calcium/magnesium/potassium/sodium oxybates (Rx)

Brand and Other Names:Xywav
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Dosing & Uses

AdultPediatric

Dosage Forms & Strengths

oral solution, Schedule III

  • 500mg/mL
  • Equivalent to 0.413 g/mL of oxybate

Narcolepsy

Indicated for cataplexy or excessive daytime sleepiness in patients aged ≥7 years with narcolepsy

4.5 g per night PO divided into 2 doses (2.25 g HS and 2.25 g taken 2.5-4 hr later) initially

May increase dose by up to 1.5 g/night at weekly intervals (additional 0.75 g HS and 0.75 g taken 2.5-4 hr later), to recommended dosage range of 6-9 g/night; not to exceed 9 g/night

Gradually titrate dose based on efficacy and tolerability; unequal dosages may be required for some patients to achieve optimal treatment

Recommended adult dosage regimens

  • 6 g/night PO divided into 2 doses (3 g HS and 3 g taken 2.5-4 hr later)
  • 7.5 g/night PO divided into 2 doses (3.75 g HS and 3.75 g taken 2.5-4 hr later)
  • 9 g/night PO divided into 2 doses (4.5 g HS and 4.5 g taken 2.5-4 hr later)

Dosage Modifications

Renal impairment

  • No dosage adjustment necessary

Hepatic impairment

  • Reduce initial dosage by one half of the original dosage per night, divided into 2 doses

Coadministration with divalproex sodium

  • Patients already stabilized on calcium/magnesium/potassium/sodium oxybates: When adding divalproex sodium, reduce initial nightly sodium oxybate dose by ≥20%
  • Patients already taking divalproex sodium: Initiate calcium/magnesium/potassium/sodium oxybates at a lower starting dose; monitor response and adjust dose accordingly

Dosing Considerations

Transitioning from sodium oxybate

  • On the first night of dosing with calcium/magnesium/potassium/sodium oxybates, initiate at the same dose (gram for gram) and regimen as sodium oxybate
  • Titrate as needed based on efficacy and tolerability

Dosage Forms & Strengths

oral solution, Schedule III

  • 500mg/mL
  • Equivalent to 0.413 g/mL of oxybate

Narcolepsy

Indicated for cataplexy or excessive daytime sleepiness in patients aged ≥7 years with narcolepsy

<7 years: Safety and efficacy not established

≥7 years

  • <20 kg: Consider a lower starting dosage, maximum weekly dosage increases, and total maximum nightly dosage; unequal dosages may be required for some patients to achieve optimal treatment
  • 20 to <30 kg: Initiate at ≤1 g HS and ≤1 g taken 2.5-4 hr later; may increase at weekly intervals up to 0.5-g/dose; not to exceed 3 g/dose
  • 30 to <45 kg: Initiate at ≤1.5 g HS and ≤1.5 g taken 2.5-4 hr later; may increase at weekly intervals up to 0.5-g/dose; not to exceed 3.75 g/dose
  • ≥45 kg: Initiate at ≤2.25 g HS and ≤2.25 g taken 2.5-4 hr later; may increase at weekly intervals up to 0.75-g/dose; not to exceed 4.5 g/dose
  • Gradually titrate dose based on efficacy and tolerability; unequal dosages may be required for some patients to achieve optimal treatment

Dosage Modifications

Renal impairment

  • No dosage adjustment necessary

Hepatic impairment

  • Reduce initial dosage by one half of the original dosage per night, divided into 2 doses

Coadministration with divalproex sodium

  • Patients already stabilized on calcium/magnesium/potassium/sodium oxybates: When adding divalproex sodium, reduce initial nightly sodium oxybate dose by ≥20%
  • Patients already taking divalproex sodium: Initiate calcium/magnesium/potassium/sodium oxybates at a lower starting dose; monitor response and adjust dose accordingly

Dosing Considerations

Transitioning from sodium oxybate

  • On first night of dosing with calcium/magnesium/potassium/sodium oxybates, initiate at the same dose (gram for gram) and regimen as sodium oxybate
  • Titrate as needed based on efficacy and tolerability
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Interactions

Interaction Checker

and calcium/magnesium/potassium/sodium oxybates

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            Adverse Effects

            >10%

            Adults

            • Headache (20%)
            • Nausea (13%)
            • Adolescents H4
            • Enuresis (18%)
            • Nausea (17%)
            • Headache (16%)
            • Vomiting (16%)
            • Weight decreased (12%)

            1-10%

            Adults

            • Dizziness (10%)
            • Decreased appetite (8%)
            • Parasomnia (6%)
            • Diarrhea (6%)
            • Hyperhidrosis (6%)
            • Anxiety (5%)
            • Vomiting (5%)
            • Fatigue (4%)
            • Dry mouth (4%)
            • Depressed mood (4%)
            • Enuresis (4%)
            • Irritability (3%)
            • Paresthesia (3%)
            • Depression (3%)
            • Tremor (3%)
            • Somnolence (2%)
            • Muscle spasms (2%)

            Adolescents

            • Decreased appetite (8%)
            • Dizziness (6%)

            Frequency Not Defined

            Adolescents

            • Sleep apnea syndrome

            Postmarketing Reports

            Arthralgia, fall, fluid retention, hangover, hypersensitivity, hypertension, memory impairment, nocturia, and vision blurred

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            Warnings

            Black Box Warnings

            CNS depression

            Calcium, magnesium, potassium, and sodium oxybates is a CNS depressant

            Clinically significant respiratory depression and obtundation may occur

            During clinical trials in narcolepsy, many patients were also receiving CNS stimulants

            Abuse and misuse

            Oxybate or gamma-hydroxybutyrate (GHB) is an active moiety of calcium, magnesium, potassium, and sodium oxybates

            Abuse or misuse of illicit GHB, either alone or in combination with other CNS depressants, is associated with CNS adverse reactions, including seizure, respiratory depression, decreases in the level of consciousness, coma, and death

            Risk Evaluation and Mitigation Strategy program

            • Owing to the risks of CNS depression and abuse and misuse, available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the Xywav and Xyrem REMS Program
            • Requirements of the Xywav and Xyrem REMS include the following:
              • Prescribing healthcare providers are specially certified
              • Dispensing pharmacies are specially certified
              • Drug will be dispensed and shipped only to patients who are enrolled in the Xywav and Xyrem REMS Program with documentation of safe use
              • Further information is available at www.XYWAVXYREMREMS.com or 1-866-997-3688

            Contraindications

            Concomitant sedative-hypnotic drugs or other drugs used for insomnia

            Coadministration with alcohol

            Succinic semialdehyde dehydrogenase deficiency

            Cautions

            Xywav is a Schedule III controlled substance; sodium oxybate or gamma-hydroxybutyrate (GHB), the active ingredient, is a Schedule I controlled substance; illicit use and abuse of GHB reported; carefully evaluate for a history of drug abuse and closely monitor for signs of misuse or abuse of GHB

            Risks of depression, respiratory depression, confusion, neuropsychiatric events including hallucinations, paranoia, psychosis, aggression, and agitation; use caution when considering concurrent use of sodium oxybate with other CNS depressants; monitor patients for emergent or increased depression and suicidality

            Only take at bedtime; monitor for impaired motor/cognitive function; caution patients against hazardous activities requiring complete mental alertness or motor coordination within the first 6 hr of dosing or after first initiating treatment until certain that sodium oxybate does not affect them adversely; do not operate machinery for at least 6 hr after dose

            Use with caution in patients with sleep apnea

            Evaluate episodes of parasomnias, including sleepwalking

            Do not drink alcoholic beverages

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

            Emergence of depression in patients receiving therapy requires careful and immediate evaluation; carefully monitor patients with a previous history of a depressive illness and/or suicide attempt for the emergence of depressive symptoms while receiving therapy

            Carefully monitor emergence or increase in occurrence of behavioral or psychiatric events in patients receiving therapy

            Drug interactions overview

            Coadministration with divalproex sodium resulted in a 25% mean increase in systemic exposure to sodium oxybate and greater impairment on some tests of attention and working memory

            CNS depressants

            • Use with alcohol or sedative hypnotics is contraindicated
            • Concurrent use with other CNS depressants (eg, opioid analgesics, benzodiazepines, sedating antidepressants or antipsychotics, sedating antiepileptic drugs, general anesthetics, muscle relaxants, illicit CNS depressants) may increase the risk of respiratory depression, hypotension, profound sedation, syncope, and death
            • If these CNS depressants cannot be avoided, consider reducing dose or discontinuation of one or more CNS depressants (including sodium oxybate)
            • If short-term opioid use required (eg, postoperative, perioperative), consider interrupting sodium oxybate treatment
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            Pregnancy & Lactation

            Pregnancy

            No adequate data available on the developmental risk associated with use in pregnant females

            Animal data

            • Oral administration of sodium oxybate to pregnant rats (0, 150, 350, or 1000 mg/kg/day) or rabbits (0, 300, 600, or 1200 mg/kg/day) 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

            Clinical considerations

            • Not studied in labor or delivery
            • In obstetric anesthesia using an injectable formulation of sodium oxybate, newborns had stable but were very sleepy, causing a slight decrease in Apgar scores
            • There was a fall in the rate of uterine contractions 20 minutes after injection
            • Placental transfer is rapid, and GHB has been detected in newborns at delivery after intravenous administration of GHB to mothers
            • Subsequent effects of sodium oxybate on later growth, development, and maturation in humans are unknown

            Lactation

            GHB is excreted in human milk after oral administration of sodium oxybate

            There is insufficient information on the risks to a breastfed infant, and on milk production in nursing mothers

            Pregnancy Categories

            A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

            B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

            C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

            D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

            X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

            NA: Information not available.

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            Pharmacology

            Mechanism of Action

            CNS depressant; a mixture of calcium oxybate, magnesium oxybate, potassium oxybate, and sodium oxybate (gamma-hydroxybutyrate)

            GHB is an endogenous compound and metabolite of the neurotransmitter GABA

            Exact mechanism of action for narcolepsy is unknown

            Therapeutic effects on cataplexy and excessive daytime sleepiness are possibly related to GABAb actions during sleep at noradrenergic and dopaminergic neurons

            Absorption

            Peak plasma time: 1.3 hr

            Effects of food

            • Administration immediately after a high-fat meal results in a mean reduction of peak plasma concentration of GHB

            Distribution

            Vd: 190-384 mL/kg (GHB)

            Protein bound: <1% (GHB concentrations range 3-300 mcg/mL)

            Metabolism

            Major elimination pathway is by producing carbon dioxide and water via the tricarboxylic acid (Krebs) cycle and secondarily by beta-oxidation

            Primary pathway involves a cytosolic NADP+-linked enzyme, GHB dehydrogenase, that catalyzes the conversion of sodium oxybate to succinic semialdehyde, which is then biotransformed to succinic acid by succinic semialdehyde dehydrogenase

            Succinic acid enters the Krebs cycle where it is metabolized to carbon dioxide and water

            No active metabolites identified

            Elimination

            Half-life: 0.66 hr

            Excretion

            • Urine: <5% (unchanged)
            • Feces: Negligible
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            Administration

            Oral Administration

            Prepare both doses prior to bedtime

            Dilute each dose with ~1/4 cup (~60 mL) of water in the provided empty pharmacy containers

            Take first nightly dose at least 2 hr after eating and second nightly dose 2.5-4 hr after the first dose

            Take each dose while in bed and lie down immediately after dosing, and remain in bed after each administration

            Patients may need to set an alarm to awaken for the second dose

            If second dose is missed, skip dose and do not administer again until the following night; do not take both doses at one time

            Storage

            Undiluted oral solution: Store at 25ºC (77ºF); excursions permitted to 15-30ºC (59-86ºF)

            Diluted oral solution: Use within 24 hr once diluted

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            Formulary

            FormularyPatient Discounts

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            The above information is provided for general informational and educational purposes only. Individual plans may vary and formulary information changes. Contact the applicable plan provider for the most current information.

            Tier Description
            1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
            2 This drug is available at a middle level co-pay. Most commonly, these are "preferred" (on formulary) brand drugs.
            3 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs.
            4 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            5 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            6 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            NC NOT COVERED – Drugs that are not covered by the plan.
            Code Definition
            PA Prior Authorization
            Drugs that require prior authorization. This restriction requires that specific clinical criteria be met prior to the approval of the prescription.
            QL Quantity Limits
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            Drugs that have step therapy associated with each prescription. This restriction typically requires that certain criteria be met prior to approval for the prescription.
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            Medscape prescription drug monographs are based on FDA-approved labeling information, unless otherwise noted, combined with additional data derived from primary medical literature.