Xywav (calcium, magnesium, potassium, sodium oxybates)

Brand name: Xywav

Generic: calcium, magnesium, potassium, sodium oxybates

Xywav is a prescription medicine used to treat the following symptoms in people 7 years of age or older with narcolepsy:

• sudden onset of weak or paralyzed muscles (cataplexy), or
• excessive daytime sleepiness (EDS)

It is not known if Xywav is safe and effective in children less than 7 years of age.

WARNING

CENTRAL NERVOUS SYSTEM DEPRESSION and ABUSE AND MISUSE.

Central Nervous System Depression

Xywav is a CNS depressant. Clinically significant respiratory depression and obtundation may occur in patients treated with Xywav at recommended doses. Many patients who received Xywav during clinical trials in narcolepsy were receiving central nervous system stimulants.

Abuse and Misuse

The active moiety of Xywav is oxybate or gamma-hydroxybutyrate (GHB). 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.

Because of the risks of CNS depression and abuse and misuse, Xywav is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the Xywav and Xyrem REMS.

What are the serious side effects of Xywav?

Xywav can cause serious side effects, including:

• breathing problems, including:
  • slower breathing.
  • trouble breathing.
  • short periods of not breathing while sleeping (sleep apnea). People who already have breathing or lung problems have a higher chance of having breathing problems when they take Xywav.
• mental health problems, including:
  • confusion
  • seeing or hearing things that are not real (hallucinations)
  • unusual or disturbing thoughts (abnormal thinking)
  • feeling anxious or upset
  • depression
  • thoughts of killing yourself or trying to kill yourself
  • increased tiredness
  • feelings of guilt or worthlessness
  • difficulty concentrating

Call your doctor right away if you have or your child has symptoms of mental health problems, or achange in weight or appetite.

• sleepwalking. Sleepwalking can cause injuries. Call your doctor if you start or your child starts sleepwalking. Your doctor should check you or your child.

What are the common side effects of Xywav?

The most common side effects of Xywav in adults include:

• headache
• diarrhea
• nausea
• excessive sweating (hyperhidrosis)
• dizziness
• anxiety
• decreased appetite
• vomiting
• parasomnia (a sleep disorder that can include abnormal dreams, abnormal rapid eye movement (REM) sleep, sleep paralysis, sleep talking, sleep terror, sleep-related eating disorder, sleep walking and other abnormal sleep-related events)

The most common side effects of Xywav in children include:

• bedwetting
• weight decrease
• nausea
• decreased appetite
• headache
• dizziness
• vomiting

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

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

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

• 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.

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.

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.
• 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. Prescribers are advised to monitor patient response closely and adjust dose accordingly if concomitant use of Xywav and divalproex sodium is warranted.

Adult Dosing Information

The recommended starting dosage is 4.5 grams (g) per night administered orally, divided into two doses: 2.25 g at bedtime and 2.25 g taken 2.5 to 4 hours later (see Table 1). Increase the dosage by up to 1.5 g per night per week (e.g., 0.75 g at bedtime and 0.75 g taken 2.5 to 4 hours later), to the recommended dosage range of 6 g to 9 g per night. The dosage may be gradually titrated based on efficacy and tolerability. Some patients may achieve better responses with unequal doses at bedtime and 2.5 to 4 hours later. Doses higher than 9 g per night have not been studied and ordinarily should not be administered.

Table 1: Recommended Adult Xywav Dosage Regimen (g = grams)

Pediatric Dosing Information

For pediatric patients 7 years of age and older, Xywav is administered orally twice per night. The recommended starting pediatric dosage, titration regimen, and maximum total nightly dosage are based on patient weight, as specified in Table 2. The dosage may be gradually titrated based on efficacy and tolerability. Doses higher than 9 g per night have not been studied and ordinarily should not be administered.

Table 2: Recommended Xywav Dosage for Patients 7 Years of Age and Older*

Important Administration Instructions For All Patients

• The total nightly dosage of Xywav is divided into two doses. Prepare both doses of Xywav prior to bedtime. Prior to ingestion, each dose of Xywav should be diluted with approximately ¼ cup (approximately 60 mL) of water in the empty pharmacy containers provided. Solutions prepared following dilution should be consumed within 24 hours.
• Take the first nightly dose of Xywav at least 2 hours after eating. Take the second nightly dose 2.5 to 4 hours after the first dose.
• Patients should take each dose of Xywav while in bed and lie down immediately after dosing, and remain in bed following ingestion of each dose. Xywav may cause patients to fall asleep abruptly without first feeling drowsy.
• Patients will often fall asleep within 5 minutes of taking Xywav, and will usually fall asleep within 15 minutes, though the time it takes any individual patient to fall asleep may vary from night to night.
• Patients may need to set an alarm to awaken for the second dose. If the second dose is missed, that dose should be skipped and Xywav should not be taken again until the next night. Two Xywav doses should never be taken at one time.

Patients Transitioning From Xyrem To Xywav

• On the first night of dosing with Xywav, initiate treatment at the same dose (gram for gram) and regimen as Xyrem. Titrate as needed based on efficacy and tolerability.

Dosage Modification In Patients With Hepatic Impairment

• The recommended starting dosage in patients with hepatic impairment is one-half of the original dosage per night administered orally, divided into two doses.

Dosage Adjustment With Co-Administration Of Divalproex Sodium

• When initiating divalproex sodium in patients taking a stable dosage of Xywav, a reduction of the Xywav dosage by at least 20% is recommended with initial concomitant use. When initiating Xywav in patients already taking divalproex sodium, a lower starting dosage of Xywav is recommended. Subsequently, the dosage of Xywav can be adjusted based on individual clinical response and tolerability.

Do not take Xywav if you or your child:

• takes other sleep medicines or sedatives (medicines that cause sleepiness)
• drinks alcohol
• has a rare problem called succinic semialdehyde dehydrogenase deficiency

Before taking Xywav, tell your doctor about all medical conditions, including if you or your child:

• have a history of drug abuse.
• have short periods of not breathing while sleeping (sleep apnea).
• has trouble breathing or has lung problems. You or your child may have a higher chance of having serious breathing problems when taking Xywav.
• have or had depression or has tried to harm yourself or themselves. You or your child should be watched carefully for new symptoms of depression.
• has or had behavior or other psychiatric problems such as:
  • anxiety
  • seeing or hearing things that are not real (hallucinations)
  • feeling more suspicious (paranoia)
  • being out of touch with reality (psychosis)
  • acting aggressive
  • agitation
• have liver problems.
• are pregnant or plan to become pregnant. It is not known if Xywav can harm your unborn baby.
• are breastfeeding or plan to breastfeed. Xywav passes into breast milk. You and your doctor should decide if you or your child will take Xywav or breastfeed.

Tell your doctor about all the medicines you take or your child takes, including prescription and over-the-counter medicines, vitamins, and herbal supplements.

Especially, tell your doctor if you take or your child takes other medicines to help you or your child sleep (sedatives). Know the medicines you take or your child takes. Keep a list of them to show your doctor and pharmacist when you get or your child gets a new medicine.