PDR MEMBER LOGIN:
  • PDR Search

    Required field
  • Advertisement
  • CLASSES

    GABA-Receptor Modulators

    BOXED WARNING

    Alcoholism, CNS depression, coadministration with other CNS depressants, driving or operating machinery, ethanol ingestion, respiratory depression, surgery

    Sodium oxybate causes CNS depression. Obtundation and clinically significant respiratory depression have occurred in patients treated with sodium oxybate at recommended doses due to CNS depression; many of these patients in clinical trials for narcolepsy were also receiving CNS stimulants. Coadministration with alcohol and sedative-hypnotics is contraindicated; warn patients against ethanol ingestion and do not use in patients with active alcoholism. Coadministration with other CNS depressants (e.g., opioid analgesics, benzodiazepines) may increase the risk of respiratory depression, hypotension, profound sedation, syncope, and death. If concurrent use is required, consider dose reduction or discontinuation of one or more CNS depressant (including sodium oxybate). Consider sodium oxybate interruption if the short-term use of an opioid (e.g., during or after surgery) is required. Sodium oxybate may cause patients to fall asleep abruptly without first feeling drowsy. Patients will often fall asleep within 5 to 15 minutes of administration. Patients should remain in bed during and after a dose and must refrain from engaging in hazardous occupations or activities requiring mental alertness and motor coordination (e.g., driving or operating machinery, flying an airplane) for at least 6 hours after a dose.[28528]

    Substance abuse

    Sodium oxybate is the sodium salt of gamma hydroxybutyrate (GHB), an illicit drug of abuse. Abuse or misuse of GHB, either alone or in combination with other CNS depressants, has been associated with adverse central nervous system reactions including seizure, respiratory depression, decreased levels of consciousness, coma, and death. The rapid onset of sedation and amnestic properties of sodium oxybate can be dangerous for voluntary and involuntary users. Carefully evaluate patients for a history of substance abuse and follow patients closely, observing them for signs of misuse and abuse of GHB (e.g., increase in the size or frequency of dosing, drug-seeking behavior, feigned cataplexy).

    DEA CLASS

    Rx, schedule III

    DESCRIPTION

    Sodium salt of gamma hydroxybutyric acid (GHB); CNS transmitter with sedative and anesthetic properties
    Used for cataplexy and excessive daytime sleepiness associated with narcolepsy
    GHB is not approved for medical use; illicit use is associated with severe CNS adverse reactions including seizures, respiratory depression, and death

    COMMON BRAND NAMES

    Xyrem

    HOW SUPPLIED

    Xyrem Oral Sol: 0.5g, 1mL

    DOSAGE & INDICATIONS

    For the treatment of cataplexy and excessive daytime sleepiness in patients with narcolepsy.
    Oral dosage
    Adults

    4.5 grams/night PO initially, divided into 2 equal doses of 2.25 grams, the first given at bedtime and the second given 2.5 to 4 hours later. May increase dosage by 1.5 grams/night (0.75 grams/dose) at weekly intervals. Effective dosage range: 6 to 9 grams/night. Doses more than 9 grams/night have not been studied and should not ordinarily be administered.[28528]

    Children and Adolescents 7 to 17 years weighing 45 kg or more

    4.5 grams or less/night PO initially, divided into 2 equal doses, the first given at bedtime and the second given 2.5 to 4 hours later. May increase dosage by no more than 1.5 grams/night (0.75 grams/dose) at weekly intervals. Max: 9 grams/night. For patients who sleep more than 8 hours/night, the first dose can be given at bedtime or after an initial period of sleep. Unequal dosages may be required for some patients to achieve optimal treatment.[28528]

    Children and Adolescents 7 to 17 years weighing 30 to 44 kg

    3 grams or less/night PO initially, divided into 2 equal doses, the first given at bedtime and the second given 2.5 to 4 hours later. May increase dosage by no more than 1 gram/night (0.5 gram/dose) at weekly intervals. Max: 7.5 grams/night. For patients who sleep more than 8 hours/night, the first dose can be given at bedtime or after an initial period of sleep. Unequal dosages may be required for some patients to achieve optimal treatment.[28528]

    Children and Adolescents 7 to 17 years weighing 20 to 29 kg

    2 grams or less/night PO initially, divided into 2 equal doses, the first given at bedtime and the second given 2.5 to 4 hours later. May increase dosage by no more than 1 gram/night (0.5 gram/dose) at weekly intervals. Max: 6 grams/night. For patients who sleep more than 8 hours/night, the first dose can be given at bedtime or after an initial period of sleep. Unequal dosages may be required for some patients to achieve optimal treatment.[28528]

    Children and Adolescents 7 to 17 years weighing less than 20 kg

    Specific dosing recommendations are not available; consider a lower starting dosage, lower weekly dosage increases, and lower total maximum dosage. For patients weighing 20 to 29 kg, the initial dosage is 2 grams or less/night PO, divided into 2 equal doses, the first given at bedtime and the second given 2.5 to 4 hours later. May increase dosage by no more than 1 gram/night (0.5 gram/dose) at weekly intervals. Max: 6 grams/night. For patients who sleep more than 8 hours/night, the first dose can be given at bedtime or after an initial period of sleep. Unequal dosages may be required for some patients to achieve optimal treatment.[28528]

    MAXIMUM DOSAGE

    Adults

    9 grams/night PO.

    Geriatric

    9 grams/night PO.

    Adolescents

    Weighing 45 kg or more: 9 grams/night PO.
    Weighing 30 to 44 kg: 7.5 grams/night PO.
    Weighing 20 to 29 kg: 6 grams/night PO.

    Children

    7 to 12 years weighing 45 kg or more: 9 grams/night PO.
    7 to 12 years weighing 30 to 44 kg: 7.5 grams/night PO.
    7 to 12 years weighing 20 to 29 kg: 6 grams/night PO.
    7 to 12 years weighing less than 20 kg: Specific information not available; a maximum nightly dosage less than 6 grams/night PO should be considered.
    1 to 6 years: Safety and efficacy have not been established.

    Infants

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Reduce the initial dosage by 50%.[28528]

    Renal Impairment

    Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.
     
    Intermittent hemodialysis
    Due to the rapid metabolism of sodium oxybate, hemodialysis and other forms of extracorporeal drug removal are unlikely to impact drug clearance.[28528]

    ADMINISTRATION

    Oral Administration

    Prepare both doses prior to the patient's bedtime.
    Dilute each dose with approximately 60 mL (one-fourth cup) of water in the empty child-resistant containers provided.
    For both doses, the patient should ingest the dose while in bed and should lie down and remain in bed after the dose. Ensure the second dose is kept in a safe place until given, close to the patient's bed.
    First dose: Administer at bedtime, at least 2 hours after eating.
    Second dose: Administer the second dose 2.5 to 4 hours after the first dose. Patients and/or caregivers may need to set an alarm to awaken for the second dose.
    If the second dose is missed, skip that dose and do not take sodium oxybate again until the next night.
    Storage: Discard any unused, diluted solution after 24 hours. Unused diluted solution may be disposed of down the sink drain.[28528]

    STORAGE

    Xyrem:
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F
    - Use within 24 hours from time of preparation

    CONTRAINDICATIONS / PRECAUTIONS

    Succinic semialdehyde dehydrogenase deficiency

    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.

    Behavioral changes, depression, psychiatric event, suicidal ideation

    In some cases, sodium oxybate has been associated with confusion, depression, psychosis, paranoia, hallucinations, agitation, aggression, and suicidal ideation. The emergence or increase of behavioral changes or a psychiatric event 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 oxybate.[28528]

    Complex sleep-related behaviors

    Complex sleep-related behaviors (parasomnias) including sleepwalking have been reported in both adult and pediatric patients. Significant injury may occur. Advise patients to report any unusual sleep-related behaviors to their provider. Fully evaluate episodes of sleepwalking and consider appropriate interventions.[28528]

    Alcoholism, CNS depression, coadministration with other CNS depressants, driving or operating machinery, ethanol ingestion, respiratory depression, surgery

    Sodium oxybate causes CNS depression. Obtundation and clinically significant respiratory depression have occurred in patients treated with sodium oxybate at recommended doses due to CNS depression; many of these patients in clinical trials for narcolepsy were also receiving CNS stimulants. Coadministration with alcohol and sedative-hypnotics is contraindicated; warn patients against ethanol ingestion and do not use in patients with active alcoholism. Coadministration with other CNS depressants (e.g., opioid analgesics, benzodiazepines) may increase the risk of respiratory depression, hypotension, profound sedation, syncope, and death. If concurrent use is required, consider dose reduction or discontinuation of one or more CNS depressant (including sodium oxybate). Consider sodium oxybate interruption if the short-term use of an opioid (e.g., during or after surgery) is required. Sodium oxybate may cause patients to fall asleep abruptly without first feeling drowsy. Patients will often fall asleep within 5 to 15 minutes of administration. Patients should remain in bed during and after a dose and must refrain from engaging in hazardous occupations or activities requiring mental alertness and motor coordination (e.g., driving or operating machinery, flying an airplane) for at least 6 hours after a dose.[28528]

    Substance abuse

    Sodium oxybate is the sodium salt of gamma hydroxybutyrate (GHB), an illicit drug of abuse. Abuse or misuse of GHB, either alone or in combination with other CNS depressants, has been associated with adverse central nervous system reactions including seizure, respiratory depression, decreased levels of consciousness, coma, and death. The rapid onset of sedation and amnestic properties of sodium oxybate can be dangerous for voluntary and involuntary users. Carefully evaluate patients for a history of substance abuse and follow patients closely, observing them for signs of misuse and abuse of GHB (e.g., increase in the size or frequency of dosing, drug-seeking behavior, feigned cataplexy).

    Hypoxemia, obesity, pulmonary disease, respiratory insufficiency, sleep apnea

    Sodium oxybate may impair respiratory drive, especially in patients with compromised respiratory function or preexisting respiratory insufficiency. Central apneas and clinically relevant desaturation events have been observed in both pediatric and adult patients. Use sodium oxybate with caution in patients with pulmonary disease, including sleep apnea, that places them at risk for respiratory depression or hypoxemia. Sleep-related breathing disorders tend to be more prevalent with obesity, in men, in postmenopausal women not on hormone replacement therapy, and among patients with narcolepsy.[28528]

    Hepatic disease

    Use sodium oxybate cautiously in patients with hepatic disease, since the drug is extensively metabolized in the liver. Patients with compromised liver function have an increased elimination half-life and systemic exposure to the drug. Initial dosage reduction is recommended in patients with hepatic impairment.[28528]

    Cardiac disease, heart failure, hypertension, renal disease

    Sodium oxybate has a high salt content. Consider the amount of daily sodium intake in patients sensitive to salt (e.g., those with heart failure, cardiac disease, hypertension, renal disease). The sodium content per total nightly dose is 550 mg for 3 grams; 820 mg for 4.5 grams; 1,100 mg for 6 grams; 1,400 mg for 7.5 grams; and 1,640 mg for 9 grams.

    Geriatric

    Clinical narcolepsy studies of sodium oxybate did not include sufficient numbers of geriatric subjects age 65 years and older to determine whether they respond differently from younger adult 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 geriatric patient compared to younger adults (20.5% vs. 18.9%). Frequency of headaches was markedly increased in the elderly (38.5% vs. 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.

    Labor, neonates, obstetric delivery, pregnancy

    There are no adequate data on the developmental risk associated with the use of sodium oxybate during human pregnancy. Animal studies produced no clear evidence of developmental toxicity; however, increased stillbirths and decreased postnatal viability and growth were seen at clinically relevant doses. Because there are no adequate and well-controlled studies in pregnant women, sodium oxybate should be used during pregnancy only if the benefits outweigh the potential risks to the fetus. Oral sodium oxybate has not been studied in labor or obstetric delivery. Uterine contractions diminished 20 minutes after injection of parenteral sodium oxybate during obstetric anesthesia. Neonates had stable cardiovascular and respiratory measures but were very sleepy, resulting in a slight decrease in Apgar scores.[28528] In a case of illicit use of GHB during pregnancy, the woman delivered a healthy newborn with a good Apgar score; however, the quantity of GHB ingested and the duration of drug use were not reported.[48520] Monitor exposed neonates carefully. Subsequent effects of sodium oxybate on later growth, development, and maturation in humans are unknown.[28528]

    Breast-feeding

    There is insufficient information regarding maternal use of sodium oxybate and the risk to a breast-fed infant and on milk production in the breast-feeding mother. Gamma hydroxybutyrate (GHB) is excreted in human milk after oral administration of sodium oxybate, and the developmental and health benefits of breast-feeding should be considered along with the need of the mother for sodium oxybate and any potential adverse effects on the breast-fed infant from sodium oxybate or from the underlying maternal condition. Because the available data are too limited to be conclusive, an alternate drug may be preferred (or an alternate form of feeding), especially while nursing a newborn or premature infant. If sodium oxybate administration cannot be avoided, it is advisable to avoid breast-feeding for 4 to 5 hours after each dose to minimize infant exposure to the drug, and the nursing infant should be monitored for adverse drug effects such as sedation, respiratory depression, agitation, and vomiting. In one case report, a breast-feeding mother taking 4.5 grams of sodium oxybate twice daily had a peak drug value of 23.2 mg/L at 1 hour after the dose, decreasing to 3.1 mg/L at 4 hours after the dose and 1 mg/L at 5 hours after the dose, at which time the concentration was within the proposed endogenous breast milk reference range of 0.13 to 1.03 mg/L. No adverse infant effects were reported. In a separate case, a woman with narcolepsy took sodium oxybate 4 grams each night at 10 p.m. and 2 a.m. and breast-fed her infant (or provided pumped breast milk) exclusively for 6 months except for 4 hours after the 10 p.m. dose and 4 hours after the 2 a.m. dose. According to evaluations of the infant from the Ages and Stages Questionnaires at 2, 4, and 6 months and the pediatrician's clinical impressions of growth and development, the measured parameters were within the normal range.

    ADVERSE REACTIONS

    Severe

    suicidal ideation / Delayed / Incidence not known
    apnea / Delayed / Incidence not known
    coma / Early / Incidence not known
    Cheyne-Stokes respiration / Early / Incidence not known
    seizures / Delayed / Incidence not known
    serotonin syndrome / Delayed / Incidence not known

    Moderate

    urinary incontinence / Early / 3.0-19.0
    confusion / Early / 3.0-17.0
    depression / Delayed / 0-7.0
    complex sleep-related behaviors / Early / 0-6.0
    sleep paralysis / Delayed / 0-3.0
    impaired cognition / Early / 0-3.0
    peripheral edema / Delayed / 0-3.0
    cataplexy / Delayed / 1.0-2.0
    memory impairment / Delayed / Incidence not known
    obtundation / Early / Incidence not known
    psychosis / Early / Incidence not known
    hallucinations / Early / Incidence not known
    respiratory depression / Rapid / Incidence not known
    hypertension / Early / Incidence not known
    edema / Delayed / Incidence not known
    blurred vision / Early / Incidence not known
    tolerance / Delayed / Incidence not known
    withdrawal / Early / Incidence not known
    euphoria / Early / Incidence not known
    psychological dependence / Delayed / Incidence not known
    physiological dependence / Delayed / Incidence not known
    nystagmus / Delayed / Incidence not known
    delirium / Early / Incidence not known

    Mild

    nausea / Early / 8.0-20.0
    vomiting / Early / 2.0-18.0
    headache / Early / 0-17.0
    dizziness / Early / 6.0-15.0
    weight loss / Delayed / 0-13.0
    anorexia / Delayed / 0-9.0
    drowsiness / Early / 1.0-8.0
    somnambulism / Early / 0-6.0
    anxiety / Delayed / 1.0-5.8
    tremor / Early / 0-5.0
    diarrhea / Early / 3.0-4.0
    paresthesias / Delayed / 1.0-3.0
    irritability / Delayed / 0-3.0
    abdominal pain / Early / 1.0-3.0
    hyperhidrosis / Delayed / 1.0-3.0
    xerostomia / Early / 1.0-2.0
    muscle cramps / Delayed / 0-2.0
    agitation / Early / Incidence not known
    paranoia / Early / Incidence not known
    emotional lability / Early / Incidence not known
    arthralgia / Delayed / Incidence not known
    nocturia / Early / Incidence not known
    libido increase / Delayed / Incidence not known

    DRUG INTERACTIONS

    Acetaminophen; Aspirin, ASA; Caffeine: (Moderate) Caffeine should be avoided or used cautiously with oxybates. Monitor for potential side effects such as nervousness, irritability, insomnia, and/or cardiac arrhythmias.
    Acetaminophen; Caffeine: (Moderate) Caffeine should be avoided or used cautiously with oxybates. Monitor for potential side effects such as nervousness, irritability, insomnia, and/or cardiac arrhythmias.
    Acetaminophen; Caffeine; Dihydrocodeine: (Moderate) Caffeine should be avoided or used cautiously with oxybates. Monitor for potential side effects such as nervousness, irritability, insomnia, and/or cardiac arrhythmias.
    Acetaminophen; Caffeine; Magnesium Salicylate; Phenyltoloxamine: (Moderate) Caffeine should be avoided or used cautiously with oxybates. Monitor for potential side effects such as nervousness, irritability, insomnia, and/or cardiac arrhythmias.
    Acetaminophen; Caffeine; Phenyltoloxamine; Salicylamide: (Moderate) Caffeine should be avoided or used cautiously with oxybates. Monitor for potential side effects such as nervousness, irritability, insomnia, and/or cardiac arrhythmias.
    Acetaminophen; Dextromethorphan; Doxylamine: (Contraindicated) Sodium oxybate should not be used in combination with CNS depressant anxiolytics, sedatives, and hypnotics or other sedative CNS depressant drugs.
    Alprazolam: (Contraindicated) Sodium oxybate should not be used in combination with CNS depressant anxiolytics, sedatives, and hypnotics or other sedative CNS depressant drugs. Specifically, sodium oxybate use is contraindicated in patients being treated with sedative hypnotic drugs. Sodium oxybate (GHB) has the potential to impair cognitive and motor skills. For example, the concomitant use of barbiturates and benzodiazepines increases sleep duration and may contribute to rapid onset, pronounced CNS depression, respiratory depression, or coma when combined with sodium oxybate.
    Amobarbital: (Contraindicated) Sodium oxybate should not be used in combination with CNS depressant anxiolytics, sedatives, and hypnotics or other sedative CNS depressant drugs. Specifically, sodium oxybate use is contraindicated in patients being treated with sedative hypnotic drugs. Sodium oxybate (GHB) has the potential to impair cognitive and motor skills. For example, the concomitant use of barbiturates and benzodiazepines increases sleep duration and may contribute to rapid onset, pronounced CNS depression, respiratory depression, or coma when combined with sodium oxybate.
    Amphetamine: (Moderate) Sodium oxybate has the potential to induce seizures; it has been speculated that this effect may be mediated through the action of sodium oxybate at GABA receptors. Although convulsant effects occur primarily at high dosages, sodium oxybate should be used cautiously with psychostimulants that are known to lower seizure threshold such as the amphetamines. Note that CNS stimulants, including the amphetamines, are frequently used in the treatment of narcolepsy, and clinical trials involving the use of psychostimulants with sodium oxybate have not found the combinations to be unsafe. Pharmacodynamic interactions cannot be ruled out, however.
    Amphetamine; Dextroamphetamine Salts: (Moderate) Sodium oxybate has the potential to induce seizures; it has been speculated that this effect may be mediated through the action of sodium oxybate at GABA receptors. Although convulsant effects occur primarily at high dosages, sodium oxybate should be used cautiously with psychostimulants that are known to lower seizure threshold such as the amphetamines. Note that CNS stimulants, including the amphetamines, are frequently used in the treatment of narcolepsy, and clinical trials involving the use of psychostimulants with sodium oxybate have not found the combinations to be unsafe. Pharmacodynamic interactions cannot be ruled out, however.
    Amphetamine; Dextroamphetamine: (Moderate) Sodium oxybate has the potential to induce seizures; it has been speculated that this effect may be mediated through the action of sodium oxybate at GABA receptors. Although convulsant effects occur primarily at high dosages, sodium oxybate should be used cautiously with psychostimulants that are known to lower seizure threshold such as the amphetamines. Note that CNS stimulants, including the amphetamines, are frequently used in the treatment of narcolepsy, and clinical trials involving the use of psychostimulants with sodium oxybate have not found the combinations to be unsafe. Pharmacodynamic interactions cannot be ruled out, however.
    Anxiolytics; Sedatives; and Hypnotics: (Contraindicated) Sodium oxybate should not be used in combination with CNS depressant anxiolytics, sedatives, and hypnotics or other sedative CNS depressant drugs. Specifically, sodium oxybate use is contraindicated in patients being treated with sedative hypnotic drugs. Sodium oxybate (GHB) has the potential to impair cognitive and motor skills. For example, the concomitant use of barbiturates and benzodiazepines increases sleep duration and may contribute to rapid onset, pronounced CNS depression, respiratory depression, or coma when combined with sodium oxybate.
    Aspirin, ASA; Butalbital; Caffeine: (Contraindicated) Sodium oxybate should not be used in combination with CNS depressant anxiolytics, sedatives, and hypnotics or other sedative CNS depressant drugs. Specifically, sodium oxybate use is contraindicated in patients being treated with sedative hypnotic drugs. Sodium oxybate (GHB) has the potential to impair cognitive and motor skills. For example, the concomitant use of barbiturates and benzodiazepines increases sleep duration and may contribute to rapid onset, pronounced CNS depression, respiratory depression, or coma when combined with sodium oxybate. (Moderate) Caffeine should be avoided or used cautiously with oxybates. Monitor for potential side effects such as nervousness, irritability, insomnia, and/or cardiac arrhythmias.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Contraindicated) Sodium oxybate should not be used in combination with CNS depressant anxiolytics, sedatives, and hypnotics or other sedative CNS depressant drugs. Specifically, sodium oxybate use is contraindicated in patients being treated with sedative hypnotic drugs. Sodium oxybate (GHB) has the potential to impair cognitive and motor skills. For example, the concomitant use of barbiturates and benzodiazepines increases sleep duration and may contribute to rapid onset, pronounced CNS depression, respiratory depression, or coma when combined with sodium oxybate. (Moderate) Caffeine should be avoided or used cautiously with oxybates. Monitor for potential side effects such as nervousness, irritability, insomnia, and/or cardiac arrhythmias.
    Aspirin, ASA; Caffeine: (Moderate) Caffeine should be avoided or used cautiously with oxybates. Monitor for potential side effects such as nervousness, irritability, insomnia, and/or cardiac arrhythmias.
    Aspirin, ASA; Caffeine; Dihydrocodeine: (Moderate) Caffeine should be avoided or used cautiously with oxybates. Monitor for potential side effects such as nervousness, irritability, insomnia, and/or cardiac arrhythmias.
    Aspirin, ASA; Caffeine; Orphenadrine: (Major) Sodium oxybate should not be used in combination with CNS depressant anxiolytics, sedatives, and hypnotics or other sedative CNS depressant drugs. Additive CNS depressant effects may be possible when sodium oxybate is used concurrently with skeletal muscle relaxants. (Moderate) Caffeine should be avoided or used cautiously with oxybates. Monitor for potential side effects such as nervousness, irritability, insomnia, and/or cardiac arrhythmias.
    Aspirin, ASA; Carisoprodol: (Major) Sodium oxybate should not be used in combination with CNS depressant anxiolytics, sedatives, and hypnotics or other sedative CNS depressant drugs. Additive CNS depressant effects may be possible when sodium oxybate is used concurrently with skeletal muscle relaxants.
    Aspirin, ASA; Carisoprodol; Codeine: (Major) Sodium oxybate should not be used in combination with CNS depressant anxiolytics, sedatives, and hypnotics or other sedative CNS depressant drugs. Additive CNS depressant effects may be possible when sodium oxybate is used concurrently with skeletal muscle relaxants.
    Atropine; Difenoxin: (Major) Sodium oxybate should not be used in combination with CNS depressant anxiolytics, sedatives, and hypnotics or other sedative CNS depressant drugs. Specifically, sodium oxybate use is contraindicated in patients being treated with sedative hypnotic drugs. Sodium oxybate (GHB) has the potential to impair cognitive and motor skills. Concurrent administration of diphenoxylate/difenoxin with sodium oxybate can potentiate the CNS-depressant effects of diphenoxylate/difenoxin.
    Baclofen: (Major) Sodium oxybate should not be used in combination with CNS depressant anxiolytics, sedatives, and hypnotics or other sedative CNS depressant drugs. Additive CNS depressant effects may be possible when sodium oxybate is used concurrently with skeletal muscle relaxants.
    Barbiturates: (Contraindicated) Sodium oxybate should not be used in combination with CNS depressant anxiolytics, sedatives, and hypnotics or other sedative CNS depressant drugs. Specifically, sodium oxybate use is contraindicated in patients being treated with sedative hypnotic drugs. Sodium oxybate (GHB) has the potential to impair cognitive and motor skills. For example, the concomitant use of barbiturates and benzodiazepines increases sleep duration and may contribute to rapid onset, pronounced CNS depression, respiratory depression, or coma when combined with sodium oxybate.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: (Contraindicated) Sodium oxybate should not be used in combination with CNS depressant anxiolytics, sedatives, and hypnotics or other sedative CNS depressant drugs. Specifically, sodium oxybate use is contraindicated in patients being treated with sedative hypnotic drugs. Sodium oxybate (GHB) has the potential to impair cognitive and motor skills. For example, the concomitant use of barbiturates and benzodiazepines increases sleep duration and may contribute to rapid onset, pronounced CNS depression, respiratory depression, or coma when combined with sodium oxybate.
    Benzodiazepines: (Contraindicated) Sodium oxybate should not be used in combination with CNS depressant anxiolytics, sedatives, and hypnotics or other sedative CNS depressant drugs. Specifically, sodium oxybate use is contraindicated in patients being treated with sedative hypnotic drugs. Sodium oxybate (GHB) has the potential to impair cognitive and motor skills. For example, the concomitant use of barbiturates and benzodiazepines increases sleep duration and may contribute to rapid onset, pronounced CNS depression, respiratory depression, or coma when combined with sodium oxybate.
    Benzphetamine: (Moderate) Sodium oxybate has the potential to induce seizures; it has been speculated that this effect may be mediated through the action of sodium oxybate at GABA receptors. Although convulsant effects occur primarily at high dosages, sodium oxybate should be used cautiously with psychostimulants that are known to lower seizure threshold such as the amphetamines. Note that CNS stimulants, including the amphetamines, methylphenidate, and modafinil are frequently used in the treatment of narcolepsy, and clinical trials involving the use of psychostimulants with sodium oxybate have not found the combinations to be unsafe. Pharmacodynamic interactions cannot be ruled out, however.
    Buprenorphine: (Major) Concomitant use of buprenorphine with sodium oxybate may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of buprenorphine with sodium oxybate to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
    Buprenorphine; Naloxone: (Major) Concomitant use of buprenorphine with sodium oxybate may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of buprenorphine with sodium oxybate to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
    Bupropion: (Major) Use extreme caution when coadministering bupropion with other drugs that lower the seizure threshold, such as sodium oxybate. The risk of seizures with bupropion is dose related and is also related to patient factors, clinical situations, and concomitant medications that lower the seizure threshold. Consider these risks before initiating treatment If used together, use low initial doses of bupropion and increase the dose gradually.
    Bupropion; Naltrexone: (Major) Use extreme caution when coadministering bupropion with other drugs that lower the seizure threshold, such as sodium oxybate. The risk of seizures with bupropion is dose related and is also related to patient factors, clinical situations, and concomitant medications that lower the seizure threshold. Consider these risks before initiating treatment If used together, use low initial doses of bupropion and increase the dose gradually.
    Buspirone: (Contraindicated) Sodium oxybate should not be used in combination with CNS depressant anxiolytics, sedatives, and hypnotics or other sedative CNS depressant drugs.
    Butabarbital: (Contraindicated) Sodium oxybate should not be used in combination with CNS depressant anxiolytics, sedatives, and hypnotics or other sedative CNS depressant drugs. Specifically, sodium oxybate use is contraindicated in patients being treated with sedative hypnotic drugs. Sodium oxybate (GHB) has the potential to impair cognitive and motor skills. For example, the concomitant use of barbiturates and benzodiazepines increases sleep duration and may contribute to rapid onset, pronounced CNS depression, respiratory depression, or coma when combined with sodium oxybate.
    Butalbital; Acetaminophen: (Contraindicated) Sodium oxybate should not be used in combination with CNS depressant anxiolytics, sedatives, and hypnotics or other sedative CNS depressant drugs. Specifically, sodium oxybate use is contraindicated in patients being treated with sedative hypnotic drugs. Sodium oxybate (GHB) has the potential to impair cognitive and motor skills. For example, the concomitant use of barbiturates and benzodiazepines increases sleep duration and may contribute to rapid onset, pronounced CNS depression, respiratory depression, or coma when combined with sodium oxybate.
    Butalbital; Acetaminophen; Caffeine: (Contraindicated) Sodium oxybate should not be used in combination with CNS depressant anxiolytics, sedatives, and hypnotics or other sedative CNS depressant drugs. Specifically, sodium oxybate use is contraindicated in patients being treated with sedative hypnotic drugs. Sodium oxybate (GHB) has the potential to impair cognitive and motor skills. For example, the concomitant use of barbiturates and benzodiazepines increases sleep duration and may contribute to rapid onset, pronounced CNS depression, respiratory depression, or coma when combined with sodium oxybate. (Moderate) Caffeine should be avoided or used cautiously with oxybates. Monitor for potential side effects such as nervousness, irritability, insomnia, and/or cardiac arrhythmias.
    Butalbital; Acetaminophen; Caffeine; Codeine: (Contraindicated) Sodium oxybate should not be used in combination with CNS depressant anxiolytics, sedatives, and hypnotics or other sedative CNS depressant drugs. Specifically, sodium oxybate use is contraindicated in patients being treated with sedative hypnotic drugs. Sodium oxybate (GHB) has the potential to impair cognitive and motor skills. For example, the concomitant use of barbiturates and benzodiazepines increases sleep duration and may contribute to rapid onset, pronounced CNS depression, respiratory depression, or coma when combined with sodium oxybate. (Moderate) Caffeine should be avoided or used cautiously with oxybates. Monitor for potential side effects such as nervousness, irritability, insomnia, and/or cardiac arrhythmias.
    Caffeine: (Moderate) Caffeine should be avoided or used cautiously with oxybates. Monitor for potential side effects such as nervousness, irritability, insomnia, and/or cardiac arrhythmias.
    Caffeine; Sodium Benzoate: (Moderate) Caffeine should be avoided or used cautiously with oxybates. Monitor for potential side effects such as nervousness, irritability, insomnia, and/or cardiac arrhythmias.
    Cannabidiol: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cannabidiol and sodium oxybate. CNS depressants can potentiate the effects of cannabidiol.
    Capsaicin; Metaxalone: (Major) Sodium oxybate should not be used in combination with CNS depressant anxiolytics, sedatives, and hypnotics or other sedative CNS depressant drugs. Additive CNS depressant effects may be possible when sodium oxybate is used concurrently with skeletal muscle relaxants.
    Carisoprodol: (Major) Sodium oxybate should not be used in combination with CNS depressant anxiolytics, sedatives, and hypnotics or other sedative CNS depressant drugs. Additive CNS depressant effects may be possible when sodium oxybate is used concurrently with skeletal muscle relaxants.
    Cenobamate: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and sodium oxybate. Concurrent use may result in additive CNS depression.
    Cetirizine: (Moderate) Concurrent use of cetirizine/levocetirizine with sodium oxybate should generally be avoided. Coadministration may increase the risk of CNS depressant-related side effects. If concurrent use is necessary, monitor for excessive sedation and somnolence.
    Cetirizine; Pseudoephedrine: (Moderate) Concurrent use of cetirizine/levocetirizine with sodium oxybate should generally be avoided. Coadministration may increase the risk of CNS depressant-related side effects. If concurrent use is necessary, monitor for excessive sedation and somnolence.
    Chlordiazepoxide: (Contraindicated) Sodium oxybate should not be used in combination with CNS depressant anxiolytics, sedatives, and hypnotics or other sedative CNS depressant drugs. Specifically, sodium oxybate use is contraindicated in patients being treated with sedative hypnotic drugs. Sodium oxybate (GHB) has the potential to impair cognitive and motor skills. For example, the concomitant use of barbiturates and benzodiazepines increases sleep duration and may contribute to rapid onset, pronounced CNS depression, respiratory depression, or coma when combined with sodium oxybate.
    Chlordiazepoxide; Amitriptyline: (Contraindicated) Sodium oxybate should not be used in combination with CNS depressant anxiolytics, sedatives, and hypnotics or other sedative CNS depressant drugs. Specifically, sodium oxybate use is contraindicated in patients being treated with sedative hypnotic drugs. Sodium oxybate (GHB) has the potential to impair cognitive and motor skills. For example, the concomitant use of barbiturates and benzodiazepines increases sleep duration and may contribute to rapid onset, pronounced CNS depression, respiratory depression, or coma when combined with sodium oxybate.
    Chlordiazepoxide; Clidinium: (Contraindicated) Sodium oxybate should not be used in combination with CNS depressant anxiolytics, sedatives, and hypnotics or other sedative CNS depressant drugs. Specifically, sodium oxybate use is contraindicated in patients being treated with sedative hypnotic drugs. Sodium oxybate (GHB) has the potential to impair cognitive and motor skills. For example, the concomitant use of barbiturates and benzodiazepines increases sleep duration and may contribute to rapid onset, pronounced CNS depression, respiratory depression, or coma when combined with sodium oxybate.
    Chlorpromazine: (Major) Additive CNS depressant effects may be possible when sodium oxybate is used concurrently with phenothiazines.
    Chlorzoxazone: (Major) Sodium oxybate should not be used in combination with CNS depressant anxiolytics, sedatives, and hypnotics or other sedative CNS depressant drugs. Additive CNS depressant effects may be possible when sodium oxybate is used concurrently with skeletal muscle relaxants.
    Clobazam: (Contraindicated) Sodium oxybate should not be used in combination with CNS depressant anxiolytics, sedatives, and hypnotics or other sedative CNS depressant drugs. Specifically, sodium oxybate use is contraindicated in patients being treated with sedative hypnotic drugs. Sodium oxybate (GHB) has the potential to impair cognitive and motor skills. For example, the concomitant use of barbiturates and benzodiazepines increases sleep duration and may contribute to rapid onset, pronounced CNS depression, respiratory depression, or coma when combined with sodium oxybate.
    Clonazepam: (Contraindicated) Sodium oxybate should not be used in combination with CNS depressant anxiolytics, sedatives, and hypnotics or other sedative CNS depressant drugs. Specifically, sodium oxybate use is contraindicated in patients being treated with sedative hypnotic drugs. Sodium oxybate (GHB) has the potential to impair cognitive and motor skills. For example, the concomitant use of barbiturates and benzodiazepines increases sleep duration and may contribute to rapid onset, pronounced CNS depression, respiratory depression, or coma when combined with sodium oxybate.
    Clorazepate: (Contraindicated) Sodium oxybate should not be used in combination with CNS depressant anxiolytics, sedatives, and hypnotics or other sedative CNS depressant drugs. Specifically, sodium oxybate use is contraindicated in patients being treated with sedative hypnotic drugs. Sodium oxybate (GHB) has the potential to impair cognitive and motor skills. For example, the concomitant use of barbiturates and benzodiazepines increases sleep duration and may contribute to rapid onset, pronounced CNS depression, respiratory depression, or coma when combined with sodium oxybate.
    Cocaine: (Major) Sodium oxybate has the potential to induce seizures; it has been speculated that this effect may be mediated through the action of sodium oxybate at GABA receptors. Although convulsant effects occur primarily at high dosages, sodium oxybate should be used cautiously with drugs that are known to lower seizure threshold such as cocaine.
    Codeine; Phenylephrine; Promethazine: (Major) Additive CNS depressant effects may be possible when sodium oxybate is used concurrently with phenothiazines.
    Codeine; Promethazine: (Major) Additive CNS depressant effects may be possible when sodium oxybate is used concurrently with phenothiazines.
    COMT inhibitors: (Major) COMT inhibitors should be given cautiously with other agents that cause CNS depression, including sodium oxybate, due to the possibility of additive sedation. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
    Cyclobenzaprine: (Major) Sodium oxybate should not be used in combination with CNS depressant anxiolytics, sedatives, and hypnotics or other sedative CNS depressant drugs. Additive CNS depressant effects may be possible when sodium oxybate is used concurrently with skeletal muscle relaxants.
    Dantrolene: (Major) Sodium oxybate should not be used in combination with CNS depressant anxiolytics, sedatives, and hypnotics or other sedative CNS depressant drugs. Additive CNS depressant effects may be possible when sodium oxybate is used concurrently with skeletal muscle relaxants.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Major) One case report describes a possible interaction between sodium oxybate and ritonavir and saquinavir, leading to repetitive, clonic contractions. The patient also experienced shallow respirations, a heart rate of 40 beats per min, and was responsive only to painful stimuli. The exact contribution of ritonavir and saquinavir to this reaction cannot be determined since several other compounds were detected through a urinary toxin screen.
    Deutetrabenazine: (Moderate) Concurrent use of deutetrabenazine and drugs that can cause CNS depression, such as sodium oxybate, may have additive effects and worsen drowsiness or sedation. Advise patients about worsened somnolence and not to drive or perform other tasks requiring mental alertness until they know how deutetrabenazine affects them.
    Dextroamphetamine: (Moderate) Sodium oxybate has the potential to induce seizures; it has been speculated that this effect may be mediated through the action of sodium oxybate at GABA receptors. Although convulsant effects occur primarily at high dosages, sodium oxybate should be used cautiously with psychostimulants that are known to lower seizure threshold such as the amphetamines. Note that CNS stimulants, including the amphetamines, are frequently used in the treatment of narcolepsy, and clinical trials involving the use of psychostimulants with sodium oxybate have not found the combinations to be unsafe. Pharmacodynamic interactions cannot be ruled out, however.
    Diazepam: (Contraindicated) Sodium oxybate should not be used in combination with CNS depressant anxiolytics, sedatives, and hypnotics or other sedative CNS depressant drugs. Specifically, sodium oxybate use is contraindicated in patients being treated with sedative hypnotic drugs. Sodium oxybate (GHB) has the potential to impair cognitive and motor skills. For example, the concomitant use of barbiturates and benzodiazepines increases sleep duration and may contribute to rapid onset, pronounced CNS depression, respiratory depression, or coma when combined with sodium oxybate.
    Diphenoxylate; Atropine: (Major) Sodium oxybate should not be used in combination with CNS depressant anxiolytics, sedatives, and hypnotics or other sedative CNS depressant drugs. Specifically, sodium oxybate use is contraindicated in patients being treated with sedative hypnotic drugs. Sodium oxybate (GHB) has the potential to impair cognitive and motor skills. Concurrent administration of diphenoxylate/difenoxin with sodium oxybate can potentiate the CNS-depressant effects of diphenoxylate/difenoxin.
    Doxylamine: (Contraindicated) Sodium oxybate should not be used in combination with CNS depressant anxiolytics, sedatives, and hypnotics or other sedative CNS depressant drugs.
    Doxylamine; Pyridoxine: (Contraindicated) Sodium oxybate should not be used in combination with CNS depressant anxiolytics, sedatives, and hypnotics or other sedative CNS depressant drugs.
    Dronabinol: (Moderate) Concomitant use of dronabinol with other CNS depressants like sodium oxybate can potentiate the effects of dronabinol on respiratory depression.
    Droperidol: (Contraindicated) Sodium oxybate should not be used in combination with CNS depressant anxiolytics, sedatives, and hypnotics or other sedative CNS depressant drugs.
    Ergotamine; Caffeine: (Moderate) Caffeine should be avoided or used cautiously with oxybates. Monitor for potential side effects such as nervousness, irritability, insomnia, and/or cardiac arrhythmias.
    Esketamine: (Major) Closely monitor patients receiving esketamine and sodium oxybate for sedation and other CNS depressant effects. Instruct patients who receive a dose of esketamine not to drive or engage in other activities requiring alertness until the next day after a restful sleep.
    Estazolam: (Contraindicated) Sodium oxybate should not be used in combination with CNS depressant anxiolytics, sedatives, and hypnotics or other sedative CNS depressant drugs. Specifically, sodium oxybate use is contraindicated in patients being treated with sedative hypnotic drugs. Sodium oxybate (GHB) has the potential to impair cognitive and motor skills. For example, the concomitant use of barbiturates and benzodiazepines increases sleep duration and may contribute to rapid onset, pronounced CNS depression, respiratory depression, or coma when combined with sodium oxybate.
    Ethanol: (Contraindicated) Alcohol is contraindicated in patients using sodium oxybate or other oxybates. Dangerous, additive CNS depressant effects are possible, including respiratory depression. Patients should be strongly warned against the use of any alcohol-containing beverages in conjunction with oxybates. (Contraindicated) Ethanol is contraindicated in patients using sodium oxybate or other oxybates. Dangerous, additive CNS depressant effects are possible, including respiratory depression. Patients should be strongly warned against the use of any alcoholic beverages in conjunction with oxybates.
    Ethiodized Oil: (Major) Sodium oxybate lowers seizure threshold and should be discontinued at least 48 hours before myelography and should not be resumed for at least 24 hours postprocedure.
    Fenfluramine: (Moderate) Use fenfluramine and sodium oxybate with caution due to an increased risk of serotonin syndrome and additive CNS depression. Monitor for excessive sedation, somnolence, and serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Fluphenazine: (Major) Additive CNS depressant effects may be possible when sodium oxybate is used concurrently with phenothiazines.
    Flurazepam: (Contraindicated) Sodium oxybate should not be used in combination with CNS depressant anxiolytics, sedatives, and hypnotics or other sedative CNS depressant drugs. Specifically, sodium oxybate use is contraindicated in patients being treated with sedative hypnotic drugs. Sodium oxybate (GHB) has the potential to impair cognitive and motor skills. For example, the concomitant use of barbiturates and benzodiazepines increases sleep duration and may contribute to rapid onset, pronounced CNS depression, respiratory depression, or coma when combined with sodium oxybate.
    Food: (Moderate) Oxybates should be administered on an empty stomach. Patients should administer their first bedtime dose at least 2 hours after eating and take their bedtime dosages at a consistent time in relation to meals each night. Food significantly decreases the bioavailability of sodium oxybate and other oxybates.
    Gabapentin: (Major) Concomitant use of sodium oxybate with gabapentin may cause excessive sedation, somnolence, and respiratory depression. If concurrent use is necessary, initiate gabapentin at the lowest recommended dose and monitor patients for symptoms of respiratory depression and sedation. Educate patients about the risks and symptoms of excessive CNS depression and respiratory depression.
    General anesthetics: (Major) Sodium oxybate should not be used in combination with CNS depressant anxiolytics, sedatives, and hypnotics or other sedative CNS depressant drugs. Additive CNS depressant effects may be possible when sodium oxybate is used concurrently with general anesthetics.
    Green Tea: (Major) Some, but not all, green tea products contain caffeine. Additive CNS stimulant effects are likely to occur when caffeine is coadministered with other CNS stimulants or psychostimulants. Caffeine should be avoided or used cautiously with sodium oxybate.
    Hydroxyzine: (Contraindicated) Sodium oxybate should not be used in combination with CNS depressant anxiolytics, sedatives, and hypnotics or other sedative CNS depressant drugs.
    Iodixanol: (Major) Sodium oxybate lowers seizure threshold and should be discontinued at least 48 hours before myelography and should not be resumed for at least 24 hours postprocedure.
    Iohexol: (Major) Sodium oxybate lowers seizure threshold and should be discontinued at least 48 hours before myelography and should not be resumed for at least 24 hours postprocedure.
    Iopamidol: (Major) Sodium oxybate lowers seizure threshold and should be discontinued at least 48 hours before myelography and should not be resumed for at least 24 hours postprocedure.
    Iopromide: (Major) Sodium oxybate lowers seizure threshold and should be discontinued at least 48 hours before myelography and should not be resumed for at least 24 hours postprocedure.
    Ioversol: (Major) Sodium oxybate lowers seizure threshold and should be discontinued at least 48 hours before myelography and should not be resumed for at least 24 hours postprocedure.
    Isosulfan Blue: (Major) Sodium oxybate lowers seizure threshold and should be discontinued at least 48 hours before myelography and should not be resumed for at least 24 hours postprocedure.
    Lasmiditan: (Moderate) Monitor for excessive sedation, somnolence, and serotonin syndrome during coadministration of lasmiditan and sodium oxybate. Inform patients taking this combination of the risks and symptoms of excessive CNS depression and serotonin syndrome, particularly after a dose increase or the addition of other serotonergic medications to an existing regimen. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Lemborexant: (Contraindicated) Coadministration of sodium oxybate with other sedative hypnotic drugs, such as lemborexant, is contraindicated. The concurrent use of sodium oxybate and other CNS depressants may increase the risk of respiratory depression, hypotension, profound sedation, syncope, and death.
    Levocetirizine: (Moderate) Concurrent use of cetirizine/levocetirizine with sodium oxybate should generally be avoided. Coadministration may increase the risk of CNS depressant-related side effects. If concurrent use is necessary, monitor for excessive sedation and somnolence.
    Lisdexamfetamine: (Moderate) Sodium oxybate has the potential to induce seizures; it has been speculated that this effect may be mediated through the action of sodium oxybate at GABA receptors. Although convulsant effects occur primarily at high dosages, sodium oxybate should be used cautiously with psychostimulants that are known to lower seizure threshold such as the amphetamines. Note that CNS stimulants, including the amphetamines, methylphenidate, and modafinil are frequently used in the treatment of narcolepsy, and clinical trials involving the use of psychostimulants with sodium oxybate have not found the combinations to be unsafe. Pharmacodynamic interactions cannot be ruled out, however.
    Lofexidine: (Moderate) Monitor for additive sedation during coadministration of lofexidine and sodium oxybate. Lofexidine can potentiate the effects of CNS depressants. Patients should be advised to avoid driving or performing any other tasks requiring mental alertness until the effects of the combination are known.
    Lopinavir; Ritonavir: (Major) One case report describes a possible interaction between sodium oxybate and ritonavir and saquinavir, leading to repetitive, clonic contractions. The patient also experienced shallow respirations, a heart rate of 40 beats per min, and was responsive only to painful stimuli. The exact contribution of ritonavir and saquinavir to this reaction cannot be determined since several other compounds were detected through a urinary toxin screen.
    Lorazepam: (Contraindicated) Sodium oxybate should not be used in combination with CNS depressant anxiolytics, sedatives, and hypnotics or other sedative CNS depressant drugs. Specifically, sodium oxybate use is contraindicated in patients being treated with sedative hypnotic drugs. Sodium oxybate (GHB) has the potential to impair cognitive and motor skills. For example, the concomitant use of barbiturates and benzodiazepines increases sleep duration and may contribute to rapid onset, pronounced CNS depression, respiratory depression, or coma when combined with sodium oxybate.
    Lumateperone: (Moderate) Monitor for excessive sedation and somnolence during coadministration of lumateperone and sodium oxybate. Concurrent use may result in additive CNS depression.
    Meperidine; Promethazine: (Major) Additive CNS depressant effects may be possible when sodium oxybate is used concurrently with phenothiazines.
    Mephobarbital: (Contraindicated) Sodium oxybate should not be used in combination with CNS depressant anxiolytics, sedatives, and hypnotics or other sedative CNS depressant drugs. Specifically, sodium oxybate use is contraindicated in patients being treated with sedative hypnotic drugs. Sodium oxybate (GHB) has the potential to impair cognitive and motor skills. For example, the concomitant use of barbiturates and benzodiazepines increases sleep duration and may contribute to rapid onset, pronounced CNS depression, respiratory depression, or coma when combined with sodium oxybate.
    Mesoridazine: (Major) Additive CNS depressant effects may be possible when sodium oxybate is used concurrently with phenothiazines.
    Metaxalone: (Major) Sodium oxybate should not be used in combination with CNS depressant anxiolytics, sedatives, and hypnotics or other sedative CNS depressant drugs. Additive CNS depressant effects may be possible when sodium oxybate is used concurrently with skeletal muscle relaxants.
    Methamphetamine: (Moderate) Sodium oxybate has the potential to induce seizures; it has been speculated that this effect may be mediated through the action of sodium oxybate at GABA receptors. Although convulsant effects occur primarily at high dosages, sodium oxybate should be used cautiously with psychostimulants that are known to lower seizure threshold such as the amphetamines. Note that CNS stimulants, including the amphetamines, methylphenidate, and modafinil are frequently used in the treatment of narcolepsy, and clinical trials involving the use of psychostimulants with sodium oxybate have not found the combinations to be unsafe. Pharmacodynamic interactions cannot be ruled out, however.
    Methohexital: (Contraindicated) Sodium oxybate should not be used in combination with CNS depressant anxiolytics, sedatives, and hypnotics or other sedative CNS depressant drugs. Specifically, sodium oxybate use is contraindicated in patients being treated with sedative hypnotic drugs. Sodium oxybate (GHB) has the potential to impair cognitive and motor skills. For example, the concomitant use of barbiturates and benzodiazepines increases sleep duration and may contribute to rapid onset, pronounced CNS depression, respiratory depression, or coma when combined with sodium oxybate.
    Methylphenidate Derivatives: (Moderate) The stimulant effects of methylphenidate derivatives can be additive when used concurrently with other psychostimulants, such as sodium oxybate. The combination may increase the incidence of side effects; if these combinations cannot be avoided the patient should be closely observed for signs of nervousness, irritability, insomnia, arrhythmias, or other stimulant-related problems. Sodium oxybate has the potential to induce seizures; it has been speculated that this effect may be mediated through the action of sodium oxybate at GABA receptors. Although convulsant effects occur primarily at high dosages, sodium oxybate should be used cautiously with psychostimulants that are known to lower seizure threshold. Note that CNS stimulants, including methylphenidate, are frequently used in the treatment of narcolepsy, and clinical trials involving the use of psychostimulants with sodium oxybate have not found the combinations to be unsafe. Pharmacodynamic interactions cannot be ruled out, however.
    Midazolam: (Contraindicated) Sodium oxybate should not be used in combination with CNS depressant anxiolytics, sedatives, and hypnotics or other sedative CNS depressant drugs. Specifically, sodium oxybate use is contraindicated in patients being treated with sedative hypnotic drugs. Sodium oxybate (GHB) has the potential to impair cognitive and motor skills. For example, the concomitant use of barbiturates and benzodiazepines increases sleep duration and may contribute to rapid onset, pronounced CNS depression, respiratory depression, or coma when combined with sodium oxybate.
    Monoamine oxidase inhibitors: (Major) Avoid use within 2 weeks of each other. Data for an interaction with sodium oxybate and MAOIs are lacking, but use of other CNS depressants may potentiate the CNS-depressant effects of sodium oxybate.
    Nabilone: (Moderate) Concomitant use of nabilone with other CNS depressants like sodium oxybate can potentiate the effects of nabilone on respiratory depression.
    Nirmatrelvir; Ritonavir: (Major) One case report describes a possible interaction between sodium oxybate and ritonavir and saquinavir, leading to repetitive, clonic contractions. The patient also experienced shallow respirations, a heart rate of 40 beats per min, and was responsive only to painful stimuli. The exact contribution of ritonavir and saquinavir to this reaction cannot be determined since several other compounds were detected through a urinary toxin screen.
    Non-Ionic Contrast Media: (Major) Sodium oxybate lowers seizure threshold and should be discontinued at least 48 hours before myelography and should not be resumed for at least 24 hours postprocedure.
    Ombitasvir; Paritaprevir; Ritonavir: (Major) One case report describes a possible interaction between sodium oxybate and ritonavir and saquinavir, leading to repetitive, clonic contractions. The patient also experienced shallow respirations, a heart rate of 40 beats per min, and was responsive only to painful stimuli. The exact contribution of ritonavir and saquinavir to this reaction cannot be determined since several other compounds were detected through a urinary toxin screen.
    Opiate Agonists: (Major) Concomitant use of opioid agonists with sodium oxybate may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medication with sodium oxybate to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
    Orphenadrine: (Major) Sodium oxybate should not be used in combination with CNS depressant anxiolytics, sedatives, and hypnotics or other sedative CNS depressant drugs. Additive CNS depressant effects may be possible when sodium oxybate is used concurrently with skeletal muscle relaxants.
    Oxazepam: (Contraindicated) Sodium oxybate should not be used in combination with CNS depressant anxiolytics, sedatives, and hypnotics or other sedative CNS depressant drugs. Specifically, sodium oxybate use is contraindicated in patients being treated with sedative hypnotic drugs. Sodium oxybate (GHB) has the potential to impair cognitive and motor skills. For example, the concomitant use of barbiturates and benzodiazepines increases sleep duration and may contribute to rapid onset, pronounced CNS depression, respiratory depression, or coma when combined with sodium oxybate.
    Ozanimod: (Major) Coadministration of ozanimod with sodium oxybate is not recommended due to the potential for hypertensive crisis. If coadministration is necessary, closely monitor patients for hypertension. An active metabolite of ozanimod inhibits MAO-B, which may increase the potential for hypertensive crisis. Sodium oxybate has been associated with cases of serotonin syndrome. Excess serotonin may contribute to the development of hypertensive crisis.
    Pemoline: (Contraindicated) Patients should be closely observed for signs of nervousness, irritability, insomnia, arrhythmias, or other CNS-stimulant related side effects if these medications are used in combination.
    Pentobarbital: (Contraindicated) Sodium oxybate should not be used in combination with CNS depressant anxiolytics, sedatives, and hypnotics or other sedative CNS depressant drugs. Specifically, sodium oxybate use is contraindicated in patients being treated with sedative hypnotic drugs. Sodium oxybate (GHB) has the potential to impair cognitive and motor skills. For example, the concomitant use of barbiturates and benzodiazepines increases sleep duration and may contribute to rapid onset, pronounced CNS depression, respiratory depression, or coma when combined with sodium oxybate.
    Perphenazine: (Major) Additive CNS depressant effects may be possible when sodium oxybate is used concurrently with phenothiazines.
    Perphenazine; Amitriptyline: (Major) Additive CNS depressant effects may be possible when sodium oxybate is used concurrently with phenothiazines.
    Phendimetrazine: (Contraindicated) Phendimetrazine is a phenylalkaline sympathomimetic agent. All sympathomimetics and psychostimulants, including other anorexiants, should be used cautiously or avoided in patients receiving phendimetrazine. The combined use of these agents may have the potential for additive side effects, such as hypertensive crisis or cardiac arrhythmia.
    Phenobarbital: (Contraindicated) Sodium oxybate should not be used in combination with CNS depressant anxiolytics, sedatives, and hypnotics or other sedative CNS depressant drugs. Specifically, sodium oxybate use is contraindicated in patients being treated with sedative hypnotic drugs. Sodium oxybate (GHB) has the potential to impair cognitive and motor skills. For example, the concomitant use of barbiturates and benzodiazepines increases sleep duration and may contribute to rapid onset, pronounced CNS depression, respiratory depression, or coma when combined with sodium oxybate.
    Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (Contraindicated) Sodium oxybate should not be used in combination with CNS depressant anxiolytics, sedatives, and hypnotics or other sedative CNS depressant drugs. Specifically, sodium oxybate use is contraindicated in patients being treated with sedative hypnotic drugs. Sodium oxybate (GHB) has the potential to impair cognitive and motor skills. For example, the concomitant use of barbiturates and benzodiazepines increases sleep duration and may contribute to rapid onset, pronounced CNS depression, respiratory depression, or coma when combined with sodium oxybate.
    Phenothiazines: (Major) Additive CNS depressant effects may be possible when sodium oxybate is used concurrently with phenothiazines.
    Phentermine: (Contraindicated) Because phentermine is a sympathomimetic and anorexic agent, it should not be used in combination with other psychostimulants.
    Phentermine; Topiramate: (Contraindicated) Because phentermine is a sympathomimetic and anorexic agent, it should not be used in combination with other psychostimulants.
    Phenytoin: (Moderate) In primates, sodium oxybate blood levels were elevated with phenytoin pretreatment. The clinical relevance of these pharmacokinetic changes have not been evaluated.
    Pregabalin: (Major) Concomitant use of sodium oxybate with pregabalin may cause excessive sedation, somnolence, and respiratory depression. If concurrent use is necessary, initiate pregabalin at the lowest recommended dose and monitor patients for symptoms of respiratory depression and sedation. Educate patients about the risks and symptoms of excessive CNS depression and respiratory depression.
    Primidone: (Contraindicated) Sodium oxybate should not be used in combination with CNS depressant anxiolytics, sedatives, and hypnotics or other sedative CNS depressant drugs. Specifically, sodium oxybate use is contraindicated in patients being treated with sedative hypnotic drugs. Sodium oxybate (GHB) has the potential to impair cognitive and motor skills. For example, the concomitant use of barbiturates and benzodiazepines increases sleep duration and may contribute to rapid onset, pronounced CNS depression, respiratory depression, or coma when combined with sodium oxybate.
    Procarbazine: (Contraindicated) Although procarbazine appears to be less likely than other MAOIs to produce serious drug interactions, clinicians should minimize the use of sympathomimetics, such as sodium oxybate, in patients receiving procarbazine. Sympathomimetics should not be used within 14 days after the use of a MAOI.
    Prochlorperazine: (Major) Additive CNS depressant effects may be possible when sodium oxybate is used concurrently with phenothiazines.
    Promethazine: (Major) Additive CNS depressant effects may be possible when sodium oxybate is used concurrently with phenothiazines.
    Promethazine; Dextromethorphan: (Major) Additive CNS depressant effects may be possible when sodium oxybate is used concurrently with phenothiazines.
    Promethazine; Phenylephrine: (Major) Additive CNS depressant effects may be possible when sodium oxybate is used concurrently with phenothiazines.
    Quazepam: (Contraindicated) Sodium oxybate should not be used in combination with CNS depressant anxiolytics, sedatives, and hypnotics or other sedative CNS depressant drugs. Specifically, sodium oxybate use is contraindicated in patients being treated with sedative hypnotic drugs. Sodium oxybate (GHB) has the potential to impair cognitive and motor skills. For example, the concomitant use of barbiturates and benzodiazepines increases sleep duration and may contribute to rapid onset, pronounced CNS depression, respiratory depression, or coma when combined with sodium oxybate.
    Rasagiline: (Moderate) Although sympathomimetics and psychostimulants are contraindicated for use with other monoamine oxidase inhibitors (MAOIs), hypertensive reactions generally are not expected to occur during concurrent use with rasagiline because of the selective monoamine oxidase-B (MAO-B) inhibition of rasagiline at manufacturer recommended doses.
    Remimazolam: (Contraindicated) Sodium oxybate should not be used in combination with CNS depressant anxiolytics, sedatives, and hypnotics or other sedative CNS depressant drugs. Specifically, sodium oxybate use is contraindicated in patients being treated with sedative hypnotic drugs. Sodium oxybate (GHB) has the potential to impair cognitive and motor skills. For example, the concomitant use of barbiturates and benzodiazepines increases sleep duration and may contribute to rapid onset, pronounced CNS depression, respiratory depression, or coma when combined with sodium oxybate.
    Ritonavir: (Major) One case report describes a possible interaction between sodium oxybate and ritonavir and saquinavir, leading to repetitive, clonic contractions. The patient also experienced shallow respirations, a heart rate of 40 beats per min, and was responsive only to painful stimuli. The exact contribution of ritonavir and saquinavir to this reaction cannot be determined since several other compounds were detected through a urinary toxin screen.
    Saquinavir: (Minor) One case report describes a possible interaction between sodium oxybate and ritonavir and saquinavir, leading to repetitive, clonic contractions. The patient also experienced shallow respirations, a heart rate of 40 beats per min, and was responsive only to painful stimuli. The exact contribution of ritonavir and saquinavir to this reaction cannot be determined since several other compounds were detected through a urinary toxin screen.
    Secobarbital: (Contraindicated) Sodium oxybate should not be used in combination with CNS depressant anxiolytics, sedatives, and hypnotics or other sedative CNS depressant drugs. Specifically, sodium oxybate use is contraindicated in patients being treated with sedative hypnotic drugs. Sodium oxybate (GHB) has the potential to impair cognitive and motor skills. For example, the concomitant use of barbiturates and benzodiazepines increases sleep duration and may contribute to rapid onset, pronounced CNS depression, respiratory depression, or coma when combined with sodium oxybate.
    Selegiline: (Moderate) Monitor for excessive sedation and somnolence during coadministration of selegiline and sodium oxybate. Concurrent use may result in additive CNS depression.
    Skeletal Muscle Relaxants: (Major) Sodium oxybate should not be used in combination with CNS depressant anxiolytics, sedatives, and hypnotics or other sedative CNS depressant drugs. Additive CNS depressant effects may be possible when sodium oxybate is used concurrently with skeletal muscle relaxants.
    St. John's Wort, Hypericum perforatum: (Major) St. John's wort, Hypericum Perforatum may reduce the neuronal uptake of monoamines and should be used cautiously with sympathomimetics.
    Temazepam: (Contraindicated) Sodium oxybate should not be used in combination with CNS depressant anxiolytics, sedatives, and hypnotics or other sedative CNS depressant drugs. Specifically, sodium oxybate use is contraindicated in patients being treated with sedative hypnotic drugs. Sodium oxybate (GHB) has the potential to impair cognitive and motor skills. For example, the concomitant use of barbiturates and benzodiazepines increases sleep duration and may contribute to rapid onset, pronounced CNS depression, respiratory depression, or coma when combined with sodium oxybate.
    Thiethylperazine: (Major) Additive CNS depressant effects may be possible when sodium oxybate is used concurrently with phenothiazines.
    Thiopental: (Contraindicated) Sodium oxybate should not be used in combination with CNS depressant anxiolytics, sedatives, and hypnotics or other sedative CNS depressant drugs. Specifically, sodium oxybate use is contraindicated in patients being treated with sedative hypnotic drugs. Sodium oxybate (GHB) has the potential to impair cognitive and motor skills. For example, the concomitant use of barbiturates and benzodiazepines increases sleep duration and may contribute to rapid onset, pronounced CNS depression, respiratory depression, or coma when combined with sodium oxybate.
    Thioridazine: (Major) Additive CNS depressant effects may be possible when sodium oxybate is used concurrently with phenothiazines.
    Triazolam: (Contraindicated) Sodium oxybate should not be used in combination with CNS depressant anxiolytics, sedatives, and hypnotics or other sedative CNS depressant drugs. Specifically, sodium oxybate use is contraindicated in patients being treated with sedative hypnotic drugs. Sodium oxybate (GHB) has the potential to impair cognitive and motor skills. For example, the concomitant use of barbiturates and benzodiazepines increases sleep duration and may contribute to rapid onset, pronounced CNS depression, respiratory depression, or coma when combined with sodium oxybate.
    Trifluoperazine: (Major) Additive CNS depressant effects may be possible when sodium oxybate is used concurrently with phenothiazines.
    Trimethobenzamide: (Major) Sodium oxybate should not be used in combination with CNS depressants. Additive CNS depressant effects may be possible when sodium oxybate is used concurrently with drugs like trimethobenzamide.
    Valproic Acid, Divalproex Sodium: (Major) Concomitant use of oxybates with valproic acid (or valproate or divalproex sodium) results in an increased systemic exposure to GHB, which may cause increased attention and working memory impairment. Reduce the total oxybates dosage at least 20% in patients starting valproic acid or a related derivative. When initiating oxybates in a patient already taking valproic acid or a related derivative, start the oxybates at a lower initial dosage. Subsequently, the oxybates dosage can be adjusted based on clinical response and tolerability.

    PREGNANCY AND LACTATION

    Pregnancy

    There is insufficient information regarding maternal use of sodium oxybate and the risk to a breast-fed infant and on milk production in the breast-feeding mother. Gamma hydroxybutyrate (GHB) is excreted in human milk after oral administration of sodium oxybate, and the developmental and health benefits of breast-feeding should be considered along with the need of the mother for sodium oxybate and any potential adverse effects on the breast-fed infant from sodium oxybate or from the underlying maternal condition. Because the available data are too limited to be conclusive, an alternate drug may be preferred (or an alternate form of feeding), especially while nursing a newborn or premature infant. If sodium oxybate administration cannot be avoided, it is advisable to avoid breast-feeding for 4 to 5 hours after each dose to minimize infant exposure to the drug, and the nursing infant should be monitored for adverse drug effects such as sedation, respiratory depression, agitation, and vomiting. In one case report, a breast-feeding mother taking 4.5 grams of sodium oxybate twice daily had a peak drug value of 23.2 mg/L at 1 hour after the dose, decreasing to 3.1 mg/L at 4 hours after the dose and 1 mg/L at 5 hours after the dose, at which time the concentration was within the proposed endogenous breast milk reference range of 0.13 to 1.03 mg/L. No adverse infant effects were reported. In a separate case, a woman with narcolepsy took sodium oxybate 4 grams each night at 10 p.m. and 2 a.m. and breast-fed her infant (or provided pumped breast milk) exclusively for 6 months except for 4 hours after the 10 p.m. dose and 4 hours after the 2 a.m. dose. According to evaluations of the infant from the Ages and Stages Questionnaires at 2, 4, and 6 months and the pediatrician's clinical impressions of growth and development, the measured parameters were within the normal range.

    MECHANISM OF ACTION

    Sodium oxybate (also known as the sodium salt of 'GHB') is an endogenous 4-carbon fatty acid that is thought to act as a neurotransmitter in the regulation of sleep cycles, blood flow, emotion, and memory. Its actions are thought to be mediated through brain receptors specific for GHB as well as through binding to GABA-B receptors. At low doses, the drug inhibits presynaptic dopamine release, while at high doses, dopamine release may be stimulated. It is believed that sodium oxybate decreases the symptoms of narcolepsy by inducing REM sleep and increasing delta sleep. The precise mechanism by which sodium oxybate produces anti-cataplectic activity in patients with narcolepsy is unknown. Anesthetic induction is thought to occur from a general CNS depressant effect on the cerebrospinal axis and occurs at higher dosages. Intoxication with sodium oxybate or GHB can produce severe symptoms including seizures, respiratory depression, CNS depression, coma, and death.

    PHARMACOKINETICS

    Sodium oxybate is administered orally. Pharmacokinetics are non-linear, with blood levels increasing 3.7-fold as the dose is doubled from 4.5 to 9 grams; single doses more than 4.5 grams have not been studied clinically. The pharmacokinetics are not altered with repeat administration. Less than 1% of the drug is bound to plasma proteins. Sodium oxybate readily crosses the blood-brain barrier and the placenta.
     
    Animal studies indicate that metabolism is the major elimination pathway for sodium oxybate, producing carbon dioxide and water via the Krebs cycle and secondarily via beta-oxidation. The primary pathway involves a cytosolic NADP+-linked enzyme, GHB dehydrogenase, which catalyzes the conversion of sodium oxybate to succinic semialdehyde, which is then transformed to succinic acid by succinic semialdehyde dehydrogenase. Succinic acid enters the Krebs cycle and is converted to carbon dioxide and water. A second mitochondrial oxidoreductase enzyme, a transhydrogenase, also contributes to the conversion to succinic semialdehyde in the presence of alpha-ketoglutarate. An alternate pathway of biotransformation involves beta-oxidation via 3,4-dihydroxybutyrate to carbon dioxide and water. Sodium oxybate is also metabolized in the central nervous system; however, the exact pathway has not been described. No active metabolites have been described. The elimination of the drug appears to be capacity-limited.[26475] The elimination of sodium oxybate is almost entirely by biotransformation to carbon dioxide, which is then expired. On average, less than 5% of a dose is excreted renally as the parent compound within 6 to 8 hours of dosing. Fecal excretion is negligible. The elimination half-life is 0.5 to 1 hour.[28528] Although laboratory assays are not routinely available, GHB is detectable in plasma and urine using gas chromatographic-mass spectrometric (GC-MS).[26474] The drug is virtually undetectable in the urine after 12 hours.
     
    Affected cytochrome P450 (CYP450) enzymes and drug transporters: none
    Results of in vitro studies with human liver microsomes indicate that sodium oxybate does not significantly inhibit CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, or CYP3A at a concentration that is significantly higher than plasma concentrations achieved with therapeutic doses.[28528]

    Oral Route

    Sodium oxybate is rapidly absorbed after oral administration, with an absolute bioavailability of 88%. The average time to peak plasma concentration (Tmax) ranges from 0.5 to 1.25 hours. Absorption is delayed and decreased (increase in average Tmax from 0.75 to 2 hours, 59% decrease in Cmax, 37% decrease in AUC) when the drug is administered with a high-fat meal. The average peak plasma concentrations (Cmax) after administration of each of the two 2.25 gram doses given under fasting conditions 4 hours apart are similar. Sedation occurs within 15 to 45 minutes, with the maximal effect occurring 45 to 90 minutes after a dose. The duration of action is typically 2 to 3 hours.[28528]