Ranjit B. Mani, MD, HFD-120 Medical Review
`NBA 21196, Xyrem, Orphan Medical, inc.
`
`Page 106 of 135
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`
`13102 Patient # 0232
`
`This patient has already been described in Section 10.5.2. The adverse event occurred
`shortly after she finished participating in Study OMC-SXB-21.
`
`13.103 Patient # 0931
`
`This 29 year old woman had taken Xyrem® from 7/5/99 until she developed the serious
`adverse event listed in the table above in April 2000. At screening, she did not disclose
`that she had a past history of depression.
`'
`
`Her dose of Xyrem® at the time of the adverse event was 4.5 g/day. She was also
`receiving modafinil 600 mg/day.
`
`On 4/27/00 the study coordinator was informed that the patient had been hallucinating
`and had lost her job owing to a diminished ability to function at work. On 4/29/00 the
`patient was found to be unarousable in her car by emergency personnel: on being
`awakened she became violently agitated, but was also slow in responding to questions.
`She was hospitalized and treated with multiple medications for agitation. Her urine drug
`screen was positive for benzodiazepines. The patient later reported that on 4/29/00 she
`pulled off the road to sleep at which time she took both nightly doses of Xyrem® together
`without dilution. She was diagnosed to have a bipolar disorder.
`
`She did not take any Xyrem® after 4/29/00 and at a follow-up visit on 6/14/00 appeared
`mentally well.
`
`13.10.4 Patient # 1131
`
`This 46 year old man was begun on Xyrem® on 4/30/99. At study entry he did not
`disclose that he had a past history of depression and a previous suicide attempt.
`Concomitant-medications at study entry included modafinil 400 mg/day, ibuprofen, an
`aspirin-acetaminophen-caffeine combination pill, dextroamphetamine and bupropion (for
`smoking cessation).
`
`His regular dose of Xyrem® at the time of the serious adverse event described below
`was 9 g/day.
`
`He took an overdose of Xyrem® (subsequently estimated at 150 g) on 2/2/00. His wife
`found him unresponsive and incontinent of urine and feces that day. He was initially
`unresponsive with apneic spells, but with normal arterial blood gases. He later became
`combative and finally awoke, at which time he was observed to be depressed. He,
`reported multiple major sources of stress. He required psychiatric hospitalization and did
`not resume Xyrem®.
`
`13.105 Patient # 14043
`
`This 26 year old woman had previously participated in the Scharf trial and had received
`GHB since 7/5/89. She entered the OMC-SXB—7 trial on 8/30/99. Her past medical
`history was remarkable for obsessive compulsive disorder. Concomitant medications
`during the OMC-SXB-7 trial include fluvoxamine, buspirone and methylphenidate.
`
`On 4/2/00 she took her usual dose of Xyrem® (7.5 g/day) and then attempted suicide by
`taking 56 tablets of buspirone 5 mg. She immediately told her father what had
`.
`happened, was taken to an emergency room where she was treated and released. She
`
`_/"»
`
`

`

`Ranjit B. Mani, MD, HFD-120 Medical Review
`NBA 21196, Xyrem, Orphan Medical, Inc.
`
`Page 10'/ of 135
`6/15/01
`
`reported being increasingly self-critical from January 2000 onward after beginning
`methylphenidate. After discontinuing Xyrem® (last dose on 4/4/00) she became more
`negative in outlook and noted an increase in cataplexy and in sleepiness.
`
`[3.10.6 Patient # 2030
`
`This 18 year old man began taking Xyrem® on 5/28/99 and was maintained on a stable
`dose of 9 g/day thereafter. Concomitant medications included zolpidem, protriptyline,
`modafinil (200 mg/day), fluoxetine 20 mg/day, methylphenidate 40-45 mg/day. He
`reported no previous psychiatric history.
`
`On 12/15/99 he began experiencing paranoia, confusion and hallucinations. He reported
`increasing his dose of methylphenidate earlier while preparing for examinations. He was
`hospitalized and treated with multiple medications. Xyrem® was stopped on 12/22/99.
`He improved and his psychosis was attributed to methylphenidate overuse and to sleep
`deprivation.
`
`13.11 Adverse Event Discontinuations
`
`10 patients, including the patient who died, discontinued treatment on account of
`an adverse event. They are summarized in the following table. With the
`exception of Patient 1305 all the others are listed under Deaths and Serious
`Adverse Events
`’
`
`COSTART Preferred Term
`Liver functioa tests
`abnormal"
`
`Relationship to
`Trial Drug
`
`Manic depressive reacnion
`[bipolar affective
`disorder}
`
`In 0
`
`'U
`
`Possibly reinted
`
`ri.
`
`.
`
`Suicide attempt"
`
`.~Ju':
`LON
`
`....lL.)(3C:U!0
`
`13.11.] Patient 1305
`
`This 75 year old woman entered the OMC-SXB-7 trial after participating in the OMC-
`GHB-2 and OMC—GHB-3 trials. She had received Xyrem® since 8/5/97 and was on a
`stable dose of 9 g/day from 7/8/99. Her neurological history was unremarkable except
`for narcolepsy with cataplexy. Her concomitant medications included ibuprofen,
`conjugated estrogen, medroxyprogesterone, and long and short-acting methylphenidate.
`
`On 2/12/00 she began experiencing an intermittent “movement disorder”. A nocturnal
`polysomnogram confirmed that she had periodic leg movements (it is unclear if the
`
`

`

`Ranjit B. Mani, MD, HFD-120 Medical Review
`NDA 21196. Xyrem, Orphan Medical, Inc.
`
`Page 1 10 of 135
`6/15/01
`
`.
`
`.
`
`. Every patient and prescribing physician will be registered with /"" ’ in
`a secure database. The database will contain the physician’s 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
`Prescriptions by physician specialty
`Prescriptions by patient name
`Prescriptions by volume (frequency)
`Prescriptions by dose
`if required by the patient’5 insurance company the product may be shipped by
`“a“ 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 GHB before shipping
`the drug there.
`Prescription refills will be permitted in the number specified in the original
`prescription. In addition
`.
`if 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 for monitoring and future instances thoroughly questioned
`. The quantity of medication to provided with each refill will be guided by the
`following
`.
`_- 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 materialIn 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. "
`
`0
`
`-
`
`.
`
`‘
`
`14.1.2 Drug Product Kit
`
`The drug product kit will consist of
`. The drug product, a clear solution, in a
`mechanism that is child-resistant
`
`
`
`amber bottle with a closure
`
`. The Press-ln-Bottle-Adapter (PlBA Well)‘which will be inserted into the bottle by the
`pharmacist
`
`

`

`Ranjit s. Mani, MD, HFD-120 Medical Review
`NDA 21196, Xyrem, Orphan Medical, lnc.
`
`f
`
`Page 11 1 of 135
`6/15/01
`
`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 patient information sheet*
`
`Every box of Xyrem® shipped to the patient will contain all the above items
`
`*The patient information sheet includes the following information
`Dosing instructions
`Preparation of dose
`The steps involved in dose preparation and use are as follows
`.
`Remove bottle cap
`'
`Insert measuring device into bottle containing PlBA Well
`Draw up prescribed dose
`Remove measuring device from bottle
`Empty dose into first dosing cup
`Dilute with 60 mL of water
`Repeat procedures with second dosing cup
`L Place second dosing cup at bedside after securing lid
`Set alarm for no later than 4 hours after first dose
`Drink first dose sitting up and immediately lay down
`Awake for second dose.
`Drink second dose sitting up
`-
`Side-effects
`
`Special concerns: memory problems, dependence, withdrawal, changes in behavior and
`thinking, pregnancy
`Safe use of Xyrem®:
`.
`scheduling
`.
`selfvobservation for behavioral changes
`-
`cautions regarding concurrent use of medications and alcohol, driving, operating machinery, piloting an aircraft
`and pregnancy
`caution against sharing Xyrem® with others
`sale storage and disposal
`
`.
`.
`
`14.1.3 Xyrem® Physician Success Program
`
`This program consists of a videotape and printed material.
`
`14.1.3.1 Distribution
`
`This program will be distributed as follows
`“Customer targets.” This phrase refers to a database of physicians who have
`prescribed modafinil more than 4 times (about 4000 physicians have done so
`at present but the data will be refreshed when Xyrem® is launched). When
`Xyrem® is launched the program will be mailed to the target physicians as
`well as handed to them by sales representatives. The mailing as well as the
`receipt from sales representatives will be documented. No physician samples
`will be provided by the sales representatives
`When a physician prescribes the drug for the first time, he/she will receive
`also be mailed the program: the mailing will be documented as will a follow-up
`phone call to the physician confirming receipt
`
`

`

`Ranjit e. Mani, MD, HFD-120 Medical Review
`NDA 21196, Xyrem, Orphan Medical, Inc.
`
`Page 1 12 of 135
`6/15/01
`
`14.1.3.2 Videotape
`
`The draft video "story-board" prepared by the sponsor contains the following
`elements
`
`The identity and medical uses of Xyrem®
`A short history of the development of this drug
`The need for patients to follow the physician’s instructions in their entirety. Among
`other instructions the physician will need to tell patients that
`.
`The optimal dose of Xyrem® will need to be reached by titration over a number of Weeks
`0
`lmprovements in symptoms may not be fully apparent until 60-90 days after the drug is
`first begun
`Instructions regarding the frequency of dosing, emphasizing the need to take the
`medication twice every night.
`Very detailed instructions regarding the preparation of individual doses
`The need to place the second nightly dosage cup in an area not accessible to
`children, to store the medication bottle in a secure location and to consume the entire
`content of both dosing cups, sitting up.
`Directions as to when the bottle is to be disposed of (Le, when the solution can no
`longer be drawn out of the bottle with the dispensing device), and emphasis oh the
`need to empty the bottle completely and deface the label with a marker pen before
`throwing it away
`Federal scheduling of Xyrem® for legal and illegal use, the latter for punitive
`purposes
`The need to follow all standard procedures used for prescribing controlled
`substances
`.
`
`‘
`
`'
`
`A listing of types of patient behavior that may indicate misuse or abuse of Xyrem®
`The need to make clear to the patient that he or she may be legally responsible for
`the careless use and/or illicit distribution of Xyrem®
`.
`Penalties for misusing or abusing Xyrem®
`The provision of an optional Patient Consent (“Patient/Physician Responsibility
`Contract”) form in the information package. The form is intended to have patimts
`acknowledge in writing that they understand the safety, abuse, diversion and other
`issues that relate to the use of Xyrem®, and their responsibility to use the medication
`as prescribed by that patient; this form is intended to be kept as part of the patient’s
`medical record.
`
`14.1.3.3 Printed Materials
`
`These are provided in a binder and consist of the following items
`A medical record template that covers the history, physical examination,
`assessment, treatment plan, prescription record, and a checklist of questions‘fOr the
`patient at each visit that covers the following: what dosage the patient is taking,
`whether the patient is taking 2 nightly divided doses, whether the patient is
`experiencing any side effects and whether the patient‘s symptoms have improved.
`A tabular outline of how Schedules l and Ill apply to the dispensing, distribution,
`diversion potential, patient access, tracking ability and manufacturing of drugs, and
`how the same items apply to Xyrem®
`An outline of how to identify patients who may be abusing Xyrem®
`Adverse effects associated with the use of Xyrem®
`
`

`

`Ranjit B. Mani, MD, HFD-12O Medical Review
`NDA 21196, Xyrem, Orphan Medical, Inc.
`
`_
`
`Page 1 13 of 135
`6/15/01
`
`. A “Patient Physician Responsibility Contract” to be signed by both the patient and
`physician
`A series of instruction cards (contain print and graphics) to be used for by a
`physician for educating patients about all aspects of Xyrem®
`
`.
`
`14.1.4 Xyrem® Patient Success Program
`
`14.1.4.1 Videotape
`
`The draft video “story—board” prepared by the sponsor contains the following
`elements (the patient is instructed to watch the videotape prior to reading the
`printed materials)
`
`.
`
`. The identity and medical uses of Xyrem®
`o A short history of the development of this drug
`. The need to follow the physician’s instructions completely and precisely, and to
`contact the physician in the event of questions
`Instructions regarding the frequency of dosing, emphasizing the need to take the
`medication twice every night.
`. Very detailed instructions regarding the preparation of individual doses
`0 The need to place the second nightly dosage cup in an area not accessible to
`children, to store the medication bottle in a secure location and to consume the entire
`content of both dosing cups
`o Directions as to when the bottle is to be disposed of (i.e., when the solution can no
`longer be drawn out of the bottle with the dispensing device), and the need to empty
`the bottle completely and deface the label with a marker pen before throwing it away
`. The patient’s legal liability in relation to the use of Xyrem®
`.
`Federal scheduling for legal and illegal use
`.
`A statement that the patient may be legally responsible for the careless use and/or illicit
`distribution of Xyrem®
`
`0
`
`Penalties for misusing or abusing the drug
`
`14.1.4.2 Printed Materials '
`
`These are provided in a binder and consist of the following items about Xyrem®
`o The drug’s identity, and the reason for its prescription
`.
`Its most common side effects (dizziness, headache and nausea) and the less
`common ones (pain, sleep disorder, confusion, infection, vomiting and urinary
`incontinence)
`7
`o The mechanism for filling prescriptions
`o The need to follow physician instructions and not to alter the dose of medication
`without consulting the doctor
`. The contents of the drug product kit that will accompany every bottle of the drug
`0
`Instructions regarding the frequency and variability of dosing, emphasizing the need
`to take the medication twice every night.
`0 The need to wait a period of weeks to months until titrated to the optimal dose and
`until the full therapeutic benefits of the drug are seen
`-
`The lack of interactions with other medications
`
`‘
`
`.
`
`Storage instructions
`Action to be taken in case of accidental ingestion
`Insurance coverage
`
`

`

`Ranjit B. Mani, MD, HFD-120 Medical Review
`NBA 21196. Xyrem, Orphan Medical. Inc.
`
`Page 1 14 of 135
`6/15/01
`
`.
`
`the patient’s legal liability for
`A brief statement about the scheduling of Xyrem®,
`misuse, abuse and diversion of the prescribed drug and the penalties linked to that
`liability (it is clearly stated that the use of Xyrem® by an individual for whom it is not
`prescribed is illegal)
`'
`A description of the Patient Success Program
`Resources for information (names, addresses, phone numbers and URLs) about
`Xyrem®, narcolepsy and sleep disorders in general
`A patient quiz about Xyrem®
`A patient registry application to be completed by the patient and is to contain the
`following information
`.
`Patient name, address, telephone number, fax number, e-mail address, date of birth
`gender, social security number, patient record number, and medical insurance details
`(company name, patient number and group number)
`Physician name, specialty, clinic name and address
`.
`At home storage and safety tips: these include the following
`.
`The method of shipping, and the need to sign the courier’s receipt personally
`-
`To keep Xyrem® in its original container, in a secure location and away from children and
`pets
`When mixing each nightly dose to always use the dosing cups with child-resistant, caps,
`to make certain the second nightly dose is kept in a secure place
`To re-order the drug when a 7-day supply remains,
`To report a missing or stolen supply of Xyrem® to the local police and the Xyrem®
`Patient Success Program
`,
`To call the prescribing physician or Xyrem® Patient Success Programin the event of
`questions
`Traveling tips: these include the following
`.
`To keep Xyrem® in its original container and to take only the number of bottles needed
`for the trip, making certain that what is not taken on the trip is in a secure place at home
`To keep Xyrem® in a secure location at all times
`To remember to take the dispensing device and dosing cups with child-resistant caps
`when traveling
`. Not to include Xyrem® in checked baggage
`.
`To return home with the Xyrem® taken on the trip
`.
`The need to be aware that, if traveling internationally, Xyrem® might be subject :to
`different regulations in foreign countries
`To contact the Patient Success Program in the event of traveling without Xyrem® or
`needing a fresh supply in the event of an extended stay.
`,
`Reimbursement information
`
`0
`.
`
`.
`
`14.2 OPDRA Comments
`The Office Of Post-Marketing Drug Risk Assessment reviewed the Risk ,
`Management Program proposed for Xyrem®. The opinion of that office was
`conveyed to this Division in a formal review and in a discussion held February 5,
`2001.
`'
`
`The final recommendations of that Office were as follows:
`
`The verification process conducted by '-‘-———-—-—-- 'on receiving a formal
`prescription should include confirmation of the patient’3 diagnosis
`Confirmation that physicians have read and grasped the educational material
`provided by the sponsor could be obtained by requiring each physician to
`complete a questionnaire prior to dispensing of the drug to the patient
`
`,_,,.r —r~r
`
`7
`
`

`

`Ranjit B. Mani, MD, HFD~120 Medical Review
`. NDA 21196, Xyrem, Orphan Medical, Inc.
`
`Page 1 16 of 135
`6/15/01
`
`. Total-free phone numbers that physicians and patients can contact in the
`event of questions should be clearly indicated on the product and on all
`printed materials
`0 The label on the bottle and all patient information enclosures should carry
`
`warnings of the risks of using Xyrem® especially if taken in combination with
`alcohol, benzodiazepines and other central nervous system depressant drugs
`. Proper use, handling and disposal measures should also include the following
`. Child-resistant packaging
`-
`Storage in a secure container (e.g., a lock box)
`. Comprehensive patient, family and child safety educational programs
`0
`Instructions and training for patients and caregivers on dilution and measuring
`techniques and use of the PIBA Well and ExaCta-Med dispenser
`
`14.3.3 Appropriate Prescribing For The Labeled Orphan Indication
`
`in order to ensure that Xyrem® will be appropriately prescribed for its labeled
`indication the following have been suggested
`. The central pharmacy should be described in the product labeling and other
`educational and promotional materials
`. The central pharmacy should track prescriptions and refills regardless of third-
`party payer participation in the monitoring of quantity and frequency of drug
`dispensing
`. A sponsor-physician agreement should state that Xyrem® will be used only in
`the treatment of narcolepsy-cataplexy
`o A physician- patient agreement should also be completed
`. Documentation of patient and physician education regarding the use and risks
`of Xyrem® prior to dispensing the first prescription
`. Certification of physicians for prescribing Xyrem®: the types of physicians
`who may prescribe Xyrem® should be described in the risk management
`program, the sponsor should also consider developing a course of instruction
`for physicians to train themIn sleep disorders and in the safe and appropriate
`use of Xyrem® (this could be an additional requirement for certification‘
`
`14. 3. 4 Prevention 0[ Misuse And Overdose
`
`The following have been suggested
`. The penalties for abuse and diversion of Schedule I compounds under the
`Controlled Substances Act should be clearly indicatedIn material supplied to
`the patient
`. An active post-marketing surveillance program that consists of the following
`. Spontaneous and solicited reports from physicians and other healthcare .~
`providers
`. Sponsor tracking of excessive or inappropriate prescribing
`.
`Plan to monitor signals of off-label use
`0
`Provision of periodic updates to the Agency regarding instances of misuse
`abuse, diversion and overdose
`. Voluntary restriction on quantity dispensed per month or per prescription
`s
`
`

`

`Ranjit B. Mani, MD, HFD-120 Medical Review
`NBA 21196, Xyrem, Orphan Medical, Inc.
`
`Page 1 17 of 135
`6/15/01
`
`. A “Dear Healthcare Provider” letter advising of Agency action (i.e., approval of
`drug) and describing the risk management program
`0 A plan to measure the success of the risk management program
`
`14.4 Joint Risk Management Recommendations
`
`At a joint internal meeting chaired by Dr R. Temple, Office Director, that was held
`on 4/26/01 it was decided to ask the sponsor to consider including the following
`additional elements in the risk management program. Those present at the
`meeting included representatives of this Division, the Controlled Substances
`Staff and the Office Of Post-Marketing Drug Risk Assessment
`- Obtaining physician agreement to use GHB only for cataplexy, at the time of the first
`prescription
`. Obtaining a physician undertaking, at the time ofihe first prescription to report
`instances of misuse and overuse of GHB to the sponsor
`. Requiring active post—marketing surveillance by the sponsor (e.g., through physician
`surveys) to look for specific adverse events
`. Making certain that that the pharmacist carefully tracks all GHB prescriptions (even
`for cash-paying patients) to see if excessive quantities are being prescribed
`. Obtaining the physician’s signed confirmation that he/she fully understands how
`GHB is to be used prior to the first prescription being filled
`'
`. Obtaining the patient’s signed confirmation that he/she fully understands how GHB is
`to be used prior to the first prescription being mailed
`
`15. Labeling Review
`
`This has been done in a separate document entitled “NDA 21196 Labeling
`Review”
`
`16. Overall Comments
`
`16.1 Clinical Safety
`
`-
`0 When GHB is used to treat narcolepsy in doses of 3-9 g/day the most .
`common, and seemingly drug and dose-related adverse events have included
`the following: headache, unspecified pain, nausea and dizziness. Urinary
`incontinence is slightly less common, but apparently dose and drug-related as
`well. More serious, but much less common, adverse events seen at the same
`dose range, and that could be attributed to Xyrem®, have included vomiting,
`confusion, restlessness, agitation, paranoia, hallucinations, somnolence and
`generalized weakness. No deaths that could be attributed to study drug have
`been reported at therapeutic doses of GHB
`.
`. One healthy 39 year old woman participating in a pharmacokinetic trial.
`developed dizziness, nausea, vomiting, respiratory depression and fecal
`incontinence, after a single (and initial) oral dose of 4.5 g of GHB,
`administered after an overnight fast.
`. A single older narcoleptic patient who had been taking GHB for approximately
`1 1/2 years was hospitalized after an overdose of GHB 18 9. At the time'of
`hospitalization, he was comatose and unresponsive. He needed intubation
`and artificial ventilation, and awoke 6 hours later. This incident suggests that
`
`

`

`Ranjit B. Mani, MD, HFD-120 Medical Review
`NDA 21196, Xyrem, Orphan Medical, Inc.
`
`Page 1 18 of 135
`6/15/01
`
`the safety margin between therapeutic and toxic doses, even in narcoleptic
`patients maintained chronically on GHB, may not be very wide
`. At therapeutic doses of GHB all adverse events appear to be reversible
`. While currently there is no strong evidence that GHB in therapeutic doses is
`epileptogenic or that episodes of urinary and fecal incontinence due to GHB
`are due to seizures, there is insufficient data at present to rule out either
`possibility.
`“Recreational” use of GHB generally at doses presumed or known to be
`higher than the therapeutic has been associated with adverse events that
`included fatalities attributable to the depressant effects of this drug on the
`nervous system. However concurrent use of alcohol and of other drugs with
`effects on the central nervous system has been reported in many of these
`instances
`
`.
`
`0 There is no evidence that GHB is toxic to any major organ other than the
`nervous system.
`
`16. 2 Clinical Efficacy
`This may be summarized as follows (please see the NDA Efficacy ReVIew for full
`details)
`0 Currently there are no drugs approved for the treatment of cataplexy. There
`are several drugs approved for the treatment of excessive daytime sleepiness
`accompanying narcolepsy, or for narcolepsy as a generic entity These are
`modafinil, methylphenidate and dextroamphetamine.
`. There appears to be adequate evidenceIn this application that GHB is
`superior to placebo in treating cataplexy. This evidence comes from at least
`two, and possibly three randomized, double-blind, placebo-controlled trials.
`0 The efficacy of GHB in treating narcolepsy is most consistently seen at a
`dose of 9 g/day. It does not appear that doses < 4. 5 g/day are effective
`0 ThereIs currently inadequate evidence that GHBIs effectiveIn treating
`daytime sleepiness accompanying narcolepsy
`
`16.3 Withdrawal Phenomena And Abuse Potential
`
`0 There is no evidence from a small formal study with a randomized withdrawal
`paradigm (OMC-SXB-21) that the abrupt discontinuation of therapeutic doses
`of GHB used for 6 months to 3 1/2 years leads to more than mild and
`infrequent withdrawal symptoms, except for a significantly increased
`frequency of cataplexy.
`0 There are however a number of anecdotal reports of an actual withdraVIlal
`syndrome and, possibly, addiction in illicit “recreational” users of GHB, GBL or
`1-4 BD. In all these individuals high doses of GHB or related drugs were
`I
`believed to have been used at frequent intervals around-the-clock.
`
`7
`
`16.4 Risk Management Program
`
`The small clinical trial safety database, the narrow margin of safety and the risks
`of abuse and misuse all call for approval to be conditional on a risk management
`system that is more stringent than that proposed by the sponsor. Key additional
`elements of such a system should include
`
`

`

`Ranjit B. Mani, MD, HFD-120 Medical Review
`NBA 21196, Xyrem, Orphan Medical, Inc.
`
`Page 1 19 of 135
`6/15/01
`
`. Dispensing of the drug exclusively to patients with a diagnosis of cataplexy
`confirmed by their physicians
`. Commitment by the sponsor to a detailed plan for active post-marketing surveillance
`for instances of diversion, abuse, misuse and adverse events of special conCem
`. Clear statements in the approved label, patient information sheet and patient and
`physician educational materials about the nature of the drug (i.e., that it contains the
`same active ingredient as illicitlyvused GHB), the limited experience with the drug
`during development, the potentially serious toxicity of both therapeutic doses and
`overdoses
`
`- Use of Subpart H of the Accelerated Approval regulations (21 CFR 314.500) so as to
`provide a means of restricting distribution of the drug and for enforcement of the risk
`management program. Justification for institution of these regulations is as follows
`. Xyrem® is intended to treat a serious disease (cataplexy)
`o Xyrem® provides meaningful benefit to patients over existing treatment
`. Xyrem® can be used safely only if its distribution or use is restricted
`
`16.5 Additional Comments
`
`See Section 20 for additional comments based on a review of an Amendment
`
`submitted on 3/23/01
`
`17. Study Site Inspections
`
`17.1 Sites Inspected
`
`The following study sites pertinent to this application were inspected by the
`Division of Scientific Investioations DSI at the re uest of this Division
`
`Orphan Medical, Inc
`(Sponsnri
`
`Minnetonka, MN
`
`
`
`
`
`Jonathan Schwartz, MD
`Oklahoma CIty, OK
`
`
`
`
`
`Lawrence Scrima, PhD
`(~Sponsor lnvesti-ator)
`Martin Scharf, PhD
`(Sponsor-Investioator
`
`Aurora, CO
`
`Cincinnati, OH
`
`OMC—GHB-2
`
`Scrima Study
`
`Scharf Study
`
`
`
`
`
`
`The results of these inspections are described in detail in a Clinical Inspection
`Summary written by Constance Lewin, MD, of the Division of Scientific
`Investigations, dated June 11,2001. Please refer to that document for full details.
`
`These inspections uncovered a number of deficiencies, the most prominent‘of
`which pertained to the Scharf open-label study and are summarized below
`
`17.2 Scharf Study Inspection
`
`At the request of this Division the Division of Scientific Investigations carried out
`an inspection of the Scharf long-term safety study. This inspection was requested
`after the Agency was informed that the Institutional Review Board for Dr Martin
`Scharf’s sponsor-investigator IND 11 w had withdrawn approval for that IND;
`the approval was stated to have been withdrawn based on protocol violations in a
`study conducted under that IND in patients with fibromyalgia.
`
`

`

`Ranjit B. Mani, MD, HFD-120 Medical Review
`NDA 21196, Xyrem, Orphan Medical, Inc.
`
`Page 120 of 135
`6/15/01
`
`In the FDA Form 483 issued to Dr Martin Scharf on 2/23/01 which was based on
`
`an inspection conducted from 2/6/01 to 2/23/01, the following deficiencies that
`are relevant to this application (and to the Scharf study in narcolepsy/cataplexy)
`were noted. These deficiencies were based on a review of records for 13 patients
`which was apparently all that could be accomplished over the inspection period
`given the disorganized state in which the study records were maintained
`. Records of subjects were not adequately maintained by the investigator to assure
`accurate reporting of the subjects’ data with respect to adverse events, test article
`accountability, informed consent and patient diaries
`Serious adverse events for 6 patients were not reported to the appropriate
`Institutional Review Board
`
`.
`
`.
`
`.
`
`.
`.
`
`2 separate diaries were noted for the same subject for the same period of time
`(November 1999): the handwriting in the diaries was different as was the data which
`was conflicting
`In each of 5 patients, a number of adverse events in source documents were not
`reported to Orphan Medical, Inc.
`In 2 patients diaries covering periods of 1-2 years could not be found
`In a number of patients drug dispensing records were not available (the absent
`records were for periods from 1 to 7 years). When dispensing logs were actually
`available, they were incomplete
`-
`
`In an effort to ensure that major adverse events in this study were captured the
`
`Division made a number of recommendations to the sponsor during meetings
`and teleconferences heldIn February-March 2001.
`. Obtaining as much information as possible about the status of the 80 patients in the
`Scharf study who did not enter the OMC-SXB-7 (treatment IND) study; if their current
`status was not known their health at the time of discontinuation from the Scharf study
`(which the majority of the 80 patients did leave) and for 1 -2 months afterward needed
`to be ascertained.
`
`. Obtaining as much inf