Xyrem

Jazz Pharmaceuticals, Inc.
Jazz Pharmaceuticals, Inc.

HIGHLIGHTS OF PRESCRIBING INFORMATIONThese highlights do not include all the information needed to use XYREM safely and effectively. See full prescribing information for XYREM. Xyrem (sodium oxybate) oral solution CIIIInitial U.S. Approval: 2002RECENT MAJOR CHANGESDosage and Administration, Dose Adjustment with Co-administration of Divalproex Sodium (2.4)                       04/2014BOXED WARNINGWARNING: CENTRAL NERVOUS SYSTEM (CNS) DEPRESSION and MISUSE AND ABUSE. See full prescribing information for complete boxed warning. • Respiratory depression can occur with Xyrem use (5.4) • Xyrem is a Schedule III controlled substance and is the sodium salt of gamma hydroxybutyrate (GHB), a Schedule I controlled substance. Abuse or misuse of illicit GHB is associated with CNS adverse reactions, including seizure, respiratory depression, decreased consciousness, coma and death (5.2, 9.2) • Because of the risks of CNS depression, abuse, and misuse, Xyrem is available only through a restricted distribution program called the Xyrem Success Program® using a centralized pharmacy. Prescribers and patients must enroll in the program. (5.3) INDICATIONS AND USAGEXyrem is a central nervous system depressant indicated for the treatment of: •Cataplexy in narcolepsy (1.1) •Excessive daytime sleepiness (EDS) in narcolepsy (1.2) Xyrem may only be dispensed to patients enrolled in the Xyrem Success Program (1).DOSAGE AND ADMINISTRATION •Initiate dose at 4.5 grams (g) per night administered orally in two equal, divided doses: 2.25 g at bedtime and 2.25 g taken 2.5 to 4 hours later (2.1) •Titrate to effect in increments of 1.5 g per night at weekly intervals (0.75 g at bedtime and 0.75 g taken 2.5 to 4 hours later) (2.1). •Recommended dose range: 6 g to 9 g per night orally (2.1). Total Nightly Dose Take at Bedtime Take 2.5 to 4 Hours Later 4.5 g per night 2.25 g 2.25 g 6 g per night 3 g 3 g 7.5 g per night 3.75 g 3.75 g 9 g per night 4.5 g 4.5 g •Take each dose while in bed and lie down after dosing (2.2). •Allow 2 hours after eating before dosing (2.2). •Prepare both doses prior to bedtime; dilute each dose with approximately ¼ cup of water in pharmacy-provided vials (2.2). •Patients with Hepatic Impairment: starting dose is 2.25 g per night administered orally in two equal, divided doses of approximately 1.13 g at bedtime and approximately 1.13 g taken 2.5 to 4 hours later (2.3). •Concomitant use with divalproex sodium: an initial reduction in Xyrem dose of at least 20% is recommended (2.4, 7.2). DOSAGE FORMS AND STRENGTHSOral solution, 0.5 g per mL (3)CONTRAINDICATIONS •Succinic semialdehyde dehydrogenase deficiency (4) •In combination with sedative hypnotics or alcohol (4) WARNINGS AND PRECAUTIONS •CNS depression: Use caution when considering the concurrent use of Xyrem with other CNS depressants (5.1). •Caution patients against hazardous activities requiring complete mental alertness or motor coordination within the first 6 hours of dosing or after first initiating treatment until certain that Xyrem does not affect them adversely (5.1). •Depression and suicidality: Monitor patients for emergent or increased depression and suicidality (5.5). •Confusion/Anxiety: Monitor for impaired motor/cognitive function (5.6). •Parasomnias: Evaluate episodes of sleepwalking (5.7). •High sodium content in Xyrem: Monitor patients with heart failure, hypertension, or impaired renal function (5.8). Side Effects Most common adverse reactions (≥ 5% and at least twice the incidence with placebo) were nausea, dizziness, vomiting, somnolence, enuresis, and tremor ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Jazz Pharmaceuticals at 1-800-520-5568, or FDA at 1-800-FDA-1088 or www.fda.gov/Medwatch. USE IN SPECIFIC POPULATIONS •Pregnancy: Based on animal data, may cause fetal harm (8.1). •Geriatric patients: Monitor for impaired motor and/or cognitive function when taking Xyrem (8.5).

FULL PRESCRIBING INFORMATION: CONTENTS*

• WARNING: CENTRAL NERVOUS SYSTEM (CNS) DEPRESSION and MISUSE AND ABUSE.
• 1 XYREM INDICATIONS AND USAGE
  • 1.1 Cataplexy in Narcolepsy
  • 1.2 Excessive Daytime Sleepiness in Narcolepsy
• 2 XYREM DOSAGE AND ADMINISTRATION
  • 2.1 Dosing Information
  • 2.2 Important Administration Instructions
  • 2.3 Dose Modification in Patients with Hepatic Impairment
• 3 DOSAGE FORMS AND STRENGTHS
• 4 XYREM CONTRAINDICATIONS
• 5 WARNINGS AND PRECAUTIONS
  • 5.1 Central Nervous System Depression
  • 5.2 Abuse and Misuse
  • 5.3 Xyrem Success Program
  • 5.4 Respiratory Depression and Sleep-Disordered Breathing
  • 5.5 Depression and Suicidality
  • 5.6 Other Behavioral or Psychiatic Adverse Reactions
  • 5.7 Parasomnias
  • 5.8 Use in Patients Sensitive to High Sodium Intake
• 6 XYREM ADVERSE REACTIONS
  • 6.1 Clinical Trials Experience
  • 6.2 Postmarketing Experience
• 7 DRUG INTERACTIONS
  • 7.1 Alcohol, Sedative Hypnotics, and CNS Depressants
  • 7.2 Divalproex Sodium
• 8 USE IN SPECIFIC POPULATIONS
  • 8.1 Pregnancy
  • 8.2 Labor and Delivery
  • 8.3 Nursing Mothers
  • 8.4 Pediatric Use
  • 8.5 Geriatric Use
  • 8.6 Hepatic Impairment
• 9 DRUG ABUSE AND DEPENDENCE
  • 9.1 Controlled Substance
  • 9.2 Abuse
  • 9.3 Dependence
• 10 OVERDOSAGE
  • 10.1 Human Experience
  • 10.2 Signs and Symptoms
  • 10.3 Recommended Treatment of Overdose
  • 10.4 Poison Control Center
• 11 XYREM DESCRIPTION
• 12 CLINICAL PHARMACOLOGY
  • 12.1 Mechanism of Action
  • 12.3 Pharmacokinetics
• 13 NONCLINICAL TOXICOLOGY
  • 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
• 14 CLINICAL STUDIES
  • 14.1 Cataplexy in Narcolepsy
  • 14.2 Excessive Daytime Sleepiness in Narcolepsy
• 16 HOW SUPPLIED/STORAGE AND HANDLING
  • 16.1 How Supplied
  • 16.2 Storage
  • 16.3 Handling and Disposal
• 17 PATIENT COUNSELING INFORMATION
• MEDICATION GUIDE
  • Instructions for Use
• PACKAGE/LABEL PRINCIPAL DISPLAY PANEL

FULL PRESCRIBING INFORMATION

1 INDICATIONS AND USAGE

Limitations of Use

Xyrem may only be dispensed to patients enrolled in the Xyrem Success Program [see Warnings and Precautions (5.3)].

1.1 Cataplexy in Narcolepsy

Xyrem (sodium oxybate) oral solution is indicated for the treatment of cataplexy in narcolepsy.

1.2 Excessive Daytime Sleepiness in Narcolepsy

Xyrem (sodium oxybate) oral solution is indicated for the treatment of excessive daytime sleepiness (EDS) in narcolepsy.

2 DOSAGE AND ADMINISTRATION

Healthcare professionals who prescribe Xyrem must enroll in the Xyrem Success Program and must comply with the requirements to ensure safe use of Xyrem [see Warnings and Precautions (5.3)].

2.1 Dosing Information

The recommended starting dose is 4.5 grams (g) per night administered orally in two equal, divided doses: 2.25 g at bedtime and 2.25 g taken 2.5 to 4 hours later (see Table 1). Increase the dose by 1.5 g per night at weekly intervals (additional 0.75 g at bedtime and 0.75 g taken 2.5 to 4 hours later) to the effective dose range of 6 g to 9 g per night orally. Doses higher than 9 g per night have not been studied and should not ordinarily be administered.

Table 1: Xyrem Dose Regimen (g = grams)

2.2 Important Administration Instructions

Take the first dose of Xyrem at least 2 hours after eating because food significantly reduces the bioavailability of sodium oxybate.

Prepare both doses of Xyrem prior to bedtime. Prior to ingestion, each dose of Xyrem should be diluted with approximately ¼ cup (approximately 60 mL) of water in the empty pharmacy vials provided. Patients should take both doses of Xyrem while in bed and lie down immediately after dosing as Xyrem may cause them to fall asleep abruptly without first feeling drowsy. Patients will often fall asleep within 5 minutes of taking Xyrem, and will usually fall asleep within 15 minutes, though the time it takes any individual patient to fall asleep may vary from night to night. Patients should remain in bed following ingestion of the first and second doses, and should not take the second dose until 2.5 to 4 hours after the first dose. Patients may need to set an alarm to awaken for the second dose. Rarely, patients may take up to 2 hours to fall asleep.

2.3 Dose Modification in Patients with Hepatic Impairment

The recommended starting dose in patients with hepatic impairment is 2.25 g per night administered orally in two equal, divided doses: approximately 1.13 g at bedtime and approximately 1.13 g taken 2.5 to 4 hours later [see Use in Specific Populations (8.6); Clinical Pharmacology (12.3)].

Pharmacokinetic and pharmacodynamics interactions have been observed when Xyrem is co-administered with divalproex sodium. For patients already stabilized on Xyrem, it is recommended that addition of divalproex sodium should be accompanied by an initial reduction in the nightly dose of Xyrem by at least 20%. For patients already taking divalproex sodium, it is recommended that prescribers use a lower starting Xyrem dose with introducing Xyrem. Prescribers should monitor patient response and adjust dose accordingly [see Drug Interactions ( 7.2 ) and Clinical Pharmacology ( 12.3 )] .

3 DOSAGE FORMS AND STRENGTHS

Xyrem is a clear to slightly opalescent oral solution, in a concentration of 0.5 g per mL.

4 CONTRAINDICATIONS

• •Xyrem is contraindicated in patients being treated with sedative hypnotic agents.
• •Patients should not drink alcohol when using Xyrem.
• •Xyrem is contraindicated in patients with succinic semialdehyde dehydrogenase deficiency. This is a rare disorder of inborn error of metabolism variably characterized by mental retardation, hypotonia, and ataxia.

5 WARNINGS AND PRECAUTIONS

5.1 Central Nervous System Depression

Xyrem is a central nervous system (CNS) depressant. Alcohol and sedative hypnotics are contraindicated in patients who are using Xyrem. The concurrent use of Xyrem with other CNS depressants, including but not limited to opioid analgesics, benzodiazepines, sedating antidepressants or antipsychotics, sedating anti-epileptic drugs, general anesthetics, muscle relaxants, and/or illicit CNS depressants, may increase the risk of respiratory depression, hypotension, profound sedation, syncope, and death. If use of these CNS depressants in combination with Xyrem is required, dose reduction or discontinuation of one or more CNS depressants (including Xyrem) should be considered. In addition, if short-term use of an opioid (e.g. post- or perioperative) is required, interruption of treatment with Xyrem should be considered.

Healthcare providers should caution patients about operating hazardous machinery, including automobiles or airplanes, until they are reasonably certain that Xyrem does not affect them adversely (e.g., impair judgment, thinking, or motor skills). Patients should not engage in hazardous occupations or activities requiring complete mental alertness or motor coordination, such as operating machinery or a motor vehicle or flying an airplane, for at least 6 hours after taking the second nightly dose of Xyrem. Patients should be queried about CNS depression‑related events upon initiation of Xyrem therapy and periodically thereafter [see Warnings and Precautions (5.3)].

5.2 Abuse and Misuse

Xyrem is a Schedule III controlled substance. The active ingredient of Xyrem, sodium oxybate or gamma-hydroxybutyrate (GHB), is a Schedule I controlled substance. Abuse of illicit GHB, either alone or in combination with other CNS depressants, is associated with CNS adverse reactions, including seizure, respiratory depression, decreases in the level of consciousness, coma, and death. The rapid onset of sedation, coupled with the amnestic features of Xyrem, particularly when combined with alcohol, has proven to be dangerous for the voluntary and involuntary user (e.g., assault victim). Because illicit use and abuse of GHB have been reported, physicians should carefully evaluate patients for a history of drug abuse and follow such patients closely, observing them for signs of misuse or abuse of GHB (e.g. increase in size or frequency of dosing, drug-seeking behavior, feigned cataplexy) [see Warnings and Precautions (5.3) and Drug Abuse and Dependence (9.2)].

5.3 Xyrem Success Program

Because of the risks of central nervous system depression and abuse/misuse, Xyrem is available only through a restricted distribution program called the Xyrem Success Program.

Required components of the Xyrem Success Program are:

• •Use of a centralized pharmacy
• •Healthcare Providers who prescribe Xyrem must complete the enrollment forms and comply with the requirements.
• •To receive Xyrem, patients must understand the risks and benefits of Xyrem.

Further information is available at www.XYREM.com or 1-866-XYREM88^® (1-866-997-3688).

5.4 Respiratory Depression and Sleep-Disordered Breathing

Xyrem may impair respiratory drive, especially in patients with compromised respiratory function. In overdoses, life-threatening respiratory depression has been reported [see Overdosage (10)].

In a study assessing the respiratory-depressant effects of Xyrem at doses up to 9 g per night in 21 patients with narcolepsy, no dose-related changes in oxygen saturation were demonstrated in the group as a whole. One of the four patients with preexisting, moderate-to-severe sleep apnea had significant worsening of the apnea/hypopnea index during treatment.

In a study assessing the effects of Xyrem 9 g per night in 50 patients with obstructive sleep apnea, Xyrem did not increase the severity of sleep-disordered breathing and did not adversely affect the average duration and severity of oxygen desaturation overall. However, there was a significant increase in the number of central apneas in patients taking Xyrem, and clinically significant oxygen desaturation (≤55%) was measured in three patients (6%) after Xyrem administration, with one patient withdrawing from the study and two continuing after single brief instances of desaturation. Prescribers should be aware that increased central apneas and clinically relevant desaturation events have been observed with Xyrem administration.

In clinical trials in 128 patients with narcolepsy, two subjects had profound CNS depression, which resolved after supportive respiratory intervention. Two other patients discontinued sodium oxybate because of severe difficulty breathing and an increase in obstructive sleep apnea. In two controlled trials assessing polysomnographic (PSG) measures in patients with narcolepsy, 40 of 477 patients were included with a baseline apnea/hypopnea index of 16 to 67 events per hour, indicative of mild to severe sleep-disordered breathing. None of the 40 patients had a clinically significant worsening of respiratory function as measured by apnea/hypopnea index and pulse oximetry at doses of 4.5 g to 9 g per night.

Prescribers should be aware that sleep-related breathing disorders tend to be more prevalent in obese patients and in postmenopausal women not on hormone replacement therapy as well as among patients with narcolepsy.

5.5 Depression and Suicidality

In clinical trials in patients with narcolepsy (n=781), there were two suicides and two attempted suicides in Xyrem-treated patients, including three patients with a previous history of depressive psychiatric disorder. Of the two suicides, one patient used Xyrem in conjunction with other drugs. Xyrem was not involved in the second suicide. Adverse reactions of depression were reported by 7% of 781 Xyrem-treated patients, with four patients (< 1%) discontinuing because of depression. In most cases, no change in Xyrem treatment was required.

In a controlled trial, with patients randomized to fixed doses of 3 g, 6 g, or 9 g per night Xyrem or placebo, there was a single event of depression at the 3 g per night dose. In another controlled trial, with patients titrated from an initial 4.5 g per night starting dose, the incidences of depression were 1 (1.7%), 1 (1.5%), 2 (3.2%), and 2 (3.6%) for the placebo, 4.5 g, 6 g, and 9 g per night doses, respectively.

The emergence of depression in patients treated with Xyrem requires careful and immediate evaluation. Patients with a previous history of a depressive illness and/or suicide attempt should be monitored carefully for the emergence of depressive symptoms while taking Xyrem.

5.6 Other Behavioral or Psychiatic Side Effects

During clinical trials in narcolepsy, 3% of 781 patients treated with Xyrem experienced confusion, with incidence generally increasing with dose.

Less than 1% of patients discontinued the drug because of confusion. Confusion was reported at all recommended doses from 6 g to 9 g per night. In a controlled trial where patients were randomized to fixed total daily doses of 3 g, 6 g, or 9 g per night or placebo, a dose-response relationship for confusion was demonstrated, with 17% of patients at 9 g per 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 per night dose, there was a single event of confusion in one patient at the 9 g per night dose. In the majority of cases in all clinical trials in narcolepsy, 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.

Anxiety occurred in 5.8% of the 874 patients receiving Xyrem in clinical trials in another population. The emergence of or increase in anxiety in patients taking Xyrem should be carefully monitored.

Other neuropsychiatric reactions reported in Xyrem clinical trials included hallucinations, paranoia, psychosis, and agitation. The emergence of thought disorders and/or behavior abnormalities requires careful and immediate evaluation.

5.7 Parasomnias

Sleepwalking, defined as confused behavior occurring at night and at times associated with wandering, was reported in 6% of 781 patients with narcolepsy treated with Xyrem in controlled and long-term open-label studies, with < 1% of patients discontinuing due to sleepwalking. Rates of sleepwalking were similar for patients taking placebo and patients taking Xyrem in controlled trials. It is unclear if some or all of the reported sleepwalking episodes correspond to true somnambulism, which is a parasomnia occurring during non-REM sleep, or to any other specific medical disorder. Five instances of significant injury or potential injury were associated with sleepwalking during a clinical trial of Xyrem in patients with narcolepsy.

Parasomnias including sleepwalking have been reported in postmarketing experience with Xyrem. Therefore, episodes of sleepwalking should be fully evaluated and appropriate interventions considered.

5.8 Use in Patients Sensitive to High Sodium Intake

Xyrem has a high salt content. In patients sensitive to salt intake (e.g., those with heart failure, hypertension, or renal impairment) consider the amount of daily sodium intake in each dose of Xyrem. Table 2 provides the approximate sodium content per Xyrem dose.

Table 2

Approximate Sodium Content per Total Nightly Dose of Xyrem (g = grams)

6 ADVERSE REACTIONS

The following adverse reactions appear in other sections of the labeling:

• •CNS depression [see Warnings and Precautions (5.1)]
• •Abuse and Misuse [see Warnings and Precautions (5.2)]
• •Respiratory Depression and Sleep-disordered Breathing [see Warnings and Precautions (5.4)]
• •Depression and Suicidality [see Warnings and Precautions (5.5)]
• •Other Behavioral or Psychiatric Adverse Reactions [see Warnings and Precautions (5.6)]
• •Parasomnias [see Warnings and Precautions (5.7)]
• •Use in Patients Sensitive to High Sodium Intake [see Warnings and Precautions (5.8)]

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

Xyrem was studied in three placebo-controlled clinical trials (Trials N1, N3, and N4, described in Sections 14.1 and 14.2) in 611 patients with narcolepsy (398 subjects treated with Xyrem, and 213 with placebo). A total of 781 patients with narcolepsy were treated with Xyrem in controlled and uncontrolled clinical trials.

Section 6.1 and Table 3 presents adverse reactions from three pooled, controlled trials (N1, N3, N4) in patients with narcolepsy.

Adverse Reactions Leading to Treatment Discontinuation:

Of the 398 Xyrem-treated patients with narcolepsy, 10.3% of patients discontinued because of adverse reactions compared with 2.8% of patients receiving placebo. The most common adverse reaction leading to discontinuation was nausea (2.8%). The majority of adverse reactions leading to discontinuation began during the first few weeks of treatment.

CommonlyObserved Adverse Reactions in Controlled Clinical Trials:

The most common adverse reactions (incidence ≥ 5% and twice the rate seen with placebo) in Xyrem-treated patients were nausea, dizziness, vomiting, somnolence, enuresis, and tremor.

Adverse Reactions Occurring at an Incidence of 2% or greater:

Table 3 lists adverse reactions that occurred at a frequency of 2% or more in any treatment group for three controlled trials and were more frequent in any Xyrem treatment group than with placebo. Adverse reactions are summarized by dose at onset. Nearly all patients in these studies initiated treatment at 4.5 g per night. In patients who remained on treatment, adverse reactions tended to occur early and to diminish over time.

Table 3
Adverse Reactions Occurring in ≥2% of Patients and More Frequently with Xyrem than Placebo in Three Controlled Trials (N1, N3, N4) by Body System and Dose at Onset

Dose-Response Information

In clinical trials in narcolepsy, a dose-response relationship was observed for nausea, vomiting, paresthesia, disorientation, irritability, disturbance in attention, feeling drunk, sleepwalking, and enuresis. The incidence of all these reactions was notably higher at 9 g per night.

In controlled trials in narcolepsy, discontinuations of treatment due to adverse reactions were greater at higher doses of Xyrem.

6.2 Postmarketing Experience

The following additional adverse reactions that have a likely causal relationship to Xyrem exposure have been identified during postmarketing use of Xyrem. These adverse reactions include: arthralgia, decreased appetite, fall, fluid retention, hangover, headache, hypersensitivity, hypertension, memory impairment, panic attack, vision blurred, and weight decreased. Because these reactions are reported voluntarily, it is not always possible to reliably estimate their frequency.

7 DRUG INTERACTIONS

7.1 Alcohol, Sedative Hypnotics, and CNS Depressants

Xyrem should not be used in combination with alcohol or sedative hypnotics. Use of other CNS depressants may potentiate the CNS-depressant effects of Xyrem.

7.2 Divalproex Sodium

Concomitant use of Xyrem with divalproex sodium resulted in a 25% mean increase in systemic exposure to Xyrem (AUC ratio range of 0.8 to 1.7) and in a greater impairment on some tests of attention and working memory. An initial Xyrem dose reduction of at least 20% is recommended if divalproex sodium is prescribed to patients already taking Xyrem [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3)]. Prescribers are advised to monitor patient response closely and adjust dose accordingly if concomitant use of Xyrem and divalproex sodium is warranted.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category C

There are no adequate and well-controlled studies in pregnant women. Xyrem should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Oral administration of sodium oxybate to pregnant rats (150, 350, or 1,000 mg/kg/day) or rabbits (300, 600, or 1,200 mg/kg/day) throughout organogenesis produced no clear evidence of developmental toxicity. The highest doses tested in rats and rabbits were approximately 1 and 3 times, respectively, the maximum recommended human dose (MRHD) of 9 g per night on a body surface area (mg/m²) basis.

Oral administration of sodium oxybate (150, 350, or 1,000 mg/kg/day) to rats throughout pregnancy and lactation resulted in increased stillbirths and decreased offspring postnatal viability and body weight gain at the highest dose tested. The no-effect dose for pre- and post-natal developmental toxicity in rats is less than the MRHD on a mg/m² basis.

8.2 Labor and Delivery

Xyrem 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.

8.3 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 Xyrem is administered to a nursing woman.

8.4 Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

8.5 Geriatric Use

Clinical studies of Xyrem in patients with narcolepsy did not include sufficient numbers of subjects age 65 years and older to determine whether they respond differently from younger subjects. In controlled trials in another population, 39 (5%) of 874 patients were 65 years or older. Discontinuations of treatment due to adverse reactions were increased in the elderly compared to younger adults (20.5% v. 18.9%). Frequency of headaches was markedly increased in the elderly (38.5% v. 18.9%). The most common adverse reactions were similar in both age categories. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

8.6 Hepatic Impairment

The starting dose of Xyrem should be reduced by one-half in patients with liver impairment [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3)].

9 DRUG ABUSE AND DEPENDENCE

9.1 Controlled Substance

Xyrem is a Schedule III controlled substance under the Federal Controlled Substances Act. Non-medical use of Xyrem could lead to penalties assessed under the higher Schedule I controls.

9.2 Abuse

Xyrem (sodium oxybate), the sodium salt of GHB, produces dose-dependent central nervous system effects, including hypnotic and positive subjective reinforcing effects. The onset of effect is rapid, enhancing its potential for abuse or misuse.

The rapid onset of sedation, coupled with the amnestic features of Xyrem, particularly when combined with alcohol, has proven to be dangerous for the voluntary and involuntary user (e.g., assault victim).

Illicit GHB is abused in social settings primarily by young adults. Some of the doses estimated to be abused are in a similar dosage range to that used for treatment of patients with cataplexy. GHB has some commonalities with ethanol over a limited dose range, and some cross tolerance with ethanol has been reported as well. Cases of severe dependence and craving for GHB have been reported when the drug is taken around the clock. Patterns of abuse indicative of dependence include: 1) the use of increasingly large doses, 2) increased frequency of use, and 3) continued use despite adverse consequences.

Because illicit use and abuse of GHB have been reported, physicians should carefully evaluate patients for a history of drug abuse and follow such patients closely, observing them for signs of misuse or abuse of GHB (e.g. increase in size or frequency of dosing, drug-seeking behavior, feigned cataplexy). Dispose of Xyrem according to state and federal regulations. It is safe to dispose of Xyrem down the sanitary sewer.

9.3 Dependence

There have been case reports of withdrawal, ranging from mild to severe, following discontinuation of illicit use of GHB at frequent repeated doses (18 g to 250 g per day) in excess of the therapeutic dose range. Signs and symptoms of GHB withdrawal following abrupt discontinuation included insomnia, restlessness, anxiety, psychosis, lethargy, nausea, tremor, sweating, muscle cramps, tachycardia, headache, dizziness, rebound fatigue and sleepiness, confusion, and, particularly in the case of severe withdrawal, visual hallucinations, agitation, and delirium. These symptoms generally abated in 3 to 14 days. In cases of severe withdrawal, hospitalization may be required. The discontinuation effects of Xyrem have not been systematically evaluated in controlled clinical trials. In the clinical trial experience with Xyrem in narcolepsy/cataplexy patients at therapeutic doses, two patients reported anxiety and one reported insomnia following abrupt discontinuation at the termination of the clinical trial; in the two patients with anxiety, the frequency of cataplexy had increased markedly at the same time.

Tolerance

Tolerance to Xyrem has not been systematically studied in controlled clinical trials. There have been some case reports of symptoms of tolerance developing after illicit use at dosages far in excess of the recommended Xyrem dosage regimen. Clinical studies of sodium oxybate in the treatment of alcohol withdrawal suggest a potential cross-tolerance with alcohol. The safety and effectiveness of Xyrem in the treatment of alcohol withdrawal have not been established.

10 OVERDOSAGE

10.1 Human Experience

Information regarding overdose with Xyrem is derived largely from reports in the medical literature that describe symptoms and signs in individuals who have ingested GHB illicitly. In these circumstances the co-ingestion of other drugs and alcohol was common, and may have influenced the presentation and severity of clinical manifestations of overdose.

In clinical trials two cases of overdose with Xyrem were reported. In the first case, an estimated dose of 150 g, more than 15 times the maximum recommended dose, caused a patient to be unresponsive with brief periods of apnea and to be incontinent of urine and feces. This individual recovered without sequelae. In the second case, death was reported following a multiple drug overdose consisting of Xyrem and numerous other drugs.

10.2 Signs and Symptoms

Information about signs and symptoms associated with overdosage with Xyrem derives from reports of its illicit use. Patient presentation following overdose is influenced by the dose ingested, the time since ingestion, the co-ingestion of other drugs and alcohol, and the fed or fasted state. Patients have exhibited varying degrees of depressed consciousness that may fluctuate rapidly between a confusional, agitated combative state with ataxia and coma. Emesis (even when obtunded), diaphoresis, headache, and impaired psychomotor skills have been observed. No typical pupillary changes have been described to assist in diagnosis; pupillary reactivity to light is maintained. Blurred vision has been reported. An increasing depth of coma has been observed at higher doses. Myoclonus and tonic-clonic seizures have been reported. Respiration may be unaffected or compromised in rate and depth. Cheyne-Stokes respiration and apnea have been observed. Bradycardia and hypothermia may accompany unconsciousness, as well as muscular hypotonia, but tendon reflexes remain intact.

10.3 Recommended Treatment of Overdose

General symptomatic and supportive care should be instituted immediately, and gastric decontamination may be considered if co-ingestants are suspected. Because emesis may occur in the presence of obtundation, appropriate posture (left lateral recumbent position) and protection of the airway by intubation may be warranted. Although the gag reflex may be absent in deeply comatose patients, even unconscious patients may become combative to intubation, and rapid-sequence induction (without the use of sedative) should be considered. Vital signs and consciousness should be closely monitored. The bradycardia reported with GHB overdose has been responsive to atropine intravenous administration. No reversal of the central depressant effects of Xyrem can be expected from naloxone or flumazenil administration. The use of hemodialysis and other forms of extracorporeal drug removal have not been studied in GHB overdose. However, due to the rapid metabolism of sodium oxybate, these measures are not warranted.

10.4 Poison Control Center

As with the management of all cases of drug overdosage, the possibility of multiple drug ingestion should be considered. The healthcare provider is encouraged to collect urine and blood samples for routine toxicologic screening, and to consult with a regional poison control center (1-800-222-1222) for current treatment recommendations.

11 DESCRIPTION

Sodium oxybate, a CNS depressant, is the active ingredient in Xyrem. The chemical name for sodium oxybate is sodium 4-hydroxybutyrate. The molecular formula is C4H7NaO3, and the molecular weight is 126.09 g/mole. The chemical structure is: