CENTER FOR DRUG EVALUATION AND
`
`RESEARCH
`
`APPLICA TION NUMBER:
`
`2 1 - 1 9 6
`
`APPROVED LABELING
`
`

`

`Xyrem® Risk Management Program
`I.
`As a condition of approval, the requirements of your Risk Management Program include the
`following, with the details of the Program set out below in III.
`
`0
`
`0
`
`o
`
`Implementation of a restricted distribution program for Xyrem
`
`Implementation of a program to educate physicians and patients about the risks and benefits of
`Xyrem, including support via ongoing contact with patients and a toll-free Helpline
`
`Filling ofthe initial prescription only after the prescriber and the patient have received and read
`the educational materials
`
`0 Maintain patient and prescribing physician registries
`
`II.
`
`You have also agreed to the following:
`
`o The bulk drug will be manufactured at a single site.
`
`0
`
`0
`
`The drug product will be manufactured at a single site.
`
`Following manufacture the drug product will be stored at a facility compliant with Schedule III
`regulations, where a consignment inventory will be maintained.
`
`0 The inventory will be owned by Orphan Medical, Inc., and the facility will be managed by a
`central pharmacy which will maintain the consignment inventory.
`0 Xyrem® will be distributed and dispensed through a primary and exclusive central pharmacy
`(which you have represented will contract with Orphan Medical to fulfill this function). Orphan
`Medical has a designated back-up distributor. Xyrem® will NOT be stocked in retail pharmacy
`outlets.
`
`III.
`
`Risk Management Program Details
`
`A. Dispensing
`
`You will ensure that Xyrem is dispensed in the following manner.
`
`Prescriptions will be communicated by facsimile or other convenient method by the physician, or the
`
`physician’s office, to the central pharmacy.
`
`Upon receipt of a prescription the central pharmacy will contact the prescribing physician and/or the
`
`physician’s office and
`
`0
`
`Identify physician’s name, license and DEA registration
`
`0 Verify the prescription
`
`0 Obtain patient insurance information
`The central pharmacy will then verify that the physician is eligible to prescribe Xyrem® by consulting
`the National Teclmical Information Services (NTIS). This stage ofverification will include
`
`confirming that the physician has an active DEA number and will check on whether any actions are
`
`pending against the physician.
`
`

`

`Ifthe physician is a first-time prescriber of Xyrem® the pharmacy will then ship, if the physician does
`not already have them, comprehensive printed materials to that physician; these materials (see
`Xyrem Physician Success ProgramSM below) also contain information regarding the proper handling
`ofthe drug with an outline of precautions to be taken against diversion
`
`You have agreed that if a patient has prescription drug coverage, the central pharmacy will then
`
`contact the patient’s insurance company to obtain coverage. The central pharmacy will notify the
`
`patient of his/her approval status.
`
`All patient registry information will be verified before the initial prescription can be filled.
`Comprehensive printed and video materials (see Xyrem Patient Success Program SM 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 the shipment.
`Prior to Xyrem® being shipped to a patient for the first time, the central pharmacist will confirm with
`the patient by telephone that the patient has read the educational materials contained in the Xyrem
`Patient Success Programs“. That confirmation will be recorded by the central pharmacist.
`
`Onoe approval has been established, the central pharmacy will verify the patient’s home address
`
`and availability for shipping, and arrange shipment through Federal Express or a similar carrier.
`
`The patient may provide the name of a designee to the central pharmacy who is authorized to
`accept shipment of Xyrem® when the patient is unable to do so. This designee must be 18 years of
`age or older.
`
`Receipt of the initial drug shipment will be ensured through the following:
`
`0 A phone call by the pharmacy to the patient, no more than 1 business day after the shipment
`has been delivered, to verify that the medication has been received; and
`
`0 The courier service’s own tracking system for shipments
`
`The package will be sent under condition that if the patient, or his/her designee is unavailable to
`accept a shipment of Xyrem® and execute the required receipt alter two delivery attempts, the
`package will be returned to the pharmacy.
`
`You have agreed that, 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 the central
`pharmacy 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 NTIS and State Boards
`
`of Pharmacy.
`
`Prescription refills will be permitted in the number specified in the original prescription. In addition,
`
`you have agreed that:
`
`0
`
`If a prescription refill is requested by the patient prior to the anticipated due date, such refills
`
`will be questioned by the pharmacist
`
`o 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.
`
`0 Repeat instances of lost, stolen, destroyed, or spilled prescriptions/supplies will be flagged
`
`for monitoring and mum: instances thoroughly questioned.
`o The first prescription will be limited to a one month’s supply of Xyrem®.
`
`0
`
`Following firrther contact between the pharmacy and patient, and verification that the patient
`understands the material in the Xyrem Patient Success Programs”, supplies of Xyrem® that
`are intended to last longer than a month may be shipped.
`
`o 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.
`
`0
`0
`
`o
`
`It is anticipated that the majority of patients will receive only one month’s shipment at a time.
`Patients will never receive more than 3 months’ supply ofXyrem® per shipment.
`
`Prescriptions for Xyrem® will be rewritten at least every 3 months
`
`B. Registries
`
`Every patient and prescribing physician will be registered with the central pharmacy in a secure
`database. The database will contain the physician’s name, address, telephone and facsimile
`
`numbers, DEA and state license numbers and prescribing fiequency. The database will be made
`
`available for review by federal and state agencies upon request. From this database it will be
`
`possible to obtain the following information:
`
`o
`
`o
`
`0
`
`0
`
`Prescriptions by physician specialty
`
`Prescriptions by patient name
`
`Prescriptions by volume (frequency)
`
`Prescriptions by dose
`
`C. Xyrem Post-Marketing Evaluation Program
`
`You have agreed that that the prescriber will be urged to see and evaluate his or her patients every
`3 months. In addition, you will urge prescribers to submit reports of all serious adverse reactions to
`
`Orphan Medical every 3 months initially with the longer term reporting requirements to be
`
`negotiated with the Agency.
`
`At each visit subsequent to the initial prescription visit, you have agreed that the prescriber will be
`
`urged to query the patient for potential adverse events associated with Xyrem use, as well as
`
`document any suggestion of inappropriate Xyrem use (e.g., premature requests for refills). To assist
`
`

`

`the prescriber in this assessment, evaluation forms are included with the physician Xyrem Success
`Program“, which are to be completed by the prescriber at Month 3 and Month 6 of a patient's
`course of therapy. It is of utmost importance that the prescriber fill out this form as completely as
`
`possible.
`
`D. Drug Product Kit
`
`Every box of Xyrem® shipped to the patient will contain all the items below:.
`
`0 The drug product, a clear solution, in a 180 mL amber bottle with a closure mechanism that is child-
`resistant
`
`. The Press-In-Bottle-Adapter (PIBA Well) which will be inserted into the bottle by the pharmacist
`0 An Exacta—Med Dispenser® which allows the patient to withde the appropriate dose of drug
`
`0 Two child-resistant dosing cups, one for each of 2 nightly doses.
`
`0 A package insert and Medication Guide
`
`E. Education materials
`
`1. Xyrem Physician Success ProgramSM
`
`This program consists of printed material(s) to educate physicians about the features of Xyrem®. When
`a physician prescribes the dmg for the first time, the physician must verify that he/she has read these
`materials before the medication will be sent to the patient.
`
`2. Xyrem Patient Success ProgramSM
`
`This program consists of a videotape and printed educational material. The patient will receive this
`material prior to the first shipment of drug. The central pharmacist will not ship the product unless the
`patient has confirmed to the pharmacist that he or she has read the educational materials.
`
`Version 4
`
`

`

`Rx only
`
`CHI
`
`Xyrem® (sodium oxybate) oral solution
`
`!WARNING: Central nervous system depressant with abuse potential.
`Should not be used with alcohol or other CNS depressants.
`
`Sodium oxybate is GHB, a known drug of abuse. Abuse has been associated with
`
`some important central nervous system (CNS) adverse events (including death). Even at
`
`recommended doses, use has been associated with confusion, depression and other
`
`neuropsychiatric events. Reports of respiratory depression occurred in clinical trials. Almost
`
`all of the patients who received sodium oxybate during clinical trials were receiving CNS
`stimulants; whether this affected respiration during the night is unknown. XyremO is available
`only through restricted distribution, the Xyrem Success Programs”, by calling 1-877-67-
`XYREM (1-877-679-9736).
`
`Important CNS adverse events associated with abuse of GHB include seizure,
`
`
`
`respiratory depression and profound decreases in level of consciousness, with instances of
`
`coma and death. For events that occurred outside of clinical trials, in people taking GHB for
`
`recreational purposes, the circumstances surrounding the events are often unclear (e.g., dose
`
`of GHB taken, the nature and amount of alcohol or any concomitant drugs).
`Under the Xyrem Success Programs”, Xyrem® is made available to prescribers
`through a single centralized pharmacy and with the following procedures: 1) The prescriber
`must contact the centralized pharmacy (1-877-67-XYREM 5” , which will provide the
`prescriber with educational materials explaining the risks and proper use of sodium oxybate,
`
`and the details of the program. 2) Once the prescriber has read the materials and returned
`
`the necessary form, the pharmacy will ship educational materials to the patient. 3) Once it is
`
`documented that the patient has read the materials, the drug will be shipped to the patient.
`The Xyrem Success ProgramSM also includes provisions for detailed surveillance of the
`patients (patients are to be seen no less frequently than every 3 months and physicians are
`
`expected to report all serious adverse events to the manufacturer) and information to help
`
`minimize the risks of inadvertent use by others. (See WARNINGS)
`
`DESCRIPTION
`
`Xyrem® (sodium oxybate) is a central nervous system depressant with anti—cataplectic activity in
`patients with narcolepsy. Sodium oxybate is intended for oral administration. The chemical name for
`
`sodium oxybate is sodium 4—hydroxybutyrate. The molecular formula is C4H7N303 and the molecular
`weight is 126.09 grams/mole. The chemical structure is:
`
`C:\WPFILES\NDA\Xyrem\approval\2l l 96drafilabel 1 7julrev.doc
`
`l
`
`

`

`ii
`
`Na+'O-C-CH2-CH2-CH2-O-H
`
`Sodium oxybate is a white to off—white, crystalline powder that is very soluble in aqueous solutions.
`Xyrem® oral solution contains 500 mg of sodimn oxybate per milliliter of USP purified water,
`neutralized to pH 7.5 with malic acid.
`
`CLINICAL PHARMACOLOGY
`
`Mechanism of Action
`
`The precise mechanism by which sodium oxybate produces an effect on cataplexy is rmknown.
`
`Pharmacokinetics
`
`Sodium oxybate is rapidly but incompletely absorbed after oral administration; absorption is delayed
`and decreased by a high fat meal. It is eliminated mainly by metabolism with a half-life of 0.5-1 hour.
`Pharmacokinetics are nonlinear with blood levels increasing 3.7-fold as dose is doubled fiom 4.5 to 9
`
`grams. The pharmacokinetics are not altered with repeat dosing.
`
`Absorption
`
`Sodimn oxybate is absorbed rapidly following oral administration with an absolute bioavailability of
`about 25%. The average peak plasma concentrations (lSt and 2nd peak) following administration of a 9
`g daily dose divided into two equivalent doses given four hours apart were 78 and 142 meg/ml,
`respectively. The average time to peak plasma concentration (Tm) ranged fiorn 0.5 to 1.25 hours in
`eight pharrnacokinetic studies. Following oral administration, the plasma levels of sodium oxybate
`increase more than proportionally with increasing dose. Single doses greater than 4.5 grams have not
`been studied. Administration of sodium oxybate immediately after a high fat meal resulted in delayed
`
`absorption (average Tmax increased from 0.75 hr to 2.0 hr) and a reduction in peak plasma level (Cm)
`by a mean of 58% and of systemic exposure (AUC) by 37%.
`
`Distribution
`
`Sodium oxybate is a hydrophilic compound with an apparent volume of distribution averaging 190—384
`ml/kg. At sodium oxybate concentrations ranging from 3 to 300 meg/ml, less than 1% is bound to
`
`plasma proteins.
`
`C:\WPFILES\NDA\Xyrem\approval\21 l96draftlabel l 7julrev.doc
`
`2
`
`

`

`Metabolism
`
`Animal studies indicate that metabolism is the major elimination pathway for sodium oxybate, producing
`
`carbon dioxide and water via the tricarboxylic acid (Krebs) cycle and secondarily by beta-oxidation.
`The primary pathway involves a cytosolic NADP+-linked enzyme, GHB dehydrogenase, that catalyses
`the conversion of sodium oxybate to succinic semialdehyde, which is then biotransfonned to succinic
`
`acid by the enzyme succinic semialdehyde dehydrogenase. Succinic acid enters the Krebs cycle where
`
`it is metabolized to carbon dioxide and water. A second mitochondrial oxidoreductase enzyme, a
`transhydrogenase, also catalyses the conversion to succinic semialdehyde in the presence of (x-
`ketoglutarate. An alternate pathway ofbiotransformation involves B-oxidation via 3,4-
`
`dihydroxybutyrate to carbon dioxide and water. No active metabolites have been identified.
`
`Studies in vitro with pooled human liver microsomes indicate that sodium oxybate does not significantly
`inhibit the activities of the human isoenzymes: CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1,
`
`or CYP3A up to the concentration of 3 mM (378 micrograms/ml). These levels are considerably higher
`than levels achieved with therapeutic doses.
`
`Elimination
`
`The clearance of sodium oxybate is almost entirely by biotransformation to carbon dioxide, which is
`
`then eliminated by expiration On average, less than 5% of unchanged drug appears in human urine
`
`within 6 to 8 hours after dosing. Fecal excretion is negligible.
`
`Special Populations
`
`Geriatric
`
`The pharmacokinetics of sodium oxybate in patients greater than the age of 65 years have not been
`studied.
`
`Pediatric
`
`The pharmacokinetics of sodium oxybate in pediatric patients under the age of 18 years have not been
`studied.
`
`Gender
`
`In a study of 18 female and 18 male healthy adult volunteers, no gender differences were detected in the
`
`pharmacokinetics of sodium oxybate following a single oral dose of 4.5 grams.
`
`Race
`
`There are insufficient data to evaluate any pharmacokinetic differences among races.
`
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`3
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`C:\WPFILES\NDA\Xyrem\approvaI\2 l I 96draftlabell 7julrev.doc
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`Renal Disease
`
`Because the kidney does not have a significant role in the excretion of sodium oxybate, no
`
`pharmacokinetic study in patients with renal dysfimction has been conducted; no effect of renal firnction
`
`on sodium oxybate pharmacokinetics would be expected.
`
`Hepatic Disease
`
`Sodium oxybate undergoes significant presystemic (hepatic first-pass) metabolism. The kinetics of
`
`sodium oxybate in 16 cirrhotic patients, halfwithout ascites, (Child’s Class A) and half with ascites
`(Child’s Class C) were compared to the kinetics in 8 healthy adults after a single oral dose of 25 mg/kg.
`AUC values were double in the cirrhotic patients, with apparent oral clearance reduced fiom 9.1 in
`
`healthy adults to 4.5 and 4.1 ml/min/kg in Class A and Class C patients, respectively. Elimination half-
`life was significantly longer in Class C and Class A patients than in control subjects (mean t1/2 of 59 and
`
`32 versus 22 minutes). It is prudent to reduce the starting dose of sodium oxybate by one-half in
`patients with liver dysfunction (see Dosage and Administration).
`
`Drug-Drug Interaction
`
`Drug interaction studies in healthy adults demonstrated no pharmacokinetic interactions between sodium
`oxybate and protriptyline hydrochloride, zolpidem tartrate, and modafinil. However, pharmacodynamic
`interactions with these drugs cannot be ruled out.
`
`CLINICAL TRIALS
`
`The efiectiveness of sodium oxybate as an anti—cataplectic agent was established in 2 randomized,
`double—blind, placebo-controlled trials (Trials 1 and 2) in patients with narcolepsy, 85% and 80%,
`respectively, of whom were also being treated with CNS stimulants. The high percentages of
`concomitant stimulant use make it impossible to assess the efiicacy and safety of Xyrem® independent
`of stimulant use. In each trial, the treatment period was 4 weeks and the total daily doses ranged firm 3
`to 9 grams, with the daily dose divided into 2 equal doses. The first dose each night was taken at
`bedtime and the second dose was taken 2.5 to 4 hours later. There were no restrictions on the time
`
`between food consumption and dosing.
`
`Trial 1 was a multi—center, double-blind, placebo—controlled, parallel-group trial that enrolled 136
`narcoleptic patients with moderate to severe cataplexy (median of 21 cataplexy attacks per week) at
`baseline. Prior to randomization, medications with possible effects on cataplexy were withdrawn, but
`stimulants were continued at stable doses. Patients were randomized to receive placebo, sodium
`oxybate 3gms/day, sodium oxybate 6gms/day, or sodium oxybate 9gms/day.
`
`Trial 2 was a multi-center, double-blind, placebo—controlled, parallel—group, randomized withdrawal
`trial that enrolled 55 narcoleptic patients who had been taking open-label sodium oxybate for 7 to 44
`months. To be included, patients were required to have a history of at least 5 cataplexy attacks per
`
`C:\WPFILES\NDA\Xyrem\approval\2l l96draftlabel l 7julrev.doc
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`5
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`

`

`week prior to any treatment for cataplexy. Patients were randomized to continued treatment with
`sodium oxybate at their stable dose or to placebo. Trial 2 was designed specificaHy to evaluate the
`continued efficacy of sodium oxybate afier long-tenn use.
`
`The primary efficacy measure in each clinical trial was the frequency of cataplexy attacks.
`
`Table 1
`
`Summary of Outcomes in Clinical Trials Supporting
`the Efficacy of Sodium Oxybate
`
`
`TriaI/
`” W _——"
`Comparison
`Dosage
`Baseline
`to Placebo
`
`Change
`
`
`
`Placebo (33)
`
`3.0 g/d (33)
`
`20.5
`
`20.0
`
`(median attacks/wk)
`-4
`
`-7
`
`-—
`
`0.5541
`
`6.0 g/d (31)
`23.0
`-10
`0.0451
`
`9.0 g/d (33)
`23.5
`-16
`0.0016
`Trial 2
`
`Placebo (29)
`
`Sodium oxybate (26)
`
`4.0
`
`1 .9
`
`(median attacks/Mo weeks)
`21.0
`
`0
`
`-
`
`<0.001
`
`In Trial 1, both the 6 gin/day and 9 gm/day doses gave statistically significant reductions in the fiequency
`of cataplexy attacks. The 3 gms/day dose had little effect. In Trial 2, following the discontinuation of
`long-term open-label sodium oxybate therapy, patients randomized to placebo experienced a significant
`increase in cataplexy (p<0.001), providing evidence of long—term efficacy of sodium oxybate. In Trial
`2, the response was numerically similar for patients treated with doses of 6-9 gms/day, but there was no
`effect seen in patients treated with doses less than 6 gins/day, suggesting little effect at these doses.
`
`INDICATIONS AND USAGE
`
`Xyrem® (sodium oxybate) oral solution is indicated for the treatment of cataplexy in patients with
`narcolepsy.
`
`In Xyrem® clinical trials, approximately 80% ofpatients maintained concomitant stimulant use (see
`BLACK BOX WARNINGS).
`
`C:\WPFlLES\NDA\Xyrem\approval\2l l 96draftlabel l 7julrev.doc
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`6
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`

`CONTRAINDICATIONS
`
`Sodium oxybate is contraindicated in patients being treated with sedative hypnotic agents.
`
`Sodium oxybate is contraindicated in patients with succinic semialdehyde dehydrogenase deficiency.
`This rare disorder is an inbom error of metabolism variably characterized by mental retardation,
`hypotonia, and ataxia.
`
`WARNINGS
`
`SEE BOXED WARNING
`
`Due to the rapid onset of its CNS depressant effects, sodium oxybate should only be ingested at
`bedtime, and while in bed. For at least 6 hours alter ingesting Sodium oxybate, patients must not engage
`in hazardous occupations or activities requiring complete mental alertness or motor coordination, such
`as operating machinery, driving a motor vehicle, or flying an airplane. When patients first start taking
`Xyrern® or any other sleep medicine, rmtil they know whether the medicine will still have some
`carryover effect on them the next day, they should use extreme care while driving a car, operating heavy
`machinery, or performing any other task that could be dangerous or requires full mental alertness.
`
`The combined use of alcohol (ethanol) with sodium oxybate may result in potentiation of the
`
`central nervous system-depressant effects of sodium oxybate and alcohol. Therefore,
`patients should be warned strongly against the use of any alcoholic beverages in conjunction
`
`with sodium oxybate. Sodium oxybate should not be used in combination with sedative
`
`hypnotics or other CNS depressants.
`
`Central Nervous System Depression/Respiratory Depression
`
`Sodium oxybate is a CNS depressant with the potential to impair respiratory drive, especially in patients
`with already-compromised respiratory function. In overdoses, life-threatening respiratory depression
`has been reported (see OVERDOSAGE). In clinical trials 2 subjects had profound CNS depression.
`A 39 year-old woman, a healthy voltmteer received a single 4.5gm dose of sodium oxybate after fasting
`for 10 hours. An hour later, while asleep, she developed decreased respiration and was treated with an
`oxygen mask. An hour later, this event recurred. She also vomited and had fecal incontinence. In
`another case, a 64 year-old narcoleptic man was found unresponsive on the floor on day 170 of
`treatment with Sodium oxybate at a total daily dose of 4.5grns/day. He was taken to an emergency
`room where he was intubated. He improved and was able to return home later the same day. Two
`other patients discontinued sodium oxybate because of severe difficulty breathing and an increase in
`obstructive sleep apnea.
`
`The respiratory depressant effects of Xyrem®, at recommended doses, were assessed in 21 patients
`with narcolepsy, and no dose-related changes in oxygen saturation were demonstrated in the group as a
`whole. One of these patients had significant concomitant pulmonary illness, and 4 ofthe 21 had
`
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`7
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`

`moderate-to—severe sleep apnea. One of the 4 patients with sleep apnea had significant worsening of
`
`the apnea/hypopnea index during treatment, but worsening did not increase at higher doses. Another
`patient discontinued treatment because of a perceived increase in clinical apnea events. Caution should
`be observed if Xyrem® is prescribed to patients with compromised respiratory function. Prescribers
`should be aware that sleep apnea has been reported with a high incidence (even 50%) in some cohorts
`
`of narcoleptic patients.
`
`Confusion/Neuropsychiatric Adverse Events
`
`During clinical trials, 7% of patients treated with sodium oxybate experienced confirsion. Fewer than
`
`1% of patients discontinued the drug because of confusion. Confusion was reported at all
`recommended doses from 6-9gms/day. In a controlled trial where patients were randomized to fixed
`
`total daily doses of 3, 6, and 9g/day or placebo, a dose-response relationship for confusion was
`demonstrated with 17% of patients at 9g/day experiencing confusion. In all cases, the confusion
`
`resolved soon alter termination of treatment. In the majority of cases, confirsion resolved with continued
`
`treatment. However, patients treated with Xyrem® who become confused should be evaluated fully,
`
`and appropriate intervention considered on an individual basis.
`
`Other neuropsychiatric events included psychosis, paranoia, hallucinations, and agitation. The
`
`emergence of thought disorders and/or behavior abnormalities when patients are treated with sodium
`
`oxybate requires carefirl and immediate evaluation.
`
`Depression
`
`In clinical trials, 6% of patients treated with sodium oxybate reported depressive symptoms. In the
`
`majority of cases, no change in sodium oxybate treatment was required. Three patients (<l%)
`discontinued because of depressive symptoms. In the controlled clinical trial, where patients were
`randomized to fixed doses of 3, 6, 9g/day or placebo, there was a single event of depression at the
`
`3g/day dose.
`
`Among patients with a previous history of depressive psychiatric disorder, there were 2 suicides and I
`
`attempted suicide recorded in the 448 patient dataset. Of the 2 suicides, one patient used sodium
`
`oxybate in conjunction with other drugs. Sodium oxybate was not involved in the second suicide.
`
`Sodium oxybate was the only drug involved in the attempted suicide. A fourth patient without a
`previous history of depression attempted suicide by taking an overdose of a drug other than sodium
`
`oxybate.
`
`The emergence of depression when patients are treated with Xyrem® requires carefirl and immediate
`evaluation. Patients with a previous history of a depressive illness and/or suicide attempt should be
`monitored especially carefully for the emergence of depressive symptoms while taking Xyrem®.
`
`Usage in the Elderly
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`8
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`

`There is very limited experience with sodium oxybate in the elderly. Therefore, elderly patients should
`be monitored closely for impaired motor and/or cognitive fimction when taking sodium oxybate.
`
`C:\WPFILES\NDA\Xyrem\approval\21 l96draftlabel l 7julrev.doc
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`PRECAUTIONS
`
`lnconfinence
`
`During clinical trials, 9% ofnarcoleptic patients treated with sodium oxybate experienced either a single
`episode or sporadic nocturnal urinary incontinence and <1% experienced a single episode of nocturnal
`fecal incontinence. Less than 1% of patients discontinued as a result of incontinence. Incontinence has
`
`been reported at all doses tested.
`
`In a controlled trial where patients were randomized to fixed total daily doses of 3, 6, and 9g/day or
`placebo, a dose-response relationship for urinary incontinence was demonstrated with 14% of patients
`at 9gday experiencing urinary incontinence. In the same trial, one patient experienced fecal
`incontinence at a dose of 9g/day and discontinued treatment as a result.
`
`If a patient experiences urinary or fecal incontinence during Xyrem® therapy, the prescriber should
`consider pursuing investigations to rule out underlying etiologies, including worsening sleep apnea or
`nocturnal seizures, although there is no evidence to suggest that incontinence has been associated with
`seizures in patients being treated with Xyrem®.
`
`Sleepwalking
`
`The term “Sleepwalking” in this section refers to confused behavior occurring at night and, at times,
`associated with wandering. It is unclear if some or all of these episodes conespond to true
`somnambulisrn, which is a parasomnia occurring during non-REM sleep, or to any other specific
`medical disorder. Sleepwalking was reported in 7% of 448 patients treated in clinical trials with sodium
`
`oxybate. In sodium oxybate-treated patients <1% discontinued due to Sleepwalking. In controlled
`trials of up to 4 weeks duration, the incidence of Sleepwalking was 1% in both placebo and sodium
`oxybate-treated patients. Sleepwalking was reported by 32% of patients treated with sodium oxybate
`for periods up to 16 years in one independent uncontrolled trial. Fewer than 1% of the patients
`discontinued due to Sleepwalking. Five instances of significant injury or potential injury were associated
`with Sleepwalking during a clinical
`trial of sodium oxybate including a fall, clothing set on fire while
`attempting to smoke, attempted ingestion of nail polish remover, and overdose of oxybate. Therefore,
`episodes of Sleepwalking should be firlly evaluated and appropriate interventions considered.
`
`Sodium Intake
`
`Daily sodium intake in patients taking sodium oxybate ranges fiom 0.5 g (for a 3 g sodium oxybate
`dose) to 1.6 g (for a 9 g sodium oxybate dose). This should be considered in patients with heart failure,
`hypertension or compromised renal function.
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`Hepatic Insufficiency
`
`Patients with compromised liver fimction will have an increased elimination half—life and systemic
`exposure to sodium oxybate. (see Pharmacokinetics). The starting dose should therefore be
`decreased by one-half in such patients, and response to dose increments monitored closely (see Dosage
`and Administration).
`
`Renal Insufficiency
`
`No studies have been conducted in patients with renal failure. Because less than 5% of sodium oxybate
`is excreted via the kidney, no dose adjustment should be necessary in patients with renal impairment.
`The sodium load associated with administration of sodium oxybate should be considered in patients with
`renal insufficiency.
`
`Information for Patients
`
`The Xyrem Patient Success ProgramSM includes detailed information about the safe and proper use of
`sodium oxybate, as well as information to help the patient prevent accidental use or abuse of sodium
`
`oxybate by others. Patients must confirm that they have read the materials before the first prescription
`will be filled. Prescribers will discuss the details of the program and the treatment (including the
`procedure for preparing the dose to be administered) prior to the initiation of treatment. Patients should
`
`also be informed that they must be seen by the prescriber fiequently during the course of their treatment,
`and that a detailed account of the adverse reactions they may have experienced will be taken. Food
`significantly decreases the bioavailability of sodium oxybate (see Pharmacokinetics). Whether sodium
`oxybate is taken in the fed or fasted state may affect both the efficacy and safety of sodium oxybate for
`a given patient Patients should be made aware of this and try to take the first dose several hours after a
`meal. Patients should be informed that sodium oxybate is associated with urinary and, less fiequently,
`fecal incontinence. Patients should be instructed to lie down and sleep after each dose of sodium
`oxybate, and not to take sodium oxybate at any time other than at night, immediately before bedtime
`and again 2.5—4 hours later. Patients should be instructed that they should not take alcohol or other
`sedative hypnotics with sodium oxybate.
`
`For additional information, patients should see the Medication Guide for Xyrem®.
`
`Laboratory Tests
`
`Laboratory tests are not required to monitor patient response or adverse events resulting from sodium
`oxybate administration
`
`In an open-label trial of long term exposure to sodium oxybate, which extended as long as 16 years for
`some patients, 30% (26/87) of patients tested had at least one positive anti-nuclear antibody (ANA)
`
`test. Of the 26, 17 patients had multiple positive ANA tests over time. The clinical course of these
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`patients was not always clearly recorded, but 1 patient was clearly diagnosed with rheumatoid arthritis
`
`at the time of the first recorded positive ANA test.
`
`Drug Interactions
`
`Interactions between sodium oxybate and three drugs commonly used in patients