ ,was found acceptable (on 11/6/01)for the
`manufacture of X'yrem®.
`
`13. Proposed Labeling
`
`This is reviewed in a separate document
`
`14. Proposed Patient Medication Guide
`
`14.1 Contents
`
`The 9-page medication guide contains sections entitled as follows
`
`14.1.1 What is the most important information I should know about Xyrem®?
`
`This section is COpied verbatim below
`
`

`

`i page(s) of
`revised draft labeling
`has been redacted
`
`frOm this portion of
`the review.
`
`

`

`Ranjit B. Mani, MD, HFD-120 Medical Review
`NBA 21196 (N-BZ). Xyrem, Orphan Medical Inc.
`
`Page 1 12 of 127
`3/4/02
`
`prescribers about the restricted distribution program, prescribing of Xyrem and the illicit use of
`GHB, are in the professional insert.”
`
`15.2 Reviewer’s Comments
`
`The advertisement contains the following statement
`
`Xyrem is a known neuromodulator of brain dopamine and serotonin
`
`The relevance of this statement to the role of Xyrem® in treating cataplexy is
`unclear. The statement should be deleted.
`
`16. Updated Exposure Data
`
`At the request of this reviewer the sponsor submitted on 2/18/02 updated
`exposure tables for Xyrem®. Similar tables were submitted with the Major
`Amendment dated 3/23/01 and were reviewed at that time.
`
`16.1 Overall Schematics For Clinical Trials In Narcoleptic Patients Included
`In NBA
`
`The submission contains 2 schematics
`
`16.1.1 Schematic For Clinical Trials Sponsored By Orphan Medical Plus Scha/f
`Trial
`
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`
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`
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`
`

`

`Ranjit B. Mani, MD, HFD-120 Medical Review
`NDA 21196 (N432), Xyrem, Orphan Medical Inc.
`
`Page 1 13 of 127
`3/4/02
`
`16.1.2 Schematic For Clinical Trials Sponsored By Orphan Medical Alone
`
`(rummueu Trials
`
`5' 'nmmmued Trials
`
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`Total Pfil‘flfl £48me
`t Iuc mum: ,urhcipuk‘d n: L-uLl: lflkK'dXR-fi 11735.5.‘935andUkK3SXB-
`My Exposure 4“ ”than. 125 subjects: 591 total
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`
`16.2 Tables
`
`16.2.1 Sponsor’s Methods For Creating Tables
`
`Tables were created for 2 different groups of patients
`. The updated Integrated Clinical Trials database which included the following
`studies through the cut-off date of 6/30/01: OMC-GHB-Z, OMC-GHB-B, OMC-
`
`SXB-6, OMC-SXB-7, Scrima,
`and OMC-SXB-20
`
`. All patients subsumed by the above bullet plus the Scharf study
`
`The sponsor used the following methods for creating these tables
`. Each patient dose was classified into one of 5 “standard” dose groups as in
`the followin table
`
`
`
`. Each patient’s exposure to these 5 standard doses was calculated for both
`groups of patients and the number of patients at each dose level for each
`duration of exposure recorded in the tables. Assignment of patients to a
`dosing category was made based on continuous exposure time in that dosing
`category
`0 For the “overall duration of exposure” category each patient’s time of
`exposure was calculated regardless of dose.
`
`

`

`Ranjit B. Mani, MD, HFD—120 Medical Review
`NBA 21196 (N-BZ), Xyrem, Orphan Medical Inc.
`
`Page 1 14 of 127
`3/4/02
`
`. Patients who received placebo only were not included in the tables
`. Duration of exposure was calculated based on a 28-day month
`o Since each patient could be represented in more than one dose category for
`the specified duration of exposure the overall exposure numbers do not
`represent arithmetical summations of the numbers in individual dose
`categories
`
`16.2.2 Tables
`
`The sponsor has presented tables for different durations of exposure
`
`16.2.2.1 Duration of Exposure 2 6 Months
`
`- 1
`
`6.2.2.2 Duration of Exposure 2 12 Months
`
`The sponsor’s table is presented below
`
`The sponsor’s table is presented below
`
`gm
`gm
`
`
`sud
`
`
`
`
`
`
`
`
`16.2.2.3 Duration of Exposure 2 24 Months
`
`The sponsor’s table is presented below
`9
`9
`9
`
`PatLents
`3.0
`/d
`4.5
`Id
`6.0
`.t'd
`
`
`
`
`———————
`
`
`9.0 g/d Overall
`
`
`
`
`16.2.2.4 Sponsor’s Comments About Above Tables
`
`The sponsor has drawn attention to the following:
`. The most commonly used dose of GHB across the 3 durations of exposure
`was 6 g/day regardless of whether data from the long-term Scharf trial were
`included or excluded
`
`. The vast majority of patients used doses ranging from 4.5 to 9 g/day, across
`durations of exposure. The Sponsor has proposed a starting dose of 4.5 g/day
`with a range of 3 to 9 g/day after titration (reviewer’s note: this does not match
`with the dose range proposed by the sponsor in the proposed labeling)
`
`16.3 Sponsor’s Overall View Of Adequacy Of Exposure
`
`. The sponsor has provided comparisons of the adequacy of exposure to
`Xyrem® with and without the Scharf study database. The following table
`summarizes the data resented b the sponsor
`
`Interated Clinical Trials PlusScharf
`
`
`
`
`
`__—-__-—
`
`
`
`_——__
`__—__
`-_—___
`
`
`
`
`

`

`Ranjit B. Mani, MD, HFD~120 Medical Review
`NBA 21196 (N-BZ), Xyrem. Orphan Medical Inc.
`
`Page 1 15 of 127
`3/4/02
`
`Stud Pool
`
`
`Health Sub‘ects'
`_— Health Sub‘ects'
`
`———__
`*Healthy subjects were exposed to single doses only
`
`lnterated Clinical Trials Plus Scharf
`
`lnte rated Clinical Trials Onl
`
`
`
`
`. The entire database contains sufficient patient exposure sufficient to meet the
`lCH guidelines at 6 months (> 300 patients) and 1 year (> 100 patients) even
`if the Scharf study data are excluded.
`
`16.4 Additional Request For Information From Sponsor
`
`On 2/22/01, an additional request for information regarding exposure data was
`transmitted to the sponsor. The request and the sponsor’s response are
`summarized below
`
`16.4. 1 Request For Information
`
`What is the total number of narcoleptic patients exposed to a 6-9 g/day dose
`range, $3 to a 9 g/day dose, of Xyrem® for any duration in the following
`groupings? (These data should be updated through 6/30/01, consistent with your
`submission of 2/18/02).
`.
`Integrated Clinical Trials
`.
`Integrated Clinical Trials plus Scharf Study
`
`16.4.2 Sponsor’s Response
`
`The sponsor has submitted a table that represents patient exposure 2 1 day, for
`doses of 2 6.0 g/day and for a dose of 9.0 g/day in the following 2 groups of
`patients
`0 The updated Integrated Clinical Trials database which included the following
`studies through the cut-off date of 6/30/01: OMC-GHB-2, OMC-GHB-3, OMC-
`
`SXB-S, OMC-SXB-7, Scrima,
`. and OMC-SXB-2O
`
`. All patients subsumed by the above bullet plus the Scharf study
`
`The sponsor used the following methods for creating this table
`0 Each patient dose was classified into one of 5 “standard" dose groups as in
`the followino table
`
`
`
`Inclusion in the 2 6.0 g/day dose group required patients to have had at least
`1 day of exposure at the 6.0 g/day, 7.5 g/day or 9 g/day dose
`Inclusion in the 9.0 g/day dose group required patients to have had at least 1
`day of exposure at the 9.0 g/day dose
`
`.
`
`The table submitted by the sponsor is below, as copied from the submission
`
`

`

`Ranjit a Mani, MD, HFD-120 Medical Review
`NBA 21196 (N—BZ). Xyrem, Orphan Medical Inc.
`
`Page 1 16 of 127
`3/4/02
`
`26-
`
`/.-~,
`
`185 + Scharf
`
`b '
`
`’Ju on;y. Exposure was aZSQ no:
`but no
`
`'-
`I
`hezore data cuteff {Juze EC 200:), sznce
`exposure woui: have been collected.
`
`16.5 Reviewer’s Comments
`
`The size of the Xyrem® NDA does meet lCH guidelines for drug exposure for
`6 months and a minimum of 1 year if one assumes that the effective dose
`ranges from 3 to 9 grams/day. The ICH guidelines are met even if the Scharf
`study is excluded
`However, if one concludes (from the efficacy studies) that the 9 g/day dose is
`the only effective dose and is that to be recommended for general use the
`number of those exposed to Xyrem® at that dose for 2 6 months and 2 12
`months does not meet ICH guidelines. If it is concluded from the efficacy
`studies that the effective dose of Xyrem® ranges from 6-9 g/day, the number
`of those exposed at that dose range for 2 6 months falls somewhat short of
`that specified in the lCH guidelines, whereas the number exposed for 12
`months does not.
`
`Note that ICH guideline E1A (July 1997) states the following (key phrases have been
`underlined by me):
`“The number of patients treated for 6 months at dosage levels intended for clinical use should be adequate to
`characterize the pattern of adverse events over time. To achieve this objective the cohort of exposed subjects
`should be large enough to observe whether more frequently occurring events increase or decrease over time as
`well as to observe delayed events of reasonable frequency (e.g., in the general range of 0.5% to 5%). Usually 300
`to 600 patients should be adequate...
`
`....... 100 patients exposed for a minimum of 1 year is considered to be acceptable to include as part of the safety
`databases The data should come from prospective studies appropriately designed to provide at least one year
`exposure at dosage levels intended for clinical use."
`The extent of exposure to GHB in patient-years is reduced by about_61%-
`once the Scharf study data are eliminated. Admittedly, the ICH guidelines do
`not specifically address the issue of desirable exposure in patient-years.
`The total number of narcoleptic patients exposed Xyrem® 9 g/day or 6—9
`g/day for any duration is very small. Even the total number of patients
`exposed to any close of Xyrem® for any duration (n=543, with the Scharf
`study data included) represents only about 36% of that required under lCH
`guidelines
`There are no lCH guidelines that address exposure requirements for orphan
`drugs. The total number of patients exposed to Xyrem® might be arbitrarily
`considered appropriate for an orphan drug used for an orphan indication (i.e.,
`
`not calculated for the j
`
`a: expcsure at
`
`the given
`
`

`

`Page 1 17 of 127
`Ranjit B. Mani. MD, HFD-120 Medical Review
`
`NDA 21196 (N-BZ), Xyrem, Orphan Medical Inc. 3/4/02
`
`.fl"
`
`cataplexy in narcolepsy); that may be especially true if the sponsor’s estimate
`that the number of diagnosed/treated cataplexy patients in the United States
`is in the range of 20,678~22,917 is correct (this estimate was conveyed to this
`Division at a meeting held on 2/28/01). The total number of patients exposed
`to Xyrem® is certainly not adequate to cover its potential use for a variety of
`much