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Sodium Oxibate

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Sodium Oxibate uses


1 INDICATIONS AND USAGE

Limitations of Use

Sodium Oxibate may only be dispensed to patients enrolled in the Sodium Oxibate REMS Program .

Sodium Oxibate is a central nervous system depressant indicated for the treatment of:


Sodium Oxibate may only be dispensed to patients enrolled in the Sodium Oxibate REMS Program (1).

1.1 Cataplexy in Narcolepsy

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

1.2 Excessive Daytime Sleepiness in Narcolepsy

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

2 DOSAGE AND ADMINISTRATION

Healthcare professionals who prescribe Sodium Oxibate must enroll in the Sodium Oxibate REMS Program and must comply with the requirements to ensure safe use of Sodium Oxibate .


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

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. 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: Sodium Oxibate Dose Regimen (g = grams)


If A Patient’s Total Nightly Dose is:


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

2.2 Important Administration Instructions

Take the first dose of Sodium Oxibate at least 2 hours after eating because food significantly reduces the bioavailability of Sodium Oxibate.

Prepare both doses of Sodium Oxibate prior to bedtime. Prior to ingestion, each dose of Sodium Oxibate should be diluted with approximately ¼ cup of water in the empty pharmacy vials provided. Patients should take both doses of Sodium Oxibate while in bed and lie down immediately after dosing as Sodium Oxibate may cause them to fall asleep abruptly without first feeling drowsy. Patients will often fall asleep within 5 minutes of taking Sodium Oxibate, 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 .

2.4 Dose Adjustment with Co-administration of Divalproex Sodium

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

3 DOSAGE FORMS AND STRENGTHS

Sodium Oxibate is a clear to slightly opalescent oral solution, in a concentration of 0.5 g per mL (0.5 g/mL of Sodium Oxibate equivalent to 0.413 g/mL of oxybate).

Oral solution, 0.5 g per mL (0.5 g/mL of Sodium Oxibate equivalent to 0.413 g/mL of oxybate) (3)

4 CONTRAINDICATIONS

5 WARNINGS AND PRECAUTIONS

5.1 Central Nervous System Depression

Sodium Oxibate is a central nervous system (CNS) depressant. Alcohol and sedative hypnotics are contraindicated in patients who are using Sodium Oxibate. The concurrent use of Sodium Oxibate 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 Sodium Oxibate is required, dose reduction or discontinuation of one or more CNS depressants (including Sodium Oxibate) should be considered. In addition, if short-term use of an opioid (e.g. post- or perioperative) is required, interruption of treatment with Sodium Oxibate should be considered.

Healthcare providers should caution patients about operating hazardous machinery, including automobiles or airplanes, until they are reasonably certain that Sodium Oxibate 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 Sodium Oxibate. Patients should be queried about CNS depression‐related events upon initiation of Sodium Oxibate therapy and periodically thereafter .

5.2 Abuse and Misuse

Sodium Oxibate is a Schedule III controlled substance. The active ingredient of Sodium Oxibate, Sodium Oxibate or gamma-hydroxybutyrate, 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 Sodium Oxibate, 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 Sodium Oxibate REMS Program

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

Required components of the Sodium Oxibate REMS Program include:


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

5.4 Respiratory Depression and Sleep-Disordered Breathing

Sodium Oxibate may impair respiratory drive, especially in patients with compromised respiratory function. In overdoses, life-threatening respiratory depression has been reported .

In a study assessing the respiratory-depressant effects of Sodium Oxibate 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 Sodium Oxibate 9 g per night in 50 patients with obstructive sleep apnea, Sodium Oxibate 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 Sodium Oxibate, and clinically significant oxygen desaturation (≤ 55%) was measured in three patients (6%) after Sodium Oxibate 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 Sodium Oxibate 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 Oxibate 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 Sodium Oxibate in conjunction with other drugs. Sodium Oxibate 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 Sodium Oxibate treatment was required.

In a controlled trial, with patients randomized to fixed doses of 3 g, 6 g, or 9 g per night Sodium Oxibate 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 Sodium Oxibate 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 Sodium Oxibate.

5.6 Other Behavioral or Psychiatric Adverse Reactions

During clinical trials in narcolepsy, 3% of 781 patients treated with Sodium Oxibate 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 Oxibate 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 Sodium Oxibate 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 Sodium Oxibate in clinical trials in another population. The emergence of or increase in anxiety in patients taking Sodium Oxibate should be carefully monitored.

Other neuropsychiatric reactions reported in Sodium Oxibate clinical trials and the post-marketing setting included hallucinations, paranoia, psychosis, aggression, 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 Sodium Oxibate 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 Sodium Oxibate 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 Sodium Oxibate in patients with narcolepsy.

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

5.8 Use in Patients Sensitive to High Sodium Intake

Sodium Oxibate 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 Sodium Oxibate. Table 2 provides the approximate sodium content per Sodium Oxibate dose.

Table 2

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


Sodium Oxibate Dose


Sodium Content/Total Nightly Exposure


3 g per night

550 mg

4.5 g per night

820 mg

6 g per night

1100 mg

7.5 g per night

1400 mg

9 g per night

1640 mg

6 ADVERSE REACTIONS

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


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, Inc. at 1-800-520-5568, or FDA at 1-800-FDA-1088 or www.fda.gov/Medwatch.

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.

Sodium Oxibate 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 Sodium Oxibate, and 213 with placebo). A total of 781 patients with narcolepsy were treated with Sodium Oxibate 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.

Commonly Observed 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 Sodium Oxibate 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 Sodium Oxibate than Placebo in Three Controlled Trials (N1, N3, N4) by Body System and Dose at Onset

System Organ Class/MedDRA Preferred Term Placebo

(n=213) %

Sodium Oxibate 4.5g

(n=185) %

Sodium Oxibate 6g

(n=258) %

Sodium Oxibate 9g

(n=178) %


ANY ADVERSE REACTION


62

45

55

70

GASTROINTESTINAL DISORDERS


Nausea

3

8

13

20

Vomiting

1

2

4

11

Diarrhea

2

4

3

4

Abdominal pain upper

2

3

1

2

Dry mouth

2

1

2

1

GENERAL DISORDERS AND ADMINISTRATIVE SITE CONDITIONS


Pain

1

1

< 1

3

Feeling drunk

1

0

< 1

3

Edema peripheral

1

3

0

0

MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS


Pain in extremity

1

3

1

1

Cataplexy

1

1

1

2

Muscle spasms

2

2

< 1

2

NERVOUS SYSTEM DISORDERS


Dizziness

4

9

11

15

Somnolence

4

1

3

8

Tremor

0

0

2

5

Paresthesia

1

2

1

3

Disturbance in attention

0

1

0

4

Sleep paralysis

1

0

1

3

PSYCHIATRIC DISORDERS


Disorientation

1

1

2

3

Anxiety

1

1

1

2

Irritability

1

0

< 1


3

Sleep walking

0

0

0

3

RENAL AND URINARY DISORDERS


Enuresis

1

3

3

7

SKIN AND SUBCUTANEOUS TISSUE DISORDERS


Hyperhidrosis

0

1

1

3

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 Sodium Oxibate.

6.2 Postmarketing Experience

The following additional adverse reactions that have a likely causal relationship to Sodium Oxibate exposure have been identified during postmarketing use of Sodium Oxibate. These adverse reactions include: arthralgia, decreased appetite, fall, fluid retention, hangover, headache, hypersensitivity, hypertension, increased libido, memory impairment, nocturia, 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

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

7.2 Divalproex Sodium

Concomitant use of Sodium Oxibate with divalproex sodium resulted in a 25% mean increase in systemic exposure to Sodium Oxibate (AUC ratio range of 0.8 to 1.7) and in a greater impairment on some tests of attention and working memory. An initial Sodium Oxibate dose reduction of at least 20% is recommended if divalproex sodium is prescribed to patients already taking Sodium Oxibate [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 Sodium Oxibate 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. Sodium Oxibate should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Oral administration of Sodium Oxibate 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 Oxibate (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

Sodium Oxibate has not been studied in labor or delivery. In obstetric anesthesia using an injectable formulation of Sodium Oxibate, 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 Oxibate were no more than 25% of the maternal concentration. No Sodium Oxibate was detected in the infant’s blood 30 minutes after delivery. Elimination curves of Sodium Oxibate between a 2-day-old infant and a 15-year-old patient were similar. Subsequent effects of Sodium Oxibate on later growth, development, and maturation in humans are unknown.

8.3 Nursing Mothers

It is not known whether Sodium Oxibate is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Sodium Oxibate 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 Sodium Oxibate 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 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 Sodium Oxibate 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

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

9.2 Abuse

Sodium Oxibate, 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 Sodium Oxibate, 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 Sodium Oxibate according to state and federal regulations. It is safe to dispose of Sodium Oxibate 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 Sodium Oxibate have not been systematically evaluated in controlled clinical trials. In the clinical trial experience with Sodium Oxibate 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 Sodium Oxibate 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 Sodium Oxibate dosage regimen. Clinical studies of Sodium Oxibate in the treatment of alcohol withdrawal suggest a potential cross-tolerance with alcohol. The safety and effectiveness of Sodium Oxibate in the treatment of alcohol withdrawal have not been established.

10 OVERDOSAGE

10.1 Human Experience

Information regarding overdose with Sodium Oxibate 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 Sodium Oxibate 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 Sodium Oxibate and numerous other drugs.

10.2 Signs and Symptoms

Information about signs and symptoms associated with overdosage with Sodium Oxibate 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, 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 Sodium Oxibate 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 Oxibate, 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 Oxibate, a CNS depressant, is the active ingredient in Sodium Oxibate. The chemical name for Sodium Oxibate is sodium 4-hydroxybutyrate. The molecular formula is C4H7NaO3, and the molecular weight is 126.09 g/mole. The chemical structure is:

Sodium Oxibate is a white to off-white, crystalline powder that is very soluble in aqueous solutions. Each mL of Sodium Oxibate contains 0.5 g of Sodium Oxibate (equivalent to 0.413 g/mL of oxybate) in USP Purified Water, neutralized to pH 7.5 with malic acid.

chemical structure

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Sodium Oxibate is a CNS depressant. The mechanism of action of Sodium Oxibate in the treatment of narcolepsy is unknown. Sodium Oxibate is the sodium salt of gamma hydroxybutyrate, an endogenous compound and metabolite of the neurotransmitter GABA. It is hypothesized that the therapeutic effects of Sodium Oxibate on cataplexy and excessive daytime sleepiness are mediated through GABAB actions at noradrenergic and dopaminergic neurons, as well as at thalamocortical neurons.

12.3 Pharmacokinetics

Pharmacokinetics of Sodium Oxibate are nonlinear and are similar following single or repeat dosing.

Absorption

Following oral administration, Sodium Oxibate is absorbed rapidly across the clinical dose range, with an absolute bioavailability of about 88%. The average peak plasma concentrations following administration of each of the two 2.25 g doses given under fasting conditions 4 hours apart were similar. The average time to peak plasma concentration (Tmax) ranged from 0.5 to 1.25 hours. Following oral administration, the plasma levels of Sodium Oxibate increased more than dose-proportionally, with blood levels increasing 3.7‐fold as total daily dose is doubled from 4.5 g to 9 g. Single doses greater than 4.5 g have not been studied. Administration of Sodium Oxibate immediately after a high-fat meal resulted in delayed absorption (average Tmax increased from 0.75 hr to 2 hr) and a reduction in Cmax by a mean of 59% and of systemic exposure (AUC) by 37%.

Distribution

Sodium Oxibate is a hydrophilic compound with an apparent volume of distribution averaging 190 mL/kg to 384 mL/kg. At Sodium Oxibate concentrations ranging from 3 mcg/mL 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 Oxibate, 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 catalyzes the conversion of Sodium Oxibate 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 second mitochondrial oxidoreductase enzyme, a transhydrogenase, also catalyzes 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.

Elimination

The clearance of Sodium Oxibate 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. Sodium Oxibate has an elimination half-life of 0.5 to 1 hour.

Specific Populations

Geriatric

There is limited experience with Sodium Oxibate in the elderly. Results from a pharmacokinetic study (n=20) in another studied population indicate that the pharmacokinetic characteristics of Sodium Oxibate are consistent among younger (age 48 to 64 years) and older (age 65 to 75 years) adults.

Pediatric

The pharmacokinetics of Sodium Oxibate in patients younger than 18 years of age 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 Oxibate oral solution following a single oral dose of 4.5 g.

Race

There are insufficient data to evaluate any pharmacokinetic differences among races.

Renal Impairment

No pharmacokinetic study in patients with renal impairment has been conducted.

Hepatic Impairment

The pharmacokinetics of Sodium Oxibate 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 subjects with normal hepatic function 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 mL/min/kg 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 patients (mean t1/2 of 59 and 32 minutes, respectively, versus 22 minutes). The starting dose of Sodium Oxibate should be reduced by one-half in patients with liver impairment .

Drug Interactions Studies

Studies in vitro with pooled human liver microsomes indicate that Sodium Oxibate 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), a level considerably higher than levels achieved with therapeutic doses.

Drug interaction studies in healthy adults (age 18 to 50 years) were conducted with Sodium Oxibate and divalproex sodium, diclofenac, and ibuprofen:


Drug interaction studies in healthy adults demonstrated no pharmacokinetic interactions between Sodium Oxibate and protriptyline hydrochloride, zolpidem tartrate, and modafinil. Also, there were no pharmacokinetic interactions with the alcohol dehydrogenase inhibitor fomepizole. However, pharmacodynamic interactions with these drugs cannot be ruled out. Alteration of gastric pH with omeprazole produced no significant change in the oxybate kinetics. In addition, drug interaction studies in healthy adults demonstrated no pharmacokinetic or clinically significant pharmacodynamic interactions between Sodium Oxibate and the SNRI duloxetine HCl.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Administration of Sodium Oxibate to rats at oral doses of up to 1,000 mg/kg/day for 83 (males) or 104 (females) weeks resulted in no increase in tumors. Plasma exposure (AUC) at the highest dose tested was 2 times that in humans at the maximum recommended human dose (MRHD) of 9 g per night.

The results of 2-year carcinogenicity studies in mouse and rat with gamma-butyrolactone, a compound that is metabolized to Sodium Oxibate in vivo, showed no clear evidence of carcinogenic activity. The plasma AUCs of Sodium Oxibate achieved at the highest doses tested in these studies were less than that in humans at the MRHD.

Mutagenesis

Sodium Oxibate was negative in the in vitro bacterial gene mutation assay, an in vitro chromosomal aberration assay in mammalian cells, and in an in vivo rat micronucleus assay.

Impairment of Fertility

Oral administration of Sodium Oxibate (150, 350, or 1,000 mg/kg/day) to male and female rats prior to and throughout mating and continuing in females through early gestation resulted in no adverse effects on fertility. The highest dose tested is approximately equal to the MRHD on a mg/m2 basis.

14 CLINICAL STUDIES

14.1 Cataplexy in Narcolepsy

The effectiveness of Sodium Oxibate in the treatment of cataplexy was established in two randomized, double-blind, placebo-controlled, multicenter, parallel-group trials in patients with narcolepsy. In Trials N1 and N2, 85% and 80% of patients, respectively, were also being treated with CNS stimulants. The high percentages of concomitant stimulant use make it impossible to assess the efficacy and safety of Sodium Oxibate independent of stimulant use. In each trial, the treatment period was 4 weeks and the total nightly Sodium Oxibate doses ranged from 3 g to 9 g, with the total nightly dose administered as 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 N1 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 Oxibate 3 g per night, Sodium Oxibate 6 g per night, or Sodium Oxibate 9 g per night.

Trial N2 was a randomized withdrawal trial with 55 narcoleptic patients who had been taking open-label Sodium Oxibate for 7 to 44 months prior to study entry. 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 Oxibate at their stable dose (ranging from 3 g to 9 g per night) or to placebo for 2 weeks. Trial N2 was designed specifically to evaluate the continued efficacy of Sodium Oxibate after long-term use.

The primary efficacy measure in Trials N1 and N2 was the frequency of cataplexy attacks.

Table 4

Median Number of Cataplexy Attacks in Trials N1 and N2


Trial/Dosage Group


Baseline


Median Change from Baseline


Comparison to Placebo (p-value)


Trial N1 (Prospective, Randomized, Parallel Group Trial)


(median attacks/week)

Placebo (n=33)

20.5

-4

–

Sodium Oxibate 6 g per night (n=31)

23.0

-10

0.0451

Sodium Oxibate 9 g per night (n=33)

23.5

-16

0.0016
  • Trial N2 (Randomized Withdrawal Trial)

(median attacks/2 weeks)

Placebo (n=29)

4.0

21

–

Sodium Oxibate (n=26)

1.9

0

< 0.001

In Trial N1, both the 6 g and 9 g per night Sodium Oxibate doses resulted in statistically significant reductions in the frequency of cataplexy attacks. The 3 g per night dose had little effect. In Trial N2, patients randomized to placebo after discontinuing long-term open-label Sodium Oxibate therapy experienced a significant increase in cataplexy attacks (p < 0.001), providing evidence of long-term efficacy of Sodium Oxibate. In Trial N2, the response was numerically similar for patients treated with doses of 6 g to 9 g per night, but there was no effect seen in patients treated with doses less than 6 g per night, suggesting little effect at these doses.

14.2 Excessive Daytime Sleepiness in Narcolepsy

The effectiveness of Sodium Oxibate in the treatment of excessive daytime sleepiness in patients with narcolepsy was established in two randomized, double-blind, placebo-controlled trials (Trials N3 and N4). Seventy-eight percent of patients in Trial N3 were also being treated with CNS stimulants.

Trial N3 was a multicenter randomized, double-blind, placebo-controlled, parallel-group trial that evaluated 228 patients with moderate to severe symptoms at entry into the study including a median Epworth Sleepiness Scale score of 18, and a Maintenance of Wakefulness Test score of 8.3 minutes. Patients were randomized to one of 4 treatment groups: placebo, Sodium Oxibate 4.5 g per night, Sodium Oxibate 6 g per night, or Sodium Oxibate 9 g per 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.

The primary efficacy measures in Trial N3 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 were 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 evaluated on a 7-point scale, centered at No Change, and ranging from Very Much Worse to Very Much Improved. In Trial N3, patients were rated by evaluators who based their assessments on the severity of narcolepsy at baseline.

In Trial N3, statistically significant improvements were seen on the Epworth Sleepiness Scale score at Week 8 and on the Clinical Global Impression of Change score at Week 8 with the 6 g and 9 g per night doses of Sodium Oxibate compared to the placebo group.

Table 5

Change from Baseline in Daytime Sleepiness Score (Epworth Sleepiness Scale) at Week 8 in Trial N3 (Range 0-24)


Treatment Group


Baseline


Week 8


Median Change from Baseline at Week 8


p-value


Placebo (n=59)

17.5

17.0

-0.5

-

Sodium Oxibate 6 g per night (n=58)

19.0

16.0

-2.0

< 0.001

Sodium Oxibate 9 g per night (n=47)

19.0

12.0

-5.0

< 0.001

Table 6

Proportion of patients with a very much or much improved Clinical Global Impression of Change in Daytime and Nighttime Symptoms in Trial N3


Treatment Group


Percentages of Responders

(Very Much Improved or Much Improved)


Change from Baseline

Significance Compared to Placebo

(p-value)


Placebo (59)

22%

-

Sodium Oxibate 6 g per night (n=58)

52%

< 0.001

Sodium Oxibate 9 g per night (n=47)

64%

< 0.001

Trial N4 was a multicenter randomized, double-blind, placebo-controlled, parallel-group 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 a Maintenance of Wakefulness Test score of 10.3 minutes. At entry, patients had to be taking modafinil at stable doses of 200 mg, 400 mg, 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 Oxibate, modafinil, or Sodium Oxibate plus modafinil. Sodium Oxibate was administered in a dose of 6 g per night for 4 weeks, followed by 9 g per night for 4 weeks. Modafinil was continued in the modafinil alone and the Sodium Oxibate plus modafinil treatment groups at the patient’s prior dose. Trial N4 was not designed to compare the effects of Sodium Oxibate to modafinil because patients receiving modafinil were not titrated to a maximal dose. Patients randomized to placebo or to Sodium Oxibate treatment were withdrawn from their stable dose of modafinil. Patients taking antidepressants could continue these medications at stable doses.

The primary efficacy measure in Trial N4 was the Maintenance of Wakefulness Test. The Maintenance of Wakefulness Test measures latency to sleep onset (in minutes) averaged over 4 sessions at 2-hour intervals following nocturnal polysomnography. For each test session, the subject was 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 N4, a statistically significant improvement in the change in the Maintenance of Wakefulness Test score from baseline at Week 8 was seen in the Sodium Oxibate and Sodium Oxibate plus modafinil groups compared to the placebo group.

This trial was not designed to compare the effects of Sodium Oxibate to modafinil, because patients receiving modafinil were not titrated to a maximally effective dose.

Table 7

Change in Baseline in the Maintenance of Wakefulness Test Score (in minutes) at Week 8 in Trial N4


Treatment Group


Baseline


Week 8


Mean Change from Baseline at Week 8


p-value


Placebo (modafinil withdrawn) (n=55)

9.7

6.9

-2.7

-

Sodium Oxibate (modafinil withdrawn) (n=50)

11.3

12.0

0.6

< 0.001

Sodium Oxibate plus modafinil (n=54)

10.4

13.2

2.7

< 0.001

16 HOW SUPPLIED/STORAGE AND HANDLING

16.1 How Supplied

Sodium Oxibate is a clear to slightly opalescent oral solution. Each prescription includes one bottle of Sodium Oxibate, a press-in-bottle-adaptor, an oral measuring device, and a Medication Guide. The pharmacy provides two empty vials with child-resistant caps with each Sodium Oxibate shipment.

Each amber bottle contains Sodium Oxibate oral solution at a concentration of 0.5 g per mL (0.5 g/mL of Sodium Oxibate equivalent to 0.413 g/mL of oxybate) and has a child-resistant cap.

One 180 mL bottle NDC 68727-100-01

16.2 Storage

Keep out of reach of children.

Sodium Oxibate should be stored at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F).

Dispense in tight containers.

Solutions prepared following dilution should be consumed within 24 hours.

16.3 Handling and Disposal

Sodium Oxibate is a Schedule III drug under the Controlled Substances Act. Sodium Oxibate should be handled according to state and federal regulations. It is safe to dispose of Sodium Oxibate down the sanitary sewer.

17 PATIENT COUNSELING INFORMATION

Sodium Oxibate REMS Program

Inform patients that Sodium Oxibate is available only through a restricted distribution program called the Sodium Oxibate REMS Program.

The contents of the Sodium Oxibate Medication Guide and educational materials are reviewed with every patient before initiating treatment with Sodium Oxibate.

Patients must read and understand the materials in the Sodium Oxibate REMS Program prior to initiating treatment. Inform the patient that they should be seen by the prescriber frequently to review dose titration, symptom response, and adverse reactions; a follow-up of every three months is recommended.

Discuss safe and proper use of Sodium Oxibate and dosing information with patients prior to the initiation of treatment. Instruct patients to store Sodium Oxibate bottles and Sodium Oxibate doses in a secure place, out of the reach of children and pets.

Alcohol or Sedative Hypnotics

Advise patients not to drink alcohol or take other sedative hypnotics if they are taking Sodium Oxibate.

Sedation

Inform patients that after taking Sodium Oxibate they are likely to fall asleep quickly (often within 5 and usually within 15 minutes), but the time it takes to fall asleep can vary from night to night. The sudden onset of sleep, including in a standing position or while rising from bed, has led to falls complicated by injuries, in some cases requiring hospitalization. Instruct patients to remain in bed following ingestion of the first and second doses. Instruct patients not to take their second dose until 2.5 to 4 hours after the first dose.

Food Effects on Sodium Oxibate

Inform patients to take the first dose at least 2 hours after eating.

Respiratory Depression

Inform patients that Sodium Oxibate can be associated with respiratory depression.

Operating Hazardous Machinery

Inform patients that until they are reasonably certain that Sodium Oxibate does not affect them adversely (e.g., impair judgment, thinking, or motor skills) they should not operate hazardous machinery, including automobiles or airplanes.

Suicidality

Instruct patients or families to contact a healthcare provider immediately if the patient develops depressed mood, markedly diminished interest or pleasure in usual activities, significant change in weight and/or appetite, psychomotor agitation or retardation, increased fatigue, feelings of guilt or worthlessness, slowed thinking or impaired concentration, or suicidal ideation.

Sleepwalking

Instruct patients and their families that Sodium Oxibate has been associated with sleepwalking and to contact their healthcare provider if this occurs.

Sodium Intake

Instruct patients who are sensitive to salt intake (e.g., those with heart failure, hypertension, or renal impairment) that Sodium Oxibate contains a significant amount of sodium and they should limit their sodium intake.

Distributed By:

Jazz Pharmaceuticals, Inc.

Palo Alto, CA 94304

Protected by U.S. Patent Nos. 6,472,431; 6,780,889; 7,262,219; 7,851,506; 8,263,650; 8,324,275; 8,461,203; 8,772,306; 8,859,619; 8,952,062

MEDICATION GUIDE

Sodium Oxibate®

(sodium oxybate)

oral solution CIII

Read this Medication Guide carefully before you start taking Sodium Oxibate and each time you get a refill. There may be new information. This information does not take the place of talking to your doctor about your medical condition or your treatment.

What is the most important information I should know about Sodium Oxibate?

Sodium Oxibate can cause serious side effects including slow breathing or changes in your alertness. Do not drink alcohol or take medicines intended to make you fall asleep while you are taking Sodium Oxibate because they can make these side effects worse. Call your doctor right away if you have any of these serious side effects.


What is Sodium Oxibate?

Sodium Oxibate is a prescription medicine used to treat the following symptoms in people who fall asleep frequently during the day, often at unexpected times (narcolepsy):


It is not known if Sodium Oxibate is safe and effective in children.

Sodium Oxibate is a controlled substance (CIII) because it contains Sodium Oxibate that can be a target for people who abuse prescription medicines or street drugs. Keep your Sodium Oxibate in a safe place to protect it from theft. Never give your Sodium Oxibate to anyone else because it may cause death or harm them. Selling or giving away this medicine is against the law.

Who should not take Sodium Oxibate?

Do not take Sodium Oxibate if you:


Before you take Sodium Oxibate, tell your doctor if you:


Tell your doctor about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements.

Especially, tell your doctor if you take other medicines to help you sleep (sedatives). Do not take medicines that make you sleepy with Sodium Oxibate.

Know the medicines you take. Keep a list of them to show your doctor and pharmacist when you get a new medicine.

How should I take Sodium Oxibate?


What are the possible side effects of Sodium Oxibate?

Sodium Oxibate can cause serious side effects, including:


Call your doctor right away if you have symptoms of mental health problems.


The most common side effects of Sodium Oxibate include:


Your side effects may increase when you take higher doses of Sodium Oxibate.

Sodium Oxibate can cause physical dependence and craving for the medicine when it is not taken as directed.

These are not all the possible side effects of Sodium Oxibate. For more information, ask your doctor or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store Sodium Oxibate?


General information about the safe and effective use of Sodium Oxibate

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use Sodium Oxibate for a condition for which it was not prescribed. Do not give Sodium Oxibate to other people, even if they have the same symptoms that you have. It may harm them.

This Medication Guide summarizes the most important information about Sodium Oxibate. If you would like more information, talk with your doctor. You can ask your pharmacist or doctor for information about Sodium Oxibate that is written for health professionals.

For more information, go to www. XYREMREMS.com or call the Sodium Oxibate REMS Program at 1-866-997-3688.

What are the ingredients in Sodium Oxibate?

Active Ingredients: Sodium Oxibate

Inactive Ingredients: purified water and malic acid

This Medication Guide has been approved by the U.S. Food and Drug Administration.

Distributed By:

Jazz Pharmaceuticals, Inc.

Palo Alto, CA 94304

Revised: April 2015

Instructions for Use

Sodium Oxibate® (ZĪE-rem)

(sodium oxybate)

oral solution CIII

Read these Instructions for Use carefully before you start taking Sodium Oxibate and each time you get a refill. There may be new information. This information does not take the place of talking to your doctor about your medical condition or your treatment.

Note:


Supplies you will need for mixing and taking Sodium Oxibate: See Figure A.


Figure A

Step 1. Take the Sodium Oxibate bottle, press-in-bottle-adaptor, and syringe out of the box.

Step 2. Remove the bottle cap from the Sodium Oxibate bottle by pushing down while turning the cap counterclockwise (to the left). See Figure B.

Figure B

Step 3.


Figure C


Figure D


Figure E

Step 4.


Figure F

Step 5.


Note: The Sodium Oxibate medicine will not flow into the syringe unless you keep the bottle upright.

Figure G

Step 6.


Figure H

Step 7.


Figure I


Step 8.


Step 9.


Distributed By:

Jazz Pharmaceuticals, Inc.

Palo Alto, CA 94304

These Instructions for Use have been approved by the U.S. Food and Drug Administration.

Revised: April 2015

Figure A Figure B Figure C Figure D Figure E Figure F Figure G Figure H Figure I

Sodium Oxibate pharmaceutical active ingredients containing related brand and generic drugs:


Sodium Oxibate available forms, composition, doses:


Sodium Oxibate destination | category:


Sodium Oxibate Anatomical Therapeutic Chemical codes:


Sodium Oxibate pharmaceutical companies:


References

  1. Dailymed."XYREM (SODIUM OXYBATE) SOLUTION [JAZZ PHARMACEUTICALS, INC.]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
  2. Dailymed."SODIUM OXYBATE: DailyMed provides trustworthy information about marketed drugs in the United States. DailyMed is the official provider of FDA label information (package inserts).". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
  3. "Sodium oxybate". https://pubchem.ncbi.nlm.nih.gov/co... (accessed August 28, 2018).

Frequently asked Questions

Can i drive or operate heavy machine after consuming Sodium Oxibate?

Depending on the reaction of the Sodium Oxibate after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Sodium Oxibate not safe to drive or operate heavy machine after consumption. Meaning that, do not drive or operate heavy duty machines after taking the capsule if the capsule has a strange reaction on your body like dizziness, drowsiness. As prescribed by a pharmacist, it is dangerous to take alcohol while taking medicines as it exposed patients to drowsiness and health risk. Please take note of such effect most especially when taking Primosa capsule. It's advisable to consult your doctor on time for a proper recommendation and medical consultations.

Is Sodium Oxibate addictive or habit forming?

Medicines are not designed with the mind of creating an addiction or abuse on the health of the users. Addictive Medicine is categorically called Controlled substances by the government. For instance, Schedule H or X in India and schedule II-V in the US are controlled substances.

Please consult the medicine instruction manual on how to use and ensure it is not a controlled substance.In conclusion, self medication is a killer to your health. Consult your doctor for a proper prescription, recommendation, and guidiance.

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Review

sdrugs.com conducted a study on Sodium Oxibate, and the result of the survey is set out below. It is noteworthy that the product of the survey is based on the perception and impressions of the visitors of the website as well as the views of Sodium Oxibate consumers. We, as a result of this, advice that you do not base your therapeutic or medical decisions on this result, but rather consult your certified medical experts for their recommendations.

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What is your opinion about drug cost? Did you feel the cost is apt, or did you feel it is expensive?
The report given by the sdrugs.com website users shows the following figures about several people who felt the medicine Sodium Oxibate is expensive, and the medicine is not expensive. The results are mixed. The perception of the cost of the medicine to be expensive or not depends on the brand name of the medicine, country, and place where it is sold, and the affordability of the patient. You can choose a generic drug in the place of the branded drug to save the cost. The efficiency of the medicine will not vary if it is generic or a branded one.
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Expensive1
100.0%

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The information was verified by Dr. Rachana Salvi, MD Pharmacology


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