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Health Considerations in Narcolepsy

There can be more to narcolepsy than the symptoms1-3

Narcolepsy is a chronic neurologic condition that typically warrants long-term treatment.2,4 The cardinal symptom is excessive daytime sleepiness,5 and approximately 70% of patients are also believed to have cataplexy.6 However, there can be more to narcolepsy than the symptoms.1-3

 

Increased prevalence of certain comorbidities has been observed in patients with narcolepsy7

The Burden of Narcolepsy Disease (BOND) study was a retrospective medical claims data analysis including a total of 9312 people with narcolepsy (≥18 years of age, continuously insured between 2006 and 2010) and 46,559 matched controls. Controls without narcolepsy were matched 5:1 on age, sex, region, and payer. The objective of the study was to evaluate medical comorbidity patterns in people with narcolepsy.7

Comorbidites with an increased prevalence in patients with narcolepsy vs controls include7:

  • Other sleep disorders, including sleep apnea, restless leg syndrome, periodic limb movement disorder, and REM behavior disorder
  • Headache/migraine
  • Mood disorders
  • Diabetes
  • Anxiety disorders
  • Cardiovascular diseases and events

Prevalence of cardiovascular diseases in patients with narcolepsy vs controls: the BOND study7

CARDIOVASCULAR DISEASES

Cardiovascular diseases had high prevalence in both narcolepsy and control groups, but they were 16.6% higher in the narcolepsy group7

 

*NOS = not otherwise specified.

 

INCREASED RATES OF CARDIOVASCULAR EVENTS AND CONDITIONS WERE OBSERVED IN PATIENTS WITH NARCOLEPSY7*

*Based on a retrospective analysis of 5 years of US medical claims (2006-2010) for patients with a diagnosis of narcolepsy (identified by ICD-9 narcolepsy diagnosis codes) vs matched controls.7

  • Increased prevalence of cardiovascular comorbidities in patients with narcolepsy may explain this increased rate7-9

Some risk factors for cardiovascular disease are modifiable in the general population10-13

SMOKING

Smoking is a major risk factor for cardiovascular disease (CVD) and stroke. Smoking cessation reduces the risk of cardiovascular morbidity and mortality.11

 

PHYSICAL ACTIVITY

Higher levels of physical activity are associated with fewer cardiovascular events.10,11,14

 

WEIGHT

Even a moderate 5% weight loss has considerable health benefits. Additional weight loss may further improve cardiometabolic outcomes.15

 

DIET

A healthy diet should be rich in fruits, vegetables, whole grains, low-fat dairy products with reduced saturated and trans fats, and reduced sodium intake.10-12,16

 

SODIUM INTAKE

For most adults, current American Heart Association guidelines recommend a dietary sodium reduction of at least 1000 mg/day.12,17

References:

  1. Thorpy MJ, Dauvilliers Y. Clinical and practical considerations in the pharmacologic management of narcolepsy. Sleep Med. 2015;16(1):9-18.
  2. Thorpy MJ, Hiller G. The medical and economic burden of narcolepsy: implications for managed care. Am Health Drug Benefits. 2017;10(5):233-241.
  3. Thorpy M, Morse AM. Reducing the clinical and socioeconomic burden of narcolepsy by earlier diagnosis and effective treatment. Sleep Med Clin. 2017;12(7):61-71.
  4. Narcolepsy fact sheet. National Institute of Neurological Disorders and Stroke website. https://www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Fact-Sheets/Narcolepsy-Fact-Sheet. Updated March 16, 2020. Accessed September 15, 2020.
  5. American Academy of Sleep Medicine. Central disorders of hypersomnolence. In: The International Classification of Sleep Disorders – Third Edition (ICSD-3) Online Version. Darien, IL: American Academy of Sleep Medicine; 2014.
  6. Overeem S. The clinical features of cataplexy. In: Baumann CR, Bassetti CL, Scammell TE, eds. Narcolepsy: Pathophysiology, Diagnosis, and Treatment. New York, NY: Springer Science+Business Media, LLC; 2011:283-290.
  7. Black J, Reaven NL, Funk SE, et al. Medical comorbidity in narcolepsy: findings from the Burden of Narcolepsy Disease (BOND) study. Sleep Med. 2017;33:13-18.
  8. Ohayon MM. Narcolepsy is complicated by high medical and psychiatric comorbidities: a comparison with the general population. Sleep Med. 2013;14(6):488-492.
  9. Cohen A, Mandrekar J, St Louis EK, Silber MH, Kotagal S. Comorbidities in a community sample of narcolepsy. Sleep Med. 2018;43:14-18.
  10. Lloyd-Jones DM, Hong Y, Labarthe D, et al. Defining and setting national goals for cardiovascular health promotion and disease reduction: the American Heart Association’s strategic Impact Goal through 2020 and beyond. Circulation. 2010;121(4):586-613.
  11. Benjamin EJ, Muntner P, Alonso A, et al; American Heart Association Council on Epidemiology and Prevention Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics—2019 update: a report from the American Heart Association. Circulation. 2019;139(10):e56-e528.
  12. Jackson SL, King SM, Zhao L, Cogswell ME. Prevalence of excess sodium intake in the United States—NHANES, 2009-2012. MMWR Morb Mortal Wkly Rep. 2016;64(52):1393-1397.
  13. Patel SA, Narayan KM, Ali MK, Mehta NK. Interstate variation in modifiable risk factors and cardiovascular mortality in the United States. PLoS One. 2014;9(7):e101531.
  14. Pinckard K, Baskin KK, Stanford Kl. Effects of exercise to improve cardiovascular health. Front Cardiovasc Med. 2019;6:69.
  15. Magkos F, Fraterrigo G, Yoshino J, et al. Effects of moderate and subsequent progressive weight loss on metabolic function and adipose tissue biology in humans with obesity. Cell Metab. 2016;23(4):591-601.
  16. Whelton PK, Carey RM, Aronow WS, et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol. 2018;71(19):e127-e248.
  17. Arnett DK, Blumenthal RS, Albert MA, et al. 2019 ACC/AHA guideline on the primary prevention of cardiovascular disease: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol. 2019;74(10):1376-1414.

INDICATIONS AND USAGE

XYWAVTM (calcium, magnesium, potassium, and sodium oxybates) oral solution, 0.5 g/mL total salts (equivalent to 0.413 g/mL of oxybate) is indicated for the treatment of cataplexy or excessive daytime sleepiness (EDS) in patients 7 years of age and older with narcolepsy.

Important Safety Information

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 CNS 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.

 

Contraindications

XYWAV is contraindicated

  • in combination with sedative hypnotics or alcohol and
  • in patients with succinic semialdehyde dehydrogenase deficiency.

 

Warnings and Precautions

Central Nervous System Depression

The concurrent use of XYWAV with other CNS depressants, including but not limited to opioid analgesics, benzodiazepines, sedating antidepressants or antipsychotics, sedating anti-epileptic drugs, general anesthetics, muscle relaxants, and/or illicit CNS depressants, may increase the risk of respiratory depression, hypotension, profound sedation, syncope, and death. If use of these CNS depressants in combination with XYWAV is required, dose reduction or discontinuation of one or more CNS depressants (including XYWAV) should be considered. In addition, if short-term use of an opioid (eg, post- or perioperative) is required, interruption of treatment with XYWAV should be considered.

 

After first initiating treatment and until certain that XYWAV does not affect them adversely (eg, impair judgment, thinking, or motor skills), caution patients against hazardous activities requiring complete mental alertness or motor coordination such as operating hazardous machinery, including automobiles or airplanes. Also caution patients against these hazardous activities for at least 6 hours after taking XYWAV. Patients should be queried about CNS depression-related events upon initiation of XYWAV therapy and periodically thereafter.

 

Abuse and Misuse

XYWAV is a Schedule III controlled substance. The active moiety of XYWAV is oxybate, also known as gamma hydroxybutyrate (GHB), a Schedule I controlled substance. Abuse 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. 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 (eg, assault victim). Physicians should carefully evaluate patients for a history of drug abuse and follow such patients closely.

 

XYWAV and XYREM REMS Program

Because of the risks of central nervous system depression and abuse and misuse, XYWAV is available only through a restricted distribution program called the Xywav and Xyrem REMS Program.

Notable requirements of the Xywav and Xyrem REMS Program include the following:

  • Healthcare Providers who prescribe XYWAV are specially certified
  • XYWAV will be dispensed only by the central pharmacy that is specially certified
  • XYWAV 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.

 

Respiratory Depression and Sleep-Disordered Breathing

XYWAV may impair respiratory drive, especially in patients with compromised respiratory function. In overdoses of oxybate and with illicit use of GHB, life-threatening respiratory depression has been reported. Increased apnea and reduced oxygenation may occur with XYWAV administration in adult and pediatric patients. A significant increase in the number of central apneas and clinically significant oxygen desaturation may occur in patients with obstructive sleep apnea treated with XYWAV. 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.

 

Depression and Suicidality

In a randomized-withdrawal clinical trial in adult patients with narcolepsy (n=201), depression and depressed mood were reported in 3% and 4%, respectively, of patients treated with XYWAV. Two patients (1%) discontinued XYWAV because of depression. In most cases, no change in XYWAV treatment was required. In clinical trials of Xyrem (same active moiety as XYWAV) in adult patients with narcolepsy (n=781), adverse reactions of depression were reported by 7% of 781 patients treated with Xyrem, with four patients (<1%) discontinuing because of depression. In most cases, no change in Xyrem treatment was required. In clinical trials of Xyrem (same active moiety as XYWAV) in adult patients with narcolepsy (n=781), there were two suicides and two attempted suicides in patients treated with Xyrem, including three patients with a previous history of depressive psychiatric disorder. Of the two suicides, one patient used Xyrem in conjunction with other drugs. Xyrem was not involved in the second suicide.

 

In the pediatric clinical trial with Xyrem (same active moiety as XYWAV) in patients with narcolepsy (n=104), one patient experienced suicidal ideation while taking Xyrem. The emergence of depression in patients treated with XYWAV requires careful and immediate evaluation. Monitor patients for the emergence of increased depressive symptoms and/or suicidality while taking XYWAV, which require careful and immediate evaluation.

 

Other Behavioral or Psychiatric Adverse Reactions

In a randomized-withdrawal clinical trial in adult patients, confusion occurred in 1% of patients treated with XYWAV and anxiety occurred in 5% of patients treated with XYWAV. One patient experienced visual hallucinations and confusion after ingesting approximately 9 grams of XYWAV. Other neuropsychiatric reactions reported in clinical trials of Xyrem (same active moiety as XYWAV) in adult patients with narcolepsy and in the postmarketing setting included hallucinations, paranoia, psychosis, aggression, and agitation.

 

In a pediatric clinical trial with Xyrem (same active moiety as XYWAV) in patients with narcolepsy, neuropsychiatric reactions, including acute psychosis, confusion, and anxiety, were reported while taking Xyrem.

 

The emergence or increase in the occurrence of behavioral or psychiatric events in patients taking XYWAV should be carefully monitored.

 

Parasomnias

Parasomnias can occur in patients taking XYWAV.

 

In a randomized-withdrawal clinical trial, parasomnias, including sleepwalking were reported in 6% of adult patients treated with XYWAV. In a clinical trial of Xyrem (same active moiety as XYWAV) in adult patients with narcolepsy, five instances of sleepwalking with potential injury or significant injury were reported. Parasomnias, including sleepwalking, have been reported in a pediatric clinical trial with sodium oxybate (same active moiety as XYWAV) and in postmarketing experience with sodium oxybate. Episodes of sleepwalking should be fully evaluated and appropriate interventions considered.

 

Most Common Adverse Reactions

In the adult clinical trial, in patients with narcolepsy, the most common adverse reactions (incidence ≥5% of XYWAV-treated patients) were headache, nausea, dizziness, decreased appetite, parasomnia, diarrhea, hyperhidrosis, anxiety, and vomiting.

 

In the pediatric clinical trial with Xyrem (same active moiety as XYWAV), that included pediatric patients 7 to 17 years of age with narcolepsy, the most common adverse reactions (≥5%) were enuresis (18%), nausea (17%), headache (16%), vomiting (16%), weight decreased (12%), decreased appetite (8%), and dizziness (6%). 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.

 

Additional Adverse Reactions

Additional adverse reactions that occurred in ≥2% of adult patients treated with XYWAV in the Open-Label Titration and Stable Dose Periods of the randomized-withdrawal study in adult patients with narcolepsy with cataplexy (Study 1) were fatigue, dry mouth, depressed mood, enuresis, irritability, paresthesia, depression, tremor, somnolence, and muscle spasms.

 

Additional adverse reactions that occurred in ≥2% of patients in clinical studies with Xyrem (but not in Study 1) and which may be relevant for XYWAV, were pain, feeling drunk, pain in extremity, cataplexy, disturbance in attention, sleep paralysis, and disorientation.

 

Discontinuation: In a randomized-withdrawal clinical trial 9 of 201 adult 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.

 

In the pediatric clinical trial with Xyrem (same active moiety as XYWAV), 5 of 104 patients reported adverse reactions that led to withdrawal from the study (hallucination, tactile; suicidal ideation; weight decreased; sleep apnea syndrome; and affect lability).

 

Drug Interactions

XYWAV should not be used in combination with alcohol or sedative hypnotics. Use of other CNS depressants may potentiate the CNS-depressant effects of XYWAV.

 

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.

 

Pregnancy and Lactation

There are no adequate data on the developmental risk associated with the use of XYWAV or sodium oxybate in pregnant women. XYWAV should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. GHB is excreted in human milk after oral administration of sodium oxybate. There is insufficient information on the risk to a breastfed infant, and there is insufficient information on milk production in nursing mothers. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for XYWAV and any potential adverse effects on the breastfed infant from XYWAV or from the underlying maternal condition.

 

Pediatric Use

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. Use of XYWAV in pediatric patients 7 years of age and older with narcolepsy is supported by evidence from an adequate and well-controlled study of sodium oxybate in pediatric patients 7 to 17 years of age, a study in adults showing a treatment effect of XYWAV similar to that observed with sodium oxybate, pharmacokinetic data of sodium oxybate from adult and pediatric patients, and pharmacokinetic data of XYWAV from healthy adult volunteers.

 

Safety and effectiveness of XYWAV in pediatric patients below the age of 7 years have not been established.

 

Geriatric Use

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.

 

Hepatic Impairment

The starting dose of XYWAV should be reduced in patients with liver impairment.

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.

 

Dependence and Tolerance

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 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.

 

Please see full Prescribing Information, including BOXED Warning.

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