Xyrem (sodium oxybate)

When initiating divalproex sodium in patients taking a stable dosage of immediate-release sodium oxybate or lower-sodium oxybate, a reduction of the sodium oxybate dosage by at least 20% is recommended. When initiating immediate-release sodium oxybate or lower-sodium oxybate in patients already taking divalproex sodium, a lower starting dosage of sodium oxybate is recommended. Subsequently, adjust the dosage of sodium oxybate based on individual clinical response and tolerability.

The manufacturer of sodium oxybate extended-release suspension states that no dosage changes are recommended based on pharmacokinetic studies. However, a pharmacodynamic interaction between sodium oxybate and divalproex sodium, a sedative antiepileptic drug, cannot be ruled out.

Sodium oxybate is available as an immediate-release oral solution (Xyrem(R)) and extended-release granules for oral suspension (Lumryz(R)). Calcium, magnesium, potassium and sodium oxybates (lower-sodium oxybate) is available as an oral solution (Xywav(R)).

Sodium oxybate oral solution (Xyrem(R)) should be stored at 25degreesC (excursions permitted between 15-30degreesC). Extended-release granules (Lumryz(R)) and lower-sodium oxybate oral solution (Xywav(R)) should be stored at 20-25degreesC (excursions permitted between 15-30degreesC).

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Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

Sodium Oxybate/Sedative Hypnotics; Alcohol

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Oxybate may be associated with respiratory depression. As oxybate is taken at bedtime, concurrent use with alcohol or hypnotics may increase the risk for respiratory depression or loss of consciousness.(1-3) Primidone is metabolized to phenobarbital.

CLINICAL EFFECTS: Concurrent use of sodium oxybate and sedative hypnotics or alcohol may further increase the risk for respiratory depression and profound sedation or coma.(1,2) Fatalities have been reported.(3)

PREDISPOSING FACTORS: Based upon FDA evaluation of deaths in patients taking sodium oxybate, risk factors may include: use of multiple drugs which depress the CNS, more rapid than recommended oxybate dose titration, exceeding the maximum recommended oxybate dose, and prescribing for unapproved uses such as fibromyalgia, insomnia or migraine. Note that in oxybate clinical trials for narcolepsy 78% - 85% of patients were also receiving concomitant CNS stimulants.(1-3)

PATIENT MANAGEMENT: The FDA states that sodium oxybate is contraindicated in patients also taking hypnotics or alcohol.(1,2) Significant quantities of alcohol may be present in medicinal products. Alcohol is is used to improve docetaxel and paclitaxel solubility. - The quantity of alcohol in paclitaxel injection formulations (0.385-0.396 grams/mL) is similar across manufacturers. A paclitaxel 200 mg dose contains approximately 13 grams of alcohol. - The quantity of alcohol in docetaxel formulations varies approximately 3-fold depending upon the manufacturer. FDA data on alcohol content (4): Product Manufacturer Alcohol/200 mg dose Docetaxel Inj. Pfizer 6.4 grams Docetaxel Inj. Sandoz 5.5 grams Docetaxel Inj. Accord 4.0 grams Taxotere-one vial Sanofi 4.0 grams formulation Docetaxel Inj. Hospira 3.7 grams Docefrez Sun Pharma 2.9 grams Taxotere-two vial Sanofi 2.0 grams formulation

DISCUSSION: The FDA evaluated sodium oxybate postmarket fatal adverse event reports from the FDA Adverse Event Reporting System(AERS)and from the manufacturer. Although report documentation was not always optimal or complete, useful information was obtained. Factors which may have contributed to fatal outcome: concomitant use of one or more drugs which depress the CNS, more rapid than recommended upward dose titration, exceeding the maximum recommended oxybate dose, and prescribing for unapproved uses such as fibromyalgia, insomnia or migraine. Many deaths occurred in patients with serious psychiatric disorders such as depression and substance abuse. Other concomitant diseases may have also contributed to respiratory and CNS depressant effects of oxybate.(3)

Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

Sodium Oxybate/Agents That May Cause Respiratory Depression

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Oxybate by itself may be associated with severe somnolence or respiratory depression. Concurrent use with other CNS depressants may further increase the risk for respiratory depression or loss of consciousness.(1-3)

CLINICAL EFFECTS: Concurrent use of sodium oxybate and sedative hypnotics or alcohol may further increase the risk for profound sedation, respiratory depression, coma, and/or death.(1,2) Fatalities have been reported.(3)

PREDISPOSING FACTORS: Based upon FDA evaluation of deaths in patients taking sodium oxybate, risk factors may include: use of multiple drugs which depress the CNS, more rapid than recommended oxybate dose titration, exceeding the maximum recommended oxybate dose, and prescribing for unapproved uses such as fibromyalgia, insomnia or migraine. Note that in oxybate clinical trials for narcolepsy 78% - 85% of patients were also receiving concomitant CNS stimulants.(1-3)

PATIENT MANAGEMENT: Avoid use of concomitant opioids, benzodiazepines, sedating antidepressants, sedating antipsychotics, general anesthetics, or muscle relaxants, particularly when predisposing risk factors are present. If combination use is required, dose reduction or discontinuation of one or more CNS depressants should be considered. If short term use of an opioid or general anesthetic is required, consider interruption of sodium oxybate treatment.(1,2) Respiratory depression can occur at any time during opioid therapy, especially during therapy initiation and following dosage increases. The risk of opioid-related overdose or overdose-related death is increased with higher opioid doses, and this risk persists over the course of therapy. Consider these risks when using concurrently with other agents that may cause CNS depression.(4) Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing an opioid reversal agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat OUD or opioid analgesics who are at increased risk of opioid overdose (such as those taking CNS depressants) and when a patient has household members/close contacts at risk for accidental overdose. Discuss the options for obtaining an opioid reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program).(5)

DISCUSSION: The FDA evaluated sodium oxybate postmarket fatal adverse event reports from the FDA Adverse Event Reporting System(AERS)and from the manufacturer. Although report documentation was not always optimal or complete, useful information was obtained. Factors which may have contributed to fatal outcome: concomitant use of one or more drugs which depress the CNS, more rapid than recommended oxybate dose titration, exceeding the maximum recommended oxybate dose, and prescribing for unapproved uses such as fibromyalgia, insomnia or migraine. Many deaths occurred in patients with serious psychiatric disorders such as depression and substance abuse. Other concomitant diseases may have also contributed to respiratory and CNS depressant effects of oxybate.(3)

Sodium Oxybate/Codeine; Tramadol

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Oxybate by itself may be associated with severe somnolence or respiratory depression. Concurrent use with other CNS depressants may further increase the risk for respiratory depression or loss of consciousness.(1-3) Codeine and tramadol are converted to their more active opioid metabolites (morphine and O-desmethyltramadol respectively) by CYP2D6.

CLINICAL EFFECTS: Concurrent use of sodium oxybate and opioids such as tramadol, or alcohol may further increase the risk for respiratory depression and profound sedation, syncope or coma.(1,2) Fatalities have been reported.(3)

PREDISPOSING FACTORS: Based upon FDA evaluation of deaths in patients taking sodium oxybate, risk factors may include: use of multiple drugs which depress the CNS, more rapid than recommended oxybate dose titration, exceeding the maximum recommended oxybate dose, and prescribing for unapproved uses such as fibromyalgia, insomnia or migraine. Note that in oxybate clinical trials for narcolepsy 78% - 85% of patients were also receiving concomitant CNS stimulants.(1-3) In patients receiving codeine or tramadol, ultrarapid metabolizers of CYP2D6 are more likely to have higher than normal systemic concentrations of the active opioid.(4) Other patients at high risk from this interaction include: adolescents between 12 and 18 years who are obese or have conditions such as obstructive sleep apnea or severe lung disease, which may increase the risk of respiratory depression; and breastfeeding women (due to the risk of serious adverse reactions in breastfed infants).(5)

PATIENT MANAGEMENT: Avoid use of oxybate when concomitant opioids, benzodiazepines, sedating antidepressants, sedating antipsychotics, general anesthetics, or muscle relaxants, particularly when predisposing risk factors are present. If combination use is required, dose reduction or discontinuation of one or more CNS depressants should be considered. If short term use of an opioid or general anesthetic is required, consider interruption of sodium oxybate treatment.(1,2) Codeine and tramadol are converted to their active opioid metabolites by CYP2D6. Ultrarapid metabolizers of CYP2D6 more rapidly convert codeine or tramadol to their active metabolites (morphine and o-desmethyltramadol respectively) and so are more likely to have higher than normal systemic concentrations of the active opioid. Respiratory depression can occur at any time during opioid therapy, especially during therapy initiation and following dosage increases. The risk of opioid-related overdose or overdose-related death is increased with higher opioid doses, and this risk persists over the course of therapy. Consider these risks when using concurrently with other agents that may cause CNS depression.(6) Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing an opioid reversal agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat OUD or opioid analgesics who are at increased risk of opioid overdose (such as those taking CNS depressants) and when a patient has household members/close contacts at risk for accidental overdose. Discuss the options for obtaining an opioid reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program).(7)

DISCUSSION: The FDA evaluated sodium oxybate postmarket fatal adverse event reports from the FDA Adverse Event Reporting System(AERS) and from the manufacturer. Although report documentation was not always optimal or complete, useful information was obtained. Factors which may have contributed to fatal outcome: concomitant use of one or more drugs which depress the CNS, more rapid than recommended oxybate dose titration, exceeding the maximum recommended oxybate dose, and prescribing for unapproved uses such as fibromyalgia, insomnia or migraine. FDA reported the case of a 5-year-old patient who received one dose of tramadol following a tonsillectomy and experienced slow, difficult breathing requiring emergency intervention and hospitalization. The child was subsequently found to be an ultrarapid metabolizer of CYP2D6.(4) Many deaths occurred in patients with serious psychiatric disorders such as depression and substance abuse. Other concomitant diseases may have also contributed to respiratory and CNS depressant effects of oxybate.(3)

Moderate Interaction: Assess the risk to the patient and take action as needed.

Sodium Oxybate/Valproic Acid

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: The exact mechanism is unknown.(1)

CLINICAL EFFECTS: Concurrent use of sodium oxybate and valproic acid may result in elevated levels of and increased clinical effects of sodium oxybate, including significant respiratory depression.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Patients receiving concurrent valproic acid may require lower dosages of sodium oxybate. In patients maintained on sodium oxybate, reduce the dosage of sodium oxybate by 20% if valproic acid is initiated. For patients already taking valproic acid, consider a lower starting dose of sodium oxybate. If valproic acid is discontinued, monitor patient response to sodium oxybate.(1)

DISCUSSION: Administration of valproic acid (1250 mg daily) increased the area-under-curve (AUC) of sodium oxybate (6 g per day dosed as 3 grams given 4 hours apart) by 25%. There was no significant change in sodium oxybate maximum concentration (Cmax).(1)

*Concomitant therapy with sedative-hypnotic agents or concomitant use with alcohol.

*Succinic semialdehyde dehydrogenase (SSADH) deficiency.

• Alcohol intoxication
• Alcohol use disorder
• Succinate-semialdehyde dehydrogenase deficiency

• Child-pugh class A hepatic impairment
• Child-pugh class B hepatic impairment
• Child-pugh class C hepatic impairment
• Depression
• Disease of liver
• Drug abuse
• Respiratory depression
• Seizure disorder
• Sleep apnea
• Suicidal ideation

• Acute cognitive impairment
• Chronic heart failure
• Hypertension
• Kidney disease with reduction in glomerular filtration rate (GFr)
• Sleep walking disorder

Adverse effects occurring in 5% or more of adult patients receiving sodium oxybate (Xyrem(R)) in controlled clinical trials and at least twice as frequently as with placebo include nausea, dizziness, vomiting, somnolence, enuresis, and tremor.

Adverse effects occurring in 5% or more of adult patients receiving extended-release sodium oxybate (Lumryz(R)) in controlled clinical trials and at least twice as frequently as with placebo include nausea, dizziness, enuresis, headache, and vomiting.

Adverse effects occurring in 5% or more of adult patients receiving lower-sodium oxybate (Xywav(R)) in controlled clinical trials for narcolepsy or idiopathic hypersomnia include nausea, headache, dizziness, anxiety, insomnia, decreased appetite, hyperhidrosis, vomiting, diarrhea, dry mouth, parasomnia, somnolence, fatigue, and tremor.

Adverse reactions occurring 5% or more of pediatric patients receiving immediate-release sodium oxybate (Xyrem(R)) include nausea, enuresis, vomiting, headache, decreased weight, decreased appetite, dizziness, and sleepwalking.

More Frequent

• Depression
• Urinary incontinence

Less Frequent

• Acute cognitive impairment
• CNS depression
• Dyspnea

Rare or Very Rare

• Accidental fall
• Angioedema
• Apnea
• Coma
• Drug-induced psychosis
• Hallucinations
• Hypersensitivity drug reaction
• Hypertension
• Infection
• Respiratory depression
• Seizure disorder
• Sleep apnea
• Suicidal ideation

More Frequent

• Dizziness
• Drowsy
• Headache disorder
• Hyperhidrosis
• Insomnia
• Nausea
• Sleep walking disorder
• Symptoms of anxiety
• Tremor
• Vomiting

Less Frequent

• Agitation
• Akathisia
• Anorexia
• Ataxia
• Constipation
• Diarrhea
• Disturbance of attention
• Dream disorder
• Dyspepsia
• Fatigue
• Muscle spasm
• Pain
• Parasomnia
• Paresthesia
• Upper abdominal pain
• Weight loss
• Xerostomia

Rare or Very Rare

• Aggressive behavior
• Altered consciousness
• Arthralgia
• Blurred vision
• Body fluid retention
• Hostility
• Hypoesthesia
• Irritability
• Loss of taste
• Memory impairment
• Nocturia
• Pain in extremities
• Panic disorder
• Paranoid disorder
• Pharyngitis
• Proteinuria
• Rhinitis
• Sedation hangover effect
• Sleep paralysis
• Stupor
• Viral infection

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Safety and efficacy of sodium oxybate immediate-release oral solution (Xyrem(R)) have been established in pediatric patients 7 years of age and older for the management of narcolepsy in a double-blind, placebo-controlled, randomized-withdrawal study.

In a study of pediatric patients with narcolepsy, serious adverse reactions included central sleep apnea and oxygen desaturation documented by polysomnography evaluation; depression; suicidal ideation; neuropsychiatric reactions including acute psychosis, confusion, and anxiety; and parasomnias including sleepwalking.

Safety and efficacy of lower-sodium oxybate (Xywav(R)) for the treatment of cataplexy or excessive daytime sleepiness in pediatric patients 7 years of age and older are supported by evidence from clinical studies of sodium oxybate in pediatric patients 7 to 17 years of age, a study in adults showing a treatment effect of lower-sodium oxybate similar to that observed with sodium oxybate, pharmacokinetic data of sodium oxybate from adult and pediatric patients, and pharmacokinetic data of lower-sodium oxybate from healthy adult volunteers.

Safety and efficacy of sodium oxybate extended-release suspension (Lumryz(R)) have been established in pediatric patients >=7 years of age for treatment of cataplexy or excessive daytime sleepiness. Sodium oxybate extended-release suspension has not been evaluated in a pediatric clinical trial; evidence supporting its use is from a double-blind, placebo-controlled, randomized-withdrawal study of immediate-release sodium oxybate.

Safety and effectiveness of sodium oxybate and lower-sodium oxybate in pediatric patients younger than 7 years of age have not been established.

There are no available data on the developmental risk associated with the use of sodium oxybate in pregnant women. Mixed evidence is available from animal studies; in pregnant rats and rabbits, administration throughout organogenesis produced no clear evidence of developmental toxicity; however, oral administration to rats throughout pregnancy and lactation resulted in increased stillbirths and decreased offspring postnatal viability and growth, at a clinically relevant dose.

Sodium oxybate and lower-sodium oxybate have not been studied in labor or delivery; but use of an injectable formulation of sodium oxybate resulted in very sleepy newborns with a decrease in Apgar scores.

Insufficient information is available on the risk of sodium oxybate to a breastfed infant, and on milk production in nursing mothers. The metabolite, GHB, is excreted in human milk after oral administration of sodium oxybate. Caution is advised if the drug is administered in nursing women.

Select dosage in geriatric patients with caution, usually starting at lower end of dosage range, because of age-related decreases in hepatic, renal, and/or cardiac function and considering concomitant disease and other drug therapy.

Clinical studies of sodium oxybate and lower-sodium oxybate in patients with narcolepsy or idiopathic hypersomnia did not include sufficient numbers of patients 65 years of age or older to determine whether geriatric patients respond differently than younger adults. In clinical trials of sodium oxybate in another patient population (i.e., patients with disorders other than narcolepsy), the incidence of headaches was higher in geriatric patients compared with younger adults. In general, dosage selection in geriatric patients should be cautious, usually starting at the lower end of the dosage range, because of the greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease and drug therapy in these patients. Geriatric patients receiving sodium oxybate should be monitored for impaired motor or cognitive function.