Xywav

What Is Xywav?

Xywav (calcium, magnesium, potassium, and sodium oxybates) is a central nervous system depressant indicated for the treatment of cataplexy or excessive daytime sleepiness (EDS) in patients 7 years of age and older with narcolepsy.

What Are Side Effects of Xywav?

Side effects of Xywav include:

• headache,
• nausea,
• dizziness,
• decreased appetite,
• abnormal sleep behaviors (parasomnia),
• diarrhea,
• increased sweating,
• anxiety,
• vomiting
,
• bed wetting (in children), and
• weight loss

Dosage for Xywav

The adult starting dose of Xywav is 4.5 g per night orally, divided into two doses. Titrate to effect in increments of up to 1.5 g per night per week. The recommended dosage range of Xywav for adults is 6 g to 9 g per night orally. The recommended pediatric starting dosage, titration regimen, and maximum total nightly dosage of Xywav are based on body weight.

Xywav In Children

The safety and effectiveness of Xywav for the treatment of cataplexy or excessive daytime sleepiness in pediatric patients 7 years of age and older with narcolepsy have been established. Xywav has not been studied in a pediatric clinical trial. Safety and effectiveness of Xywav in pediatric patients below the age of 7 years have not been established.

What Drugs, Substances, or Supplements Interact with Xywav?

Xywav may interact with other medicines such as:

• divalproex sodium,
• alcohol,
• sedative hypnotics, and
• other central nervous system (CNS) depressants

Tell your doctor all medications and supplements you use.

Xywav During Pregnancy and Breastfeeding

Tell your doctor if you are pregnant or plan to become pregnant before using Xywav; it may harm a fetus. Xywav passes into breast milk but its effects on nursing infants are unknown. Consult your doctor before breastfeeding.

Additional Information

Our Xywav (calcium, magnesium, potassium, and sodium oxybates) Oral Solution, CIII Side Effects Drug Center provides a comprehensive view of available drug information on the potential side effects when taking this medication.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

 

Xywav Consumer Information

Get emergency medical help if you have signs of an allergic reaction: hives; difficult breathing; swelling of your face, lips, tongue, or throat.

Call your doctor at once if you have:

• weak or shallow breathing, breathing that stops for short periods of time;
• severe drowsiness, feeling light-headed;
• sleepwalking (may result in an injury), waking and confused behavior at night;
• a seizure;
• depression, anxiety, unusual or unpleasant thoughts;
• feelings of low self-worth, loss of interest in things you once enjoyed;
• confusion, paranoia, hallucinations (seeing or hearing things);
• increased tiredness, trouble concentrating; or
• suicidal thoughts or actions.

Common side effects may include:

• falling asleep quickly even while standing or getting up from bed;
• sleepwalking;
• drowsiness, dizziness, headache;
• bedwetting (in children);
• sweating, anxiety; or
• nausea, vomiting, diarrhea, loss of appetite, weight loss.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Read the entire detailed patient monograph for Xywav (Calcium, Magnesium, Potassium, and Sodium Oxybates Oral Solution)

 

Xywav Professional Information

SIDE EFFECTS

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

• CNS depression [see WARNINGS AND PRECAUTIONS]
• Abuse and Misuse [see WARNINGS AND PRECAUTIONS]
• Respiratory Depression and Sleep-Disordered Breathing [see WARNINGS AND PRECAUTIONS]
• Depression and Suicidality [see WARNINGS AND PRECAUTIONS]
• Other Behavioral or Psychiatric Adverse Reactions [see WARNINGS AND PRECAUTIONS]
• Parasomnias [see WARNINGS AND PRECAUTIONS]

Clinical Trials Experience

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

Adult Patients

The safety of XYWAV was evaluated in a 16-week double-blind placebo-controlled randomized-withdrawal study in patients with narcolepsy with cataplexy (Study 1), which was followed by an open-label extension phase lasting 24 weeks [see Clinical Studies]. Study 1 included an open-label titration period (OL OTTP), a stable-dose period (SDP), and a double-blind, placebo-controlled, randomized-withdrawal period (DB RWP). A total of 201 patients, ages 18 to 70 years, received XYWAV at individually titrated doses for 14 weeks, followed by randomization to XYWAV or matching placebo for 2 weeks of treatment. The mean exposure to XYWAV during this study, including titration, the randomized withdrawal period, and the open-label extension, was 151 days. In patients who remained on treatment, adverse reactions tended to occur early and diminish over time.

Adverse Reactions Leading to Treatment Discontinuation

In Study 1, 9 of 201 patients (4%) reported adverse reactions that led to withdrawal from the study (anxiety, decreased appetite, depressed mood, depression, fatigue, headache, irritability, nausea, pain in extremity, parasomnia, somnolence, and vomiting). The most common adverse reaction leading to discontinuation was nausea (1.5%). The majority of adverse reactions leading to discontinuation began during the first few weeks of treatment.

Commonly Observed Adverse Reactions

The most common adverse reactions in Study 1 (incidence ≥ 5% of XYWAV-treated patients) were headache, nausea, dizziness, decreased appetite, parasomnia, diarrhea, hyperhidrosis, anxiety, and vomiting.

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

Table 3 lists adverse reactions observed in the open-label titration and stable dose periods of Study 1 that occurred at a frequency of 2% or greater in adult patients treated with XYWAV.

Table 3: Adverse Reactions Occurring in ≥2% of Adult Patients Treated with XYWAV in the Open-Label Titration and Stable Dose Periods in Study 1*

Adverse Reaction	Open-Label Titration Period + Stable Dose Period (14 weeks) (N=201) %
Headache	20
Nausea	13
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
*Adverse reactions related to XYWAV were reported less frequently, as an overall incidence, in patients on Xyrem at study entry than in Xyrem-naïve patients. †Includes abnormal dreams, abnormal sleep-related event, rapid eye movements sleep abnormal, sleep paralysis, sleep talking, sleep terror, sleep-related eating disorder, somnambulism ‡Includes hyperhidrosis and night sweats §Includes anxiety, agitation, panic attack, tension ¶Includes fatigue and asthenia

Adverse Reactions Observed in Clinical Studies with Xyrem (≥2%), but not in Study 1, and Which May Be Relevant for XYWAV

Pain, feeling drunk, pain in extremity, cataplexy, disturbance in attention, sleep paralysis, and disorientation.

Pediatric Patients (7 Years Of Age And Older)

In the pediatric clinical trial with Xyrem (same active moiety as XYWAV), 104 patients aged 7 to 17 years (37 patients aged 7 to 11 years; 67 patients aged 12 to 17 years) with narcolepsy received Xyrem for up to one year [see Clinical Studies]. This study included an open-label safety continuation period in which eligible patients received Xyrem for up to an additional 2 years. The median and maximum exposure across the entire study were 371 and 987 days, respectively.

Adverse Reactions Leading to Treatment Discontinuation

In the pediatric clinical trial with Xyrem, 7 of 104 patients reported adverse reactions that led to withdrawal from the study (hallucination, tactile; suicidal ideation; weight decreased; sleep apnea syndrome; affect lability; anger, anxiety, depression; and headache).

Adverse Reactions in the Xyrem Pediatric Clinical Trial

The most common adverse reactions (≥5%) were nausea (20%), enuresis (19%), vomiting (18%), headache (17%), weight decreased (13%), decreased appetite (9%), dizziness (8%), and sleepwalking (6%).

Additional information regarding safety in pediatric patients appears in the following sections:

• Respiratory Depression and Sleep-Disordered Breathing [see WARNINGS AND PRECAUTIONS]
• Depression and Suicidality [see WARNINGS AND PRECAUTIONS]
• Other Behavioral or Psychiatric Adverse Reactions [see WARNINGS AND PRECAUTIONS]
• Parasomnias [see WARNINGS AND PRECAUTIONS]

The overall adverse reaction profile of Xyrem in the pediatric clinical trial was similar to that seen in the adult clinical trial program. The safety profile in pediatric patients with XYWAV is expected to be similar to that of adult patients treated with XYWAV and to that of pediatric patients treated with Xyrem.

Postmarketing Experience

The following adverse reactions have been identified during postapproval use of sodium oxybate. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure:

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

*The sudden onset of sleep in patients taking sodium oxybate, including in a standing position or while rising from bed, has led to falls complicated by injuries, in some cases requiring hospitalization.

DRUG INTERACTIONS

Alcohol, Sedative Hypnotics, And CNS Depressants

XYWAV is contraindicated for use in combination with alcohol or sedative hypnotics. Use of other CNS depressants may potentiate the CNS-depressant effects of XYWAV [see WARNINGS AND PRECAUTIONS].

Divalproex Sodium

Concomitant use of sodium oxybate with divalproex sodium results in an increase in systemic exposure to GHB, which was shown to cause a greater impairment on some tests of attention and working memory in a clinical study [see CLINICAL PHARMACOLOGY]. A similar increase in exposure is expected with concomitant use of XYWAV and divalproex sodium; therefore, an initial dose reduction of XYWAV is recommended when used concomitantly with divalproex sodium [see DOSAGE AND ADMINISTRATION]. Prescribers are advised to monitor patient response closely and adjust dose accordingly if concomitant use of XYWAV and divalproex sodium is warranted.

Drug Abuse And Dependence

Controlled Substance

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

Abuse

The active moiety of XYWAV, oxybate, produces dose-dependent central nervous system effects, including hypnotic and positive subjective reinforcing effects. The onset of effect is rapid, enhancing its potential for abuse or misuse.

Drug abuse is the intentional non-therapeutic use of a drug product or substance, even once, for its desirable psychological or physiological effects. Misuse is the intentional use, for therapeutic purposes of a drug by an individual in a way other than prescribed by a health care provider or for whom it was not prescribed. Drug misuse and abuse may occur with or without progression to addiction. Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that may include a strong desire to take the drug, difficulties in controlling drug use (e.g., continuing drug use despite harmful consequences, giving a higher priority to drug use than other activities and obligations), and possible tolerance or physical dependence.

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

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

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

Dependence

Dependence

Physical dependence is a state that develops as a result of physiological adaptation in response to repeated drug use, manifested by withdrawal signs and symptoms after abrupt discontinuation or a significant dose reduction of a drug. There have been case reports of withdrawal, ranging from mild to severe, following discontinuation of illicit use of GHB at frequent repeated doses (18 g to 250 g per day) in excess of the recommended dosage range. Signs and symptoms of GHB withdrawal following abrupt discontinuation included insomnia, restlessness, anxiety, psychosis, lethargy, nausea, tremor, sweating, muscle cramps, tachycardia, headache, dizziness, rebound fatigue and sleepiness, confusion, and, particularly in the case of severe withdrawal, visual hallucinations, agitation, and delirium. These symptoms generally abated in 3 to 14 days. In cases of severe withdrawal, hospitalization may be required. The discontinuation effects of XYWAV have not been systematically evaluated in controlled clinical trials. In the clinical trial experience with Xyrem in narcolepsy/cataplexy patients at recommended doses, two patients reported anxiety and one reported insomnia following abrupt discontinuation at the termination of the clinical trial; in the two patients with anxiety, the frequency of cataplexy had increased markedly at the same time. In the XYWAV clinical trial in adult narcolepsy/cataplexy patients at recommended doses, one patient reported insomnia following abrupt discontinuation of XYWAV.

Tolerance

Tolerance is a physiological state characterized by a reduced response to a drug after repeated administration (i.e., a higher dose of a drug is required to produce the same effect that was once obtained at a lower dose). Tolerance to XYWAV has not been systematically studied in controlled clinical trials. There have been some case reports of symptoms of tolerance developing after illicit use at dosages far in excess of the recommended XYWAV dosage regimen. Clinical studies of sodium oxybate in the treatment of alcohol withdrawal suggest a potential cross-tolerance with alcohol. The safety and effectiveness of XYWAV in the treatment of alcohol withdrawal have not been established.

Read the entire FDA prescribing information for Xywav (Calcium, Magnesium, Potassium, and Sodium Oxybates Oral Solution)