`NDA 21-196/S-005
`FDA Approved Labeling Text dated 11/18/05
`
`Rx only
`
`Xyrem® (sodium oxybate) oral solution
`
`CIII
`
`
`Page 1
`
`!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.
`
`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).
`
`
`Xyrem is available through the Xyrem Success Program, using a centralized pharmacy 1-
`866-XYREM88® (1-866-997-3688). The Success Program provides educational materials to
`the prescriber and the patient explaining the risks and proper use of sodium oxybate, and
`the required prescription form. Once it is documented that the patient has read and/or
`understood the materials, the drug will be shipped to the patient. The Xyrem Success
`Program also recommends patient follow-up every 3 months. Physicians are expected to
`report all serious adverse events to the manufacturer. (See WARNINGS).
`
`
`DESCRIPTION
`
`Xyrem (sodium oxybate) is a central nervous system depressant that reduces excessive daytime
`sleepiness and cataplexy 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 C4H7NaO3 and the molecular weight is 126.09 grams/mole. The chemical
`structure is:
`
`O
`
`
`
`Na+ -O - C -CH2 - CH2 - CH2 - O - H
`
`
`
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`Page 2
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`
`NDA 21-196/S-005
`FDA Approved Labeling Text dated 11/18/05
`
`Sodium oxybate is a white to off-white, crystalline powder that is very soluble in aqueous
`solutions. Xyrem oral solution contains 500 mg of sodium 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 unknown.
`
`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 to 1 hour. Pharmacokinetics are nonlinear with blood levels increasing 3.7-fold as dose is
`doubled from 4.5 to 9 grams (g). The pharmacokinetics are not altered with repeat dosing.
`
`Absorption
`
`Sodium oxybate is absorbed rapidly following oral administration with an absolute
`bioavailability of about 25%. The average peak plasma concentrations (1st and 2nd peak)
`following administration of a 9 g daily dose divided into two equivalent doses given four hours
`apart were 78 and 142 micrograms/milliliter (mcg/mL), respectively. The average time to peak
`plasma concentration (Tmax) ranged from 0.5 to 1.25 hours in eight pharmacokinetic studies.
`Following oral administration, the plasma levels of sodium oxybate increase more than
`proportionally with increasing dose. Single doses greater than 4.5 g 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
`(Cmax) 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 mcg/mL, less than 1%
`is bound to plasma proteins.
`
`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 biotransformed 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
`
`

`

`Page 3
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`
`NDA 21-196/S-005
`FDA Approved Labeling Text dated 11/18/05
`
`second mitochondrial oxidoreductase enzyme, a transhydrogenase, also catalyses the conversion
`to succinic semialdehyde in the presence of α-ketoglutarate. An alternate pathway of
`biotransformation involves β-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 mcg/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 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 g.
`
`Race
`
`There are insufficient data to evaluate any pharmacokinetic differences among races.
`
`Renal Disease
`
`Because the kidney does not have a significant role in the excretion of sodium oxybate, no
`pharmacokinetic study in patients with renal dysfunction has been conducted; no effect of renal
`function on sodium oxybate pharmacokinetics would be expected.
`
`Hepatic Disease
`
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`Page 4
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`
`NDA 21-196/S-005
`FDA Approved Labeling Text dated 11/18/05
`
`
`Sodium oxybate undergoes significant presystemic (hepatic first-pass) metabolism. The kinetics
`of sodium oxybate in 16 cirrhotic patients, half without 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 from 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. Alteration of gastric pH
`with omeprazole produced no significant change in the oxybate kinetics.
`
`CLINICAL TRIALS
`
`Cataplexy
`
`The effectiveness of sodium oxybate in the treatment of cataplexy was established in two
`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 efficacy and safety of
`Xyrem® independent of stimulant use. In each trial, the treatment period was 4 weeks and the
`total daily doses ranged from 3 to 9 g, with the daily dose divided into two 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 3 g/night, sodium oxybate 6 g/night, or sodium oxybate 9 g/night.
`
`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 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
`specifically to evaluate the continued efficacy of sodium oxybate after long-term use.
`
`
`

`

`
`NDA 21-196/S-005
`FDA Approved Labeling Text dated 11/18/05
`
`The primary efficacy measure in Trials 1 and 2 was the frequency of cataplexy attacks.
`
`
`Page 5
`
`Table 1
`Summary of Outcomes in Clinical Trials Supporting
`the Efficacy of Sodium Oxybate
`
`
`Median
`Change
`From Baseline
`
`Comparison
`to Placebo
`p-value
`
`
`Baseline
`
`
`20.5
`23.0
`23.5
`Trial 2
`
`
`4.0
`1.9
`
`⎯
` 0.0451
` 0.0016
`
`(median attacks/two weeks)
`21.0
`0
`
`-
`<0.001
`
`(median attacks/week)
`-4
`-10
`-16
`
`Trial/
`Dosage
`Group (n)
`CATAPLEXY ATTACKS
`
`Trial 1
`
`
`Placebo (33)
`6.0 g/night (31)
`9.0 g/night (33)
`
`
`Placebo (29)
`Sodium oxybate (26)
`
`In Trial 1, both the 6 g/night and 9 g/night doses gave statistically significant reductions in the
`frequency of cataplexy attacks. The 3 g/night 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 to 9 g/night, but there was no effect seen in patients treated with doses less than 6
`g/night, suggesting little effect at these doses.
`
`Excessive Daytime Sleepiness
`
`The effectiveness of sodium oxybate in the treatment of excessive daytime sleepiness in
`narcolepsy was established in two randomized, double-blind, placebo-controlled trials (Trials 3
`and 4) in patients with narcolepsy. Seventy-eight percent of patients in Trial 3 were also being
`treated with CNS stimulants.
`
`Trial 3 was a multi-center randomized, double-blind, placebo-controlled, parallel-arm trial that
`evaluated 228 patients with moderate to severe symptoms at entry into the study including a
`median Epworth Sleepiness Scale (see below) score of 18, and Maintenance of Wakefulness Test
`(see below) score of 8.25 minutes. These patients were randomized to one of 4 treatment groups:
`placebo; sodium oxybate 4.5 g/night; sodium oxybate 6 g/night; and sodium oxybate 9 g/night.
`The period of double-blind treatment in this trial was 8 weeks. Antidepressants were withdrawn
`prior to randomization; stimulants were continued at stable doses.
`
`
`

`

`Page 6
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`
`NDA 21-196/S-005
`FDA Approved Labeling Text dated 11/18/05
`
`The primary efficacy measures in Trial 3 were the Epworth Sleepiness Scale and the Clinical
`Global Impression of Change. The Epworth Sleepiness Scale is intended to evaluate the extent of
`sleepiness in everyday situations by asking the patient a series of questions. In these questions,
`patients are asked to rate their chances of dozing during each of 8 activities on a scale from 0-3
`(0=never; 1=slight; 2=moderate; 3=high). Higher total scores indicate a greater tendency to
`sleepiness. The Clinical Global Impression of Change is a 7-point scale, centered at No Change,
`and ranging from Very Much Worse to Very Much Improved . In Trial 3, patients were rated by
`evaluators who based their assessments on the severity of narcolepsy at baseline.
`
`Trial 4 was a multi-center randomized, double-blind, double-dummy placebo-controlled,
`parallel-arm trial that evaluated 222 patients with moderate to severe symptoms at entry into the
`study including a median Epworth Sleepiness Scale score of 15, and Maintenance of
`Wakefulness Test (see below) score of 10.25 minutes. At entry, patients had to be taking
`modafinil for ≥ 1 month and at stable doses of 200, 400, or 600 mg daily for at least 1 month
`prior to randomization. The patients enrolled in the study were randomized to one of 4 treatment
`groups: placebo; sodium oxybate; modafinil; and sodium oxybate plus modafinil. Sodium
`oxybate was administered in a dose of 6 g/night for 4 weeks, followed by 9 g/night for 4 weeks.
`Modafinil was continued at the prior dose. Patients taking antidepressants could continue these
`medications at stable doses.
`
`The only primary efficacy measure in Trial 4 was the Maintenance of Wakefulness Test. The
`Maintenance of Wakefulness Test measures latency (in minutes) to sleep onset averaged over 4
`sessions at 2 hour intervals following nocturnal polysomnography. For each test session, the
`subject is asked to remain awake without using extraordinary measures. Each test session is
`terminated after 20 minutes if no sleep occurs, or after 10 minutes, if sleep occurs. The overall
`score is the mean sleep latency for the 4 sessions.
`
`In Trial 3, statistically significant improvements were seen on the Epworth Sleepiness Scale and
`on the Clinical Global Impression of Change at the 6 g/night and 9 g/night doses of sodium
`oxybate.
`
`
`
`
`
`
`Dose Group
`[g/night (n)]
`
`Placebo (59)
`6 (58)
`9 (47)
`
`Table 2
`Daytime Sleepiness in Trial 3
`
`Epworth Sleepiness Scale (Range 0-24)
`Baseline
`Endpoint Median Change
`from Baseline
`
`17.5
`19.0
`19.0
`
`17.0
`16.0
`12.0
`
`-0.5
`-2.0
`-5.0
`
`Change from Baseline
`Compared to Placebo
`(p-value)
`-
`< 0.001
`< 0.001
`
`
`Table 3
`
`

`

`
`NDA 21-196/S-005
`FDA Approved Labeling Text dated 11/18/05
`
`
`Page 7
`
`Clinical Global Impression of Change in Day and Nighttime Symptoms
`(Responder Analysis) in Trial 3
`
`
`
`Dose Group [g/night
`(n)]
`
`Placebo (59)
`6 (58)
`9 (47)
`
`Percent Responders
`(Very Much Improved or
`Much Improved)
`
`
`
`22%
`52%
`64%
`
`Significance Compared to
`Placebo
`(p-value)
`Change from Baseline
`-
`<0.001
`<0.001
`
`
`In Trial 4, a statistically significant improvement on the Maintenance of Wakefulness Test score
`was seen in the sodium oxybate and sodium oxybate plus modafinil groups.
`
`
`Table 4
`Daytime Sleepiness as Evaluated in Trial 4
`
`Maintenance of Wakefulness Test (minutes)
`Baseline
`Endpoint
`Mean Change
`Endpoint Compared to
`from Baseline
`Placebo
`-2.7
`-
`<0.001
`0.6
`
`9.7
`11.3
`
`6.9
`12.0
`
`10.4
`
`13.2
`
`2.7
`
`<0.001
`
`
`
`Dose Group (n)
`
`Placebo (55)
`Sodium Oxybate
`(50)
`Sodium Oxybate
`plus Modafinil
`(54)
`
`
`This trial was not capable by design of comparing the effects of sodium oxybate to modafinil,
`because patients receiving modafinil were not titrated to a maximally effective dose.
`
`INDICATIONS AND USAGE
`
`Xyrem (sodium oxybate) oral solution is indicated for the treatment of excessive daytime
`sleepiness and cataplexy in patients with narcolepsy.
`
`In Xyrem clinical trials, approximately 80% of patients maintained concomitant stimulant use
`(see BLACK BOX WARNINGS).
`
`CONTRAINDICATIONS
`
`Sodium oxybate is contraindicated in patients being treated with sedative hypnotic agents.
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`Page 8
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`NDA 21-196/S-005
`FDA Approved Labeling Text dated 11/18/05
`
`Sodium oxybate is contraindicated in patients with succinic semialdehyde dehydrogenase
`deficiency. This rare disorder is an inborn 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 after 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 Xyrem or any other sleep medicine, until they know whether the
`medicine will still have some carryover effect on them the next day, they should use extreme
`care while performing any 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 two subjects
`had profound CNS depression. A 39 year-old woman, a healthy volunteer received a single 4.5 g
`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 4.5 g/night. 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 of
`the 21 had 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. In the randomized controlled Trials 3 and 4, a total of 40 narcolepsy
`patients were included with a baseline apnea/hypopnea index of 16 to 67 events per hour
`
`

`

`Page 9
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`NDA 21-196/S-005
`FDA Approved Labeling Text dated 11/18/05
`
`indicative of mild to severe sleep disordered breathing. None of the 40 patients had a clinically
`significant worsening of their respiratory function as measured by apnea/hypopnea index and
`pulse oximetry while receiving sodium oxybate at dosages of 4.5 to 9 g/night in divided dosages.
`Nevertheless, 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, 2.6% of patients treated with sodium oxybate experienced confusion.
`Fewer than 1% of patients discontinued the drug because of confusion. Confusion was reported
`at all recommended doses from 6 to 9 g/night. In a controlled trial where patients were
`randomized to fixed total daily doses of 3, 6, and 9 g/night or placebo, a dose-response
`relationship for confusion was demonstrated with 17% of patients at 9 g/night experiencing
`confusion. In all cases in that controlled trial, the confusion resolved soon after termination of
`treatment. In Trial 3 where sodium oxybate was titrated from an initial 4.5 g/night dose, there
`was a single event of confusion in one patient at the 9 g/night dose. In the majority of cases in
`all clinical trials, confusion resolved either soon after termination of dosing or 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 careful and immediate evaluation.
`
`Depression
`
`In clinical trials, 3.2% of patients treated with sodium oxybate reported depressive symptoms. In
`the majority of cases, no change in sodium oxybate treatment was required. Four patients (<1%)
`discontinued because of depressive symptoms. In the controlled clinical trial where patients
`were randomized to fixed doses of 3, 6, 9 g/night or placebo, there was a single event of
`depression at the 3 g/night dose. In Trial 3, where patients were titrated from an initial 4.5
`g/night starting dose, the incidence of depression was 1 (1.7%), 1 (1.5%), 2 (3.2%), and 2 (3.6%)
`for the placebo, 4.5g, 6 g, and 9 g/night doses respectively.
`
`In the 717 patient dataset, there were two suicides and one attempted suicide recorded in patients
`with a previous history of depressive psychiatric disorder. Of the two 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 careful and
`immediate evaluation. Patients with a previous history of a depressive illness and/or suicide
`
`

`

`Page 10
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`NDA 21-196/S-005
`FDA Approved Labeling Text dated 11/18/05
`
`attempt should be monitored especially carefully for the emergence of depressive symptoms
`while taking Xyrem.
`
`Usage in the Elderly
`
`There is very limited experience with sodium oxybate in the elderly. Therefore, elderly patients
`should be monitored closely for impaired motor and/or cognitive function when taking sodium
`oxybate.
`
`PRECAUTIONS
`
`Incontinence
`
`During clinical trials, 7% of narcoleptic 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 9
`g/night or placebo, a dose-response relationship for urinary incontinence was demonstrated with
`14% of patients initiated at 9 g/night experiencing urinary incontinence. In the same trial, one
`patient experienced fecal incontinence when initiated at a dose of 9 g/night 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 correspond to true
`somnambulism, which is a parasomnia occurring during non-REM sleep, or to any other specific
`medical disorder. Sleepwalking was reported in 4% of 717 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 in that trial 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 fully evaluated and appropriate interventions considered.
`
`

`

`
`NDA 21-196/S-005
`FDA Approved Labeling Text dated 11/18/05
`
`
`Sodium Intake
`
`Daily sodium intake in patients taking sodium oxybate is provided below and should be
`considered in patients with heart failure, hypertension or compromised renal function.
`
`
`Page 11
`
`Table 5
`Sodium Content per Total Nightly Dose
`
`
`
`Xyrem Dose (g) Xyrem (mL)
`3
`6
`4.5
`9
`6
`12
`7.5
`15
`9
`18
`
`Sodium Content/Dose
`546 mg
`819 mg
`1092 mg
`1365 mg
`1638 mg
`
`
`Hepatic Insufficiency
`
`Patients with compromised liver function 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 Program® 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 read and/or understand the materials before
`initiating therapy. Prescribers will discuss dosing (including the procedure for preparing the
`dose to be administered) prior to the initiation of treatment. Patients should also be informed
`that they should be seen by the prescriber frequently during the course of their treatment to
`review dose titration, symptom response and adverse reactions. 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
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`meal. Patients should be informed that sodium oxybate is associated with urinary and, less
`frequently, fecal incontinence. As a safety precaution, 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 to 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 patients was not always clearly recorded, but one patient was clearly
`diagnosed with rheumatoid arthritis at the time of the first recorded positive ANA test. No
`instances of systemic lupus erythematosus have been reported in patients taking sodium oxybate.
`
`Drug Interactions
`
`Interactions between sodium oxybate and three drugs commonly used in patients with narcolepsy
`(zolpidem tartrate, protriptyline HCl, and modafinil) have been evaluated in formal studies.
`Sodium oxybate, in combination with these drugs, produced no significant pharmacokinetic
`changes for either drug (see Pharmacokinetics). However, pharmacodynamic interactions cannot
`be ruled out. Nonetheless, sodium oxybate should not be used in combination with sedative
`hypnotics or other CNS depressants. Alteration of gastric pH with omeprazole produced no
`significant change in the oxybate kinetics.
`
`Carcinogenicity, Mutagenicity, Impairment of Fertility
`
`Sodium oxybate was not carcinogenic in rats administered oral doses of up to 1000 mg/kg/day (2
`times the exposure in humans receiving the maximum recommended dose (MRHD) of 9 g/day,
`on an AUC basis) for 83 weeks in the male rats and for 104 weeks in female rats. The results of
`2-year carcinogenicity studies in mouse and rat with gamma-butyrolactone, a compound that is
`metabolized to sodium oxybate in vivo, showed no clear evidence of carcinogenic activity. The
`plasma AUCs of sodium oxybate achieved at the high doses in these studies were 1/2 (mice and
`female rats) and 1/10 (male rats) the plasma AUCs at the MRHD.
`
`Sodium oxybate was negative in the Ames microbial mutagen test, an in vitro chromosomal
`aberration assay in CHO cells, and an in vivo rat micronucleus assay.
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`Sodium oxybate did not impair fertility in rats at doses up to 1000 mg/kg (approximately equal
`to the maximum recommended human daily dose on a mg/m2 basis).
`
`Pregnancy
`
`Pregnancy Category B: Reproduction studies conducted in pregnant rats at doses up to 1000
`mg/kg (approximately equal to the maximum recommended human daily dose on a mg/m2 basis)
`and in pregnant rabbits at doses up to 1200 mg/kg (approximately 3 times the maximum
`recommended human daily dose on a mg/m2 basis) revealed no evidence of teratogenicity. In a
`study in which rats were given sodium oxybate from Day 6 of gestation through Day 21 post-
`partum, slight decreases in pup and maternal weight gains were seen at 1000 mg/kg; there were
`no drug effects on other developmental parameters. There are, however, no adequate and well-
`controlled studies in pregnant women. Because animal reproduction studies are not always
`predictive of human response, this drug should be used during pregnancy only if clearly needed.
`
`Labor and Delivery
`
`Sodium oxybate has not been studied in labor or delivery. In obstetric anesthesia using an
`injectable formulation of sodium oxybate newborns had stable cardiovascular and respiratory
`measures but were very sleepy, causing a slight decrease in Apgar scores. There was a fall in the
`rate of uterine contractions 20 minutes after injection. Placental transfer is rapid, but umbilical
`vein levels of sodium oxybate were no more than 25% of the maternal concentration. No sodium
`oxybate was detected in the infant’s blood 30 minutes after delivery. Elimination curves of
`sodium oxybate between a 2-day old infant and a 15-year old patient were similar. Subsequent
`effects of sodium oxybate on later growth, development and maturation in humans are unknown.
`
`Nursing Mothers
`
`It is not known whether sodium oxybate is excreted in human milk. Because many drugs are
`excreted in human milk, caution should be exercised when sodium oxybate is administered to a