Sleep Medicine a Special Report June 2021

Sleep Medicine A Special Report June 2021

MOBILE PHONE RELIANCE ◆ How it’s linked to young adults’ sleep problems in two studies See stories on pages 10-12

OBSTRUCTIVE SLEEP APNEA ◆ DEMENTIA ◆ Papers show New research validates phenotypes associations between disease and in Latinos 21 sleep therapies 22, 25

Published for Clinical Psychiatry News©, Family Practice News©, Internal Medicine News©, Pediatric News©, and Neurology Reviews©.

01ASUPP21Sleep.indd 1 5/17/2021 3:39:20 PM Help your patients living with narcolepsy 92% less sodium than sodium oxybate3 With XYWAV —the ﬁ rst and only lower-sodium oxybate FDA approved XYWAV contains the same active moiety at the same for treating cataplexy or EDS* in concentration as XYREM® (sodium oxybate) oral solution.1,4 patients ages 7 years and older Both contain 0.413 g/mL of oxybate in solution.1,4 1-3 with narcolepsy. Visit XywavHCP.com to sign up for information and learn more about how to start or transition

*Excessive daytime sleepiness. appropriate patients.

INDICATIONS AND USAGE XYWAV™ (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 signiﬁ cant 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.

AVAILABLE FOR PRESCRIPTION!

Consider XYWAV Learn more at Whether a patient is taking XYREM® XywavHCP.com (sodium oxybate) oral solution now or Please see additional Important Safety Information on the following pages and Brief Summary of full Prescribing is new to oxybate treatment. Information, including BOXED Warning.

Sleep_002.indd 2 5/14/21 12:19 PM Help your patients living with narcolepsy 92% less sodium than sodium oxybate3 With XYWAV —the ﬁ rst and only lower-sodium oxybate FDA approved XYWAV contains the same active moiety at the same for treating cataplexy or EDS* in concentration as XYREM® (sodium oxybate) oral solution.1,4 patients ages 7 years and older Both contain 0.413 g/mL of oxybate in solution.1,4 1-3 with narcolepsy. Visit XywavHCP.com to sign up for information and learn more about how to start or transition

*Excessive daytime sleepiness. appropriate patients.

AVAILABLE FOR PRESCRIPTION!

Sleep_003.indd 3 5/14/21 12:19 PM Important Safety Information (continued) XYWAV TM (calcium, magnesium, potassium, and sodium oxybates) oral solution, CIII During polysomnographic evaluation (PSG), central sleep apnea and oxygen desaturation BRIEF SUMMARY OF PRESCRIBING INFORMATION: Consult the full Prescribing were observed in pediatric patients with narcolepsy treated with Xyrem. Contraindications Information for complete product information. Prescribers should be aware that increased central apneas and clinically relevant Initial U.S. Approval: 2002 desaturation events have been observed with sodium oxybate administration in adult and XYWAV is contraindicated in combination with sedative hypnotics or alcohol and in patients with succinic pediatric patients. semialdehyde dehydrogenase defi ciency. WARNING: CENTRAL NERVOUS SYSTEM DEPRESSION In clinical trials of Xyrem in 128 adult patients with narcolepsy, two patients had profound and ABUSE AND MISUSE. CNS depression, which resolved after supportive respiratory intervention. Two other Warnings and Precautions • Central Nervous System Depression patients discontinued sodium oxybate because of severe difficulty breathing and an XYWAV is a CNS depressant, and respiratory depression can occur with XYWAV use increase in obstructive sleep apnea. In two controlled trials assessing PSG measures in • CNS Depression: Use caution when considering the concurrent use with other CNS depressants. If concurrent [see Warnings and Precautions (5.1)(5.4)]. Many patients who received XYWAV during adult patients with narcolepsy, 40 of 477 patients were included with a baseline apnea/ clinical trials in narcolepsy were receiving central nervous system stimulants [see hypopnea index of 16 to 67 events per hour, indicative of mild to severe sleep-disordered use is required, consider dose reduction or discontinuation of one or more CNS depressants (including XYWAV). Clinical Trials (14)]. • Abuse and Misuse breathing. None of the 40 patients had a clinically significant worsening of respiratory Consider interrupting XYWAV treatment if short-term opioid use is required. After fi rst initiating treatment The active moiety of XYWAV is oxybate or gamma-hydroxybutyrate (GHB). Abuse function, as measured by apnea/hypopnea index and pulse oximetry at doses of 4.5 g to and until certain that XYWAV does not affect them adversely, caution patients against hazardous activities or misuse of illicit GHB is associated with CNS adverse reactions, including seizure, 9 g per night. respiratory depression, decreased consciousness, coma, and death [see Warnings and Prescribers should be aware that sleep-related breathing disorders tend to be more requiring complete mental alertness or motor coordination such as operating hazardous machinery, including Precautions (5.2)]. prevalent in obese patients, in men, in postmenopausal women not on hormone automobiles or airplanes. Also caution patients against these hazardous activities for at least 6 hours after taking XYWAV is available only through a restricted program called the XYWAV and XYREM replacement therapy, and among patients with narcolepsy. REMS [see Warnings and Precautions (5.3)]. XYWAV. Patients should be queried about CNS depression-related events upon initiation of XYWAV therapy and 5.5 Depression and Suicidality periodically thereafter. 1 INDICATIONS AND USAGE Depression, and suicidal ideation and behavior can occur in patients treated with XYWAV. XYWAV is indicated for the treatment of cataplexy or excessive daytime sleepiness (EDS) In Study 1, depression and depressed mood were reported in 3% and 4%, respectively, • Abuse and Misuse: XYWAV is a Schedule III controlled substance. The rapid onset of sedation, coupled with in patients 7 years of age and older with narcolepsy. of patients treated with XYWAV. Two patients (1%) discontinued XYWAV because of the amnestic features of GHB particularly when combined with alcohol, has proven to be dangerous for the 4 CONTRAINDICATIONS depression, but in most cases, no change in XYWAV treatment was required. XYWAV is contraindicated for use in: In clinical trials of Xyrem (same active moiety as XYWAV) in adult patients with voluntary and involuntary user (eg, assault victim). • combination with sedative hypnotics [see Warnings and Precautions (5.1)]. narcolepsy (n=781), there were two suicides and two attempted suicides in patients • Respiratory Depression and Sleep-Disordered Breathing: XYWAV may impair respiratory drive, especially • combination with alcohol [see Warnings and Precautions (5.1)]. treated with Xyrem, including three patients with a previous history of depressive • patients with succinic semialdehyde dehydrogenase deficiency [see Clinical Pharmacology psychiatric disorder. Of the two suicides, one patient used Xyrem in conjunction with in patients with compromised respiratory function. In overdoses of oxybate and with illicit use of GHB, life- (12.3)]. other drugs. Xyrem was not involved in the second suicide. Adverse reactions of threatening respiratory depression has been reported. Increased apnea and reduced oxygenation may occur 5 WARNINGS AND PRECAUTIONS depression were reported by 7% of 781 patients treated with Xyrem, with four patients with XYWAV administration in adult and pediatric patients. A signifi cant increase in the number of central 5.1 Central Nervous System Depression (<1%) discontinuing because of depression. In most cases, no change in Xyrem treatment XYWAV is a central nervous system (CNS) depressant. Clinically significant respiratory was required. In a clinical trial with Xyrem in pediatric patients with narcolepsy (n=104), apneas and clinically signifi cant oxygen desaturation may occur in patients with obstructive sleep apnea treated depression and obtundation has occurred in adult patients taking sodium oxybate one patient experienced suicidal ideation and two patients reported depression while with XYWAV. Prescribers should be aware that sleep-related breathing disorders tend to be more prevalent in (same active moiety as XYWAV) at recommended doses in clinical trials and may occur taking Xyrem. in patients treated with XYWAV at recommended doses. XYWAV is contraindicated in The emergence of depression in patients treated with XYWAV requires careful and obese patients, in men, in postmenopausal women not on hormone replacement therapy, and among patients combination with alcohol and sedative hypnotics. The concurrent use of XYWAV with immediate evaluation. Patients with a previous history of a depressive illness and/ with narcolepsy. other CNS depressants, including but not limited to opioid analgesics, benzodiazepines, or suicide attempt should be monitored carefully for the emergence of depressive sedating antidepressants or antipsychotics, sedating anti-epileptic drugs, general symptoms while taking XYWAV. • Depression and Suicidality: In a randomized-withdrawal clinical trial in adult patients with narcolepsy (n=201), anesthetics, muscle relaxants, and/or illicit CNS depressants, may increase the risk of 5.6 Other Behavioral or Psychiatric Adverse Reactions depression and depressed mood were reported in patients treated with XYWAV. In most cases, no change respiratory depression, hypotension, profound sedation, syncope, and death. If use of these CNS depressants in combination with XYWAV is required, dose reduction Other behavioral and psychiatric adverse reactions can occur in patients taking XYWAV. in XYWAV treatment was required. In clinical trials of Xyrem (same active moiety as XYWAV) in adult patients or discontinuation of one or more CNS depressants (including XYWAV) should be In Study 1, confusion occurred in 1% of patients treated with XYWAV and anxiety occurred considered. In addition, if short-term use of an opioid (e.g., post- or perioperative) is in 5% of patients treated with XYWAV. One patient experienced visual hallucinations with narcolepsy (n=781), depression was reported by 7% of Xyrem-treated patients, with four patients (<1%) required, interruption of treatment with XYWAV should be considered. and confusion after ingesting approximately 9 grams of XYWAV. Other neuropsychiatric discontinuing because of depression. In the pediatric clinical trial with Xyrem in patients with narcolepsy (n=104), Healthcare providers should caution patients about operating hazardous machinery, reactions reported in clinical trials of Xyrem (same active moiety as XYWAV) in adult including automobiles or airplanes, until they are reasonably certain that XYWAV does patients with narcolepsy and in the postmarketing setting included hallucinations, one patient experienced suicidal ideation, and two patients reported depression while taking XYREM. Monitor not affect them adversely (e.g., impair judgment, thinking, or motor skills). Patients should paranoia, psychosis, aggression, and agitation. patients for the emergence of increased depressive symptoms and/or suicidality while taking XYWAV, which not engage in hazardous occupations or activities requiring complete mental alertness In a pediatric clinical trial with Xyrem in patients with narcolepsy, neuropsychiatric require careful and immediate evaluation. or motor coordination, such as operating machinery or a motor vehicle or flying an reactions, including acute psychosis, confusion, and anxiety, were reported while taking airplane, for at least 6 hours after taking XYWAV. Patients should be queried about CNS Xyrem. depression-related events upon initiation of XYWAV therapy and periodically thereafter. • Other Behavioral or Psychiatric Adverse Reactions: Monitor patients for impaired motor/cognitive function or the The emergence or increase in the occurrence of behavioral or psychiatric events in XYWAV is available only through a restricted program under a REMS [see Warnings and patients taking XYWAV should be carefully monitored. emergence of or increase in anxiety and/or confusion. The emergence or increase in the occurrence of behavioral Precautions (5.3)]. or psychiatric events in patients taking XYWAV should be carefully monitored. 5.2 Abuse and Misuse 5.7 Parasomnias • Parasomnias: In a randomized-withdrawal clinical trial, parasomnias, including sleepwalking were reported in XYWAV is a Schedule III controlled substance. The active moiety of XYWAV is oxybate, Parasomnias can occur in patients taking XYWAV. also known as gamma-hydroxybutyrate (GHB), a Schedule I controlled substance. Abuse In Study 1, parasomnias, including sleepwalking, were reported in 6% of patients treated adult patients treated with XYWAV. Parasomnias, including sleepwalking, also have been reported in a pediatric of illicit GHB, either alone or in combination with other CNS depressants, is associated with XYWAV. In a clinical trial of Xyrem (same active moiety as XYWAV) in adult patients clinical trial with sodium oxybate (same active moiety as XYWAV) and in postmarketing experience with sodium with CNS adverse reactions, including seizure, respiratory depression, decreases in the with narcolepsy, five instances of sleepwalking with potential injury or significant injury level of consciousness, coma, and death. The rapid onset of sedation, coupled with the were reported. Parasomnias, including sleepwalking, also have been reported in a oxybate. Episodes of sleepwalking should be fully evaluated and appropriate interventions considered. amnestic features of GHB, particularly when combined with alcohol, has proven to be pediatric clinical trial with sodium oxybate and in postmarketing experience with sodium dangerous for the voluntary and involuntary user (e.g., assault victim). Because illicit use oxybate. Most Common Adverse Reactions and abuse of GHB have been reported, healthcare providers should carefully evaluate Episodes of sleepwalking should be fully evaluated and appropriate interventions patients for a history of drug abuse and follow them closely, particularly for signs of considered. In the adult clinical trial, in patients with narcolepsy, the most common adverse reactions (incidence ≥5% misuse or abuse of GHB (including but not limited to increase in size or frequency of of XYWAV-treated patients) were headache, nausea, dizziness, decreased appetite, parasomnia, diarrhea, dosing, drug-seeking behavior, feigned cataplexy) [see Drug Abuse and Dependence 6 ADVERSE REACTIONS (9.2)]. If abuse is suspected, treatment with XYWAV should be discontinued. The following clinically significant adverse reactions appear in other sections of the labeling: hyperhidrosis, anxiety, and vomiting. XYWAV is available only through a restricted program under a REMS [see Warnings and • CNS depression [see Warnings and Precautions (5.1)] Precautions (5.3)]. • Abuse and Misuse [see Warnings and Precautions (5.2)] In the pediatric clinical trial with Xyrem (same active moiety as XYWAV) in patients 7 years of age and older • Respiratory Depression and Sleep-Disordered Breathing [see Warnings and Precautions (5.4)] 5.3 XYWAV and XYREM REMS • Depression and Suicidality [see Warnings and Precautions (5.5)] with narcolepsy, the most common adverse reactions (≥5%) were nausea (20%), enuresis (19%), vomiting (18%), XYWAV is available only through a restricted distribution program called the XYWAV and • Other Behavioral or Psychiatric Adverse Reactions [see Warnings and Precautions (5.6)] headache (17%), weight decreased (13%), decreased appetite (9%), dizziness (8%), and sleepwalking (6%). The safety XYREM REMS because of the risks of central nervous system depression and abuse and • Parasomnias [see Warnings and Precautions (5.7)] misuse [see Warnings and Precautions (5.1, 5.2)]. profi le in pediatric patients with XYWAV is expected to be similar to that of adult patients treated with XYWAV Notable requirements of the XYWAV and XYREM REMS include the following: 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction and to that of pediatric patients treated with Xyrem. • Healthcare Providers who prescribe XYWAV are specially certified rates observed in the clinical trials of a drug cannot be directly compared to rates in the • 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 clinical trials of another drug and may not reflect the rates observed in clinical practice. Please see additional Important Safety Information on previous page and Brief Summary of full Prescribing XYREM REMS with documentation of safe use. Adult Patients Further information is available at www.XYWAVXYREMREMS.com or 1-866-997-3688. The safety of XYWAV was evaluated in a 16-week double-blind placebo-controlled Information, including BOXED Warning, on following pages. randomized-withdrawal study in patients with narcolepsy with cataplexy (Study 1), which 5.4 Respiratory Depression and Sleep-Disordered Breathing TM was followed by an open-label extension phase lasting 24 weeks [see Clinical Studies References: 1. XYWAV (calcium, magnesium, potassium, and sodium oxybates). Prescribing Information. Palo Alto, CA: Jazz XYWAV may impair respiratory drive, especially in patients with compromised respiratory (14.1)]. Study 1 included an open-label titration period (OL OTTP), a stable-dose period Pharmaceuticals, Inc. 2. Thorpy MJ. Recently approved and upcoming treatments for narcolepsy. CNS Drugs. 2020;34(1):9-27. 3. Bogan function. In overdoses of oxybate and with illicit use of GHB, life-threatening respiratory (SDP), and a double-blind, placebo-controlled, randomized-withdrawal period (DB RWP). depression has been reported [see Overdosage (10)]. RK, Thorpy MJ, Dauvilliers Y, et al. Effi cacy and safety of calcium, magnesium, potassium, and sodium oxybates (lower-sodium oxybate A total of 201 patients, ages 18 to 70 years, received XYWAV at individually titrated doses Increased apnea and reduced oxygenation may occur with XYWAV administration in for 14 weeks, followed by randomization to XYWAV or matching placebo for 2 weeks [LXB]; JZP-258) in a placebo-controlled, double-blind, randomized withdrawal study in adults with narcolepsy with cataplexy. Sleep. adult and pediatric patients. A significant increase in the number of central apneas and ® of treatment. The mean exposure to XYWAV during this study, including titration, the Published online October 14, 2020. doi.org/10.1093/sleep/zsaa206. 4. XYREM (sodium oxybate). Prescribing Information. Palo Alto, CA: clinically significant oxygen desaturation may occur in patients with obstructive sleep randomized withdrawal period, and the open-label extension, was 151 days. In patients who Jazz Pharmaceuticals, Inc. apnea treated with XYWAV. remained on treatment, adverse reactions tended to occur early and diminish over time. In a study assessing the respiratory-depressant effects of Xyrem (same active moiety as Adverse Reactions Leading to Treatment Discontinuation XYWAV) at doses up to 9 g per night in 21 adult patients with narcolepsy, no dose-related changes in oxygen saturation were demonstrated in the group as a whole. One of the four In Study 1, 9 of 201 patients (4%) reported adverse reactions that led to withdrawal from patients with preexisting moderate-to-severe sleep apnea had significant worsening of the study (anxiety, decreased appetite, depressed mood, depression, fatigue, headache, the apnea/hypopnea index during treatment. irritability, nausea, pain in extremity, parasomnia, somnolence, and vomiting). The most common adverse reaction leading to discontinuation was nausea (1.5%). The majority In a study assessing the effects of Xyrem 9 g per night in 50 adult patients with of adverse reactions leading to discontinuation began during the first few weeks of obstructive sleep apnea, Xyrem did not increase the severity of sleep-disordered treatment. breathing and did not adversely affect the average duration and severity of oxygen desaturation overall. However, there was a significant increase in the number of central Commonly Observed Adverse Reactions apneas in patients taking Xyrem, and clinically significant oxygen desaturation (≤55%) was The most common adverse reactions in Study 1 (incidence ≥ 5% of XYWAV-treated measured in three patients (6%) after Xyrem administration, with one patient withdrawing patients) were headache, nausea, dizziness, decreased appetite, parasomnia, diarrhea, from the study and two continuing after single brief instances of desaturation. hyperhidrosis, anxiety, and vomiting. ©2021 Jazz Pharmaceuticals plc or its subsidiaries US-XYW-2100028 Rev0321

Sleep_004.indd 2 5/14/21 12:20 PM Important Safety Information (continued) XYWAV TM (calcium, magnesium, potassium, and sodium oxybates) oral solution, CIII During polysomnographic evaluation (PSG), central sleep apnea and oxygen desaturation BRIEF SUMMARY OF PRESCRIBING INFORMATION: Consult the full Prescribing were observed in pediatric patients with narcolepsy treated with Xyrem. Contraindications Information for complete product information. Prescribers should be aware that increased central apneas and clinically relevant Initial U.S. Approval: 2002 desaturation events have been observed with sodium oxybate administration in adult and XYWAV is contraindicated in combination with sedative hypnotics or alcohol and in patients with succinic pediatric patients. semialdehyde dehydrogenase defi ciency. WARNING: CENTRAL NERVOUS SYSTEM DEPRESSION In clinical trials of Xyrem in 128 adult patients with narcolepsy, two patients had profound and ABUSE AND MISUSE. CNS depression, which resolved after supportive respiratory intervention. Two other Warnings and Precautions • Central Nervous System Depression patients discontinued sodium oxybate because of severe difficulty breathing and an XYWAV is a CNS depressant, and respiratory depression can occur with XYWAV use increase in obstructive sleep apnea. In two controlled trials assessing PSG measures in • CNS Depression: Use caution when considering the concurrent use with other CNS depressants. If concurrent [see Warnings and Precautions (5.1)(5.4)]. Many patients who received XYWAV during adult patients with narcolepsy, 40 of 477 patients were included with a baseline apnea/ clinical trials in narcolepsy were receiving central nervous system stimulants [see hypopnea index of 16 to 67 events per hour, indicative of mild to severe sleep-disordered use is required, consider dose reduction or discontinuation of one or more CNS depressants (including XYWAV). Clinical Trials (14)]. • Abuse and Misuse breathing. None of the 40 patients had a clinically significant worsening of respiratory Consider interrupting XYWAV treatment if short-term opioid use is required. After fi rst initiating treatment The active moiety of XYWAV is oxybate or gamma-hydroxybutyrate (GHB). Abuse function, as measured by apnea/hypopnea index and pulse oximetry at doses of 4.5 g to and until certain that XYWAV does not affect them adversely, caution patients against hazardous activities or misuse of illicit GHB is associated with CNS adverse reactions, including seizure, 9 g per night. respiratory depression, decreased consciousness, coma, and death [see Warnings and Prescribers should be aware that sleep-related breathing disorders tend to be more requiring complete mental alertness or motor coordination such as operating hazardous machinery, including Precautions (5.2)]. prevalent in obese patients, in men, in postmenopausal women not on hormone automobiles or airplanes. Also caution patients against these hazardous activities for at least 6 hours after taking XYWAV is available only through a restricted program called the XYWAV and XYREM replacement therapy, and among patients with narcolepsy. REMS [see Warnings and Precautions (5.3)]. XYWAV. Patients should be queried about CNS depression-related events upon initiation of XYWAV therapy and 5.5 Depression and Suicidality periodically thereafter. 1 INDICATIONS AND USAGE Depression, and suicidal ideation and behavior can occur in patients treated with XYWAV. XYWAV is indicated for the treatment of cataplexy or excessive daytime sleepiness (EDS) In Study 1, depression and depressed mood were reported in 3% and 4%, respectively, • Abuse and Misuse: XYWAV is a Schedule III controlled substance. The rapid onset of sedation, coupled with in patients 7 years of age and older with narcolepsy. of patients treated with XYWAV. Two patients (1%) discontinued XYWAV because of the amnestic features of GHB particularly when combined with alcohol, has proven to be dangerous for the 4 CONTRAINDICATIONS depression, but in most cases, no change in XYWAV treatment was required. XYWAV is contraindicated for use in: In clinical trials of Xyrem (same active moiety as XYWAV) in adult patients with voluntary and involuntary user (eg, assault victim). • combination with sedative hypnotics [see Warnings and Precautions (5.1)]. narcolepsy (n=781), there were two suicides and two attempted suicides in patients • Respiratory Depression and Sleep-Disordered Breathing: XYWAV may impair respiratory drive, especially • combination with alcohol [see Warnings and Precautions (5.1)]. treated with Xyrem, including three patients with a previous history of depressive • patients with succinic semialdehyde dehydrogenase deficiency [see Clinical Pharmacology psychiatric disorder. Of the two suicides, one patient used Xyrem in conjunction with in patients with compromised respiratory function. In overdoses of oxybate and with illicit use of GHB, life- (12.3)]. other drugs. Xyrem was not involved in the second suicide. Adverse reactions of threatening respiratory depression has been reported. Increased apnea and reduced oxygenation may occur 5 WARNINGS AND PRECAUTIONS depression were reported by 7% of 781 patients treated with Xyrem, with four patients with XYWAV administration in adult and pediatric patients. A signifi cant increase in the number of central 5.1 Central Nervous System Depression (<1%) discontinuing because of depression. In most cases, no change in Xyrem treatment XYWAV is a central nervous system (CNS) depressant. Clinically significant respiratory was required. In a clinical trial with Xyrem in pediatric patients with narcolepsy (n=104), apneas and clinically signifi cant oxygen desaturation may occur in patients with obstructive sleep apnea treated depression and obtundation has occurred in adult patients taking sodium oxybate one patient experienced suicidal ideation and two patients reported depression while with XYWAV. Prescribers should be aware that sleep-related breathing disorders tend to be more prevalent in (same active moiety as XYWAV) at recommended doses in clinical trials and may occur taking Xyrem. in patients treated with XYWAV at recommended doses. XYWAV is contraindicated in The emergence of depression in patients treated with XYWAV requires careful and obese patients, in men, in postmenopausal women not on hormone replacement therapy, and among patients combination with alcohol and sedative hypnotics. The concurrent use of XYWAV with immediate evaluation. Patients with a previous history of a depressive illness and/ with narcolepsy. other CNS depressants, including but not limited to opioid analgesics, benzodiazepines, or suicide attempt should be monitored carefully for the emergence of depressive sedating antidepressants or antipsychotics, sedating anti-epileptic drugs, general symptoms while taking XYWAV. • Depression and Suicidality: In a randomized-withdrawal clinical trial in adult patients with narcolepsy (n=201), anesthetics, muscle relaxants, and/or illicit CNS depressants, may increase the risk of 5.6 Other Behavioral or Psychiatric Adverse Reactions depression and depressed mood were reported in patients treated with XYWAV. In most cases, no change respiratory depression, hypotension, profound sedation, syncope, and death. If use of these CNS depressants in combination with XYWAV is required, dose reduction Other behavioral and psychiatric adverse reactions can occur in patients taking XYWAV. in XYWAV treatment was required. In clinical trials of Xyrem (same active moiety as XYWAV) in adult patients or discontinuation of one or more CNS depressants (including XYWAV) should be In Study 1, confusion occurred in 1% of patients treated with XYWAV and anxiety occurred considered. In addition, if short-term use of an opioid (e.g., post- or perioperative) is in 5% of patients treated with XYWAV. One patient experienced visual hallucinations with narcolepsy (n=781), depression was reported by 7% of Xyrem-treated patients, with four patients (<1%) required, interruption of treatment with XYWAV should be considered. and confusion after ingesting approximately 9 grams of XYWAV. Other neuropsychiatric discontinuing because of depression. In the pediatric clinical trial with Xyrem in patients with narcolepsy (n=104), Healthcare providers should caution patients about operating hazardous machinery, reactions reported in clinical trials of Xyrem (same active moiety as XYWAV) in adult including automobiles or airplanes, until they are reasonably certain that XYWAV does patients with narcolepsy and in the postmarketing setting included hallucinations, one patient experienced suicidal ideation, and two patients reported depression while taking XYREM. Monitor not affect them adversely (e.g., impair judgment, thinking, or motor skills). Patients should paranoia, psychosis, aggression, and agitation. patients for the emergence of increased depressive symptoms and/or suicidality while taking XYWAV, which not engage in hazardous occupations or activities requiring complete mental alertness In a pediatric clinical trial with Xyrem in patients with narcolepsy, neuropsychiatric require careful and immediate evaluation. or motor coordination, such as operating machinery or a motor vehicle or flying an reactions, including acute psychosis, confusion, and anxiety, were reported while taking airplane, for at least 6 hours after taking XYWAV. Patients should be queried about CNS Xyrem. depression-related events upon initiation of XYWAV therapy and periodically thereafter. • Other Behavioral or Psychiatric Adverse Reactions: Monitor patients for impaired motor/cognitive function or the The emergence or increase in the occurrence of behavioral or psychiatric events in XYWAV is available only through a restricted program under a REMS [see Warnings and patients taking XYWAV should be carefully monitored. emergence of or increase in anxiety and/or confusion. The emergence or increase in the occurrence of behavioral Precautions (5.3)]. or psychiatric events in patients taking XYWAV should be carefully monitored. 5.2 Abuse and Misuse 5.7 Parasomnias • Parasomnias: In a randomized-withdrawal clinical trial, parasomnias, including sleepwalking were reported in XYWAV is a Schedule III controlled substance. The active moiety of XYWAV is oxybate, Parasomnias can occur in patients taking XYWAV. also known as gamma-hydroxybutyrate (GHB), a Schedule I controlled substance. Abuse In Study 1, parasomnias, including sleepwalking, were reported in 6% of patients treated adult patients treated with XYWAV. Parasomnias, including sleepwalking, also have been reported in a pediatric of illicit GHB, either alone or in combination with other CNS depressants, is associated with XYWAV. In a clinical trial of Xyrem (same active moiety as XYWAV) in adult patients clinical trial with sodium oxybate (same active moiety as XYWAV) and in postmarketing experience with sodium with CNS adverse reactions, including seizure, respiratory depression, decreases in the with narcolepsy, five instances of sleepwalking with potential injury or significant injury level of consciousness, coma, and death. The rapid onset of sedation, coupled with the were reported. Parasomnias, including sleepwalking, also have been reported in a oxybate. Episodes of sleepwalking should be fully evaluated and appropriate interventions considered. amnestic features of GHB, particularly when combined with alcohol, has proven to be pediatric clinical trial with sodium oxybate and in postmarketing experience with sodium dangerous for the voluntary and involuntary user (e.g., assault victim). Because illicit use oxybate. Most Common Adverse Reactions and abuse of GHB have been reported, healthcare providers should carefully evaluate Episodes of sleepwalking should be fully evaluated and appropriate interventions patients for a history of drug abuse and follow them closely, particularly for signs of considered. In the adult clinical trial, in patients with narcolepsy, the most common adverse reactions (incidence ≥5% misuse or abuse of GHB (including but not limited to increase in size or frequency of of XYWAV-treated patients) were headache, nausea, dizziness, decreased appetite, parasomnia, diarrhea, dosing, drug-seeking behavior, feigned cataplexy) [see Drug Abuse and Dependence 6 ADVERSE REACTIONS (9.2)]. If abuse is suspected, treatment with XYWAV should be discontinued. The following clinically significant adverse reactions appear in other sections of the labeling: hyperhidrosis, anxiety, and vomiting. XYWAV is available only through a restricted program under a REMS [see Warnings and • CNS depression [see Warnings and Precautions (5.1)] Precautions (5.3)]. • Abuse and Misuse [see Warnings and Precautions (5.2)] In the pediatric clinical trial with Xyrem (same active moiety as XYWAV) in patients 7 years of age and older • Respiratory Depression and Sleep-Disordered Breathing [see Warnings and Precautions (5.4)] 5.3 XYWAV and XYREM REMS • Depression and Suicidality [see Warnings and Precautions (5.5)] with narcolepsy, the most common adverse reactions (≥5%) were nausea (20%), enuresis (19%), vomiting (18%), XYWAV is available only through a restricted distribution program called the XYWAV and • Other Behavioral or Psychiatric Adverse Reactions [see Warnings and Precautions (5.6)] headache (17%), weight decreased (13%), decreased appetite (9%), dizziness (8%), and sleepwalking (6%). The safety XYREM REMS because of the risks of central nervous system depression and abuse and • Parasomnias [see Warnings and Precautions (5.7)] misuse [see Warnings and Precautions (5.1, 5.2)]. profi le in pediatric patients with XYWAV is expected to be similar to that of adult patients treated with XYWAV Notable requirements of the XYWAV and XYREM REMS include the following: 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction and to that of pediatric patients treated with Xyrem. • Healthcare Providers who prescribe XYWAV are specially certified rates observed in the clinical trials of a drug cannot be directly compared to rates in the • 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 clinical trials of another drug and may not reflect the rates observed in clinical practice. Please see additional Important Safety Information on previous page and Brief Summary of full Prescribing XYREM REMS with documentation of safe use. Adult Patients Further information is available at www.XYWAVXYREMREMS.com or 1-866-997-3688. The safety of XYWAV was evaluated in a 16-week double-blind placebo-controlled Information, including BOXED Warning, on following pages. randomized-withdrawal study in patients with narcolepsy with cataplexy (Study 1), which 5.4 Respiratory Depression and Sleep-Disordered Breathing TM was followed by an open-label extension phase lasting 24 weeks [see Clinical Studies References: 1. XYWAV (calcium, magnesium, potassium, and sodium oxybates). Prescribing Information. Palo Alto, CA: Jazz XYWAV may impair respiratory drive, especially in patients with compromised respiratory (14.1)]. Study 1 included an open-label titration period (OL OTTP), a stable-dose period Pharmaceuticals, Inc. 2. Thorpy MJ. Recently approved and upcoming treatments for narcolepsy. CNS Drugs. 2020;34(1):9-27. 3. Bogan function. In overdoses of oxybate and with illicit use of GHB, life-threatening respiratory (SDP), and a double-blind, placebo-controlled, randomized-withdrawal period (DB RWP). depression has been reported [see Overdosage (10)]. RK, Thorpy MJ, Dauvilliers Y, et al. Effi cacy and safety of calcium, magnesium, potassium, and sodium oxybates (lower-sodium oxybate A total of 201 patients, ages 18 to 70 years, received XYWAV at individually titrated doses Increased apnea and reduced oxygenation may occur with XYWAV administration in for 14 weeks, followed by randomization to XYWAV or matching placebo for 2 weeks [LXB]; JZP-258) in a placebo-controlled, double-blind, randomized withdrawal study in adults with narcolepsy with cataplexy. Sleep. adult and pediatric patients. A significant increase in the number of central apneas and ® of treatment. The mean exposure to XYWAV during this study, including titration, the Published online October 14, 2020. doi.org/10.1093/sleep/zsaa206. 4. XYREM (sodium oxybate). Prescribing Information. Palo Alto, CA: clinically significant oxygen desaturation may occur in patients with obstructive sleep randomized withdrawal period, and the open-label extension, was 151 days. In patients who Jazz Pharmaceuticals, Inc. apnea treated with XYWAV. remained on treatment, adverse reactions tended to occur early and diminish over time. In a study assessing the respiratory-depressant effects of Xyrem (same active moiety as Adverse Reactions Leading to Treatment Discontinuation XYWAV) at doses up to 9 g per night in 21 adult patients with narcolepsy, no dose-related changes in oxygen saturation were demonstrated in the group as a whole. One of the four In Study 1, 9 of 201 patients (4%) reported adverse reactions that led to withdrawal from patients with preexisting moderate-to-severe sleep apnea had significant worsening of the study (anxiety, decreased appetite, depressed mood, depression, fatigue, headache, the apnea/hypopnea index during treatment. irritability, nausea, pain in extremity, parasomnia, somnolence, and vomiting). The most common adverse reaction leading to discontinuation was nausea (1.5%). The majority In a study assessing the effects of Xyrem 9 g per night in 50 adult patients with of adverse reactions leading to discontinuation began during the first few weeks of obstructive sleep apnea, Xyrem did not increase the severity of sleep-disordered treatment. breathing and did not adversely affect the average duration and severity of oxygen desaturation overall. However, there was a significant increase in the number of central Commonly Observed Adverse Reactions apneas in patients taking Xyrem, and clinically significant oxygen desaturation (≤55%) was The most common adverse reactions in Study 1 (incidence ≥ 5% of XYWAV-treated measured in three patients (6%) after Xyrem administration, with one patient withdrawing patients) were headache, nausea, dizziness, decreased appetite, parasomnia, diarrhea, from the study and two continuing after single brief instances of desaturation. hyperhidrosis, anxiety, and vomiting. ©2021 Jazz Pharmaceuticals plc or its subsidiaries US-XYW-2100028 Rev0321

Sleep_005.indd 3 5/14/21 12:21 PM Adverse Reactions Occurring at an Incidence of 2% or Greater: 7 DRUG INTERACTIONS In clinical studies of sodium oxybate in another population, 39 (5%) of 874 patients were consciousness that may fluctuate rapidly between a confusional, agitated combative Table 1 lists adverse reactions observed in the open-label titration and stable dose periods 7.1 Alcohol, Sedative Hypnotics, and CNS Depressants 65 years or older. Discontinuations of treatment due to adverse reactions were increased state with ataxia and coma. Emesis (even when obtunded), diaphoresis, headache, and in the elderly compared to younger adults (21% vs. 19%). Frequency of headaches was impaired psychomotor skills have been observed. No typical pupillary changes have been of Study 1 that occurred at a frequency of 2% or greater in adult patients treated with XYWAV is contraindicated for use in combination with alcohol or sedative hypnotics. Use markedly increased in the elderly (39% vs. 19%). The most common adverse reactions described to assist in diagnosis; pupillary reactivity to light is maintained. Blurred vision XYWAV. of other CNS depressants may potentiate the CNS-depressant effects of XYWAV [see were similar in both age categories. In general, dose selection for an elderly patient has been reported. An increasing depth of coma has been observed at higher doses. Table 1: Warnings and Precautions (5.1)]. should be cautious, usually starting at the low end of the dosing range, reflecting the Myoclonus and tonic-clonic seizures have been reported. Respiration may be unaffected Adverse Reactions Occurring in ≥2% of Adult Patients Treated with XYWAV in the 7.2 Divalproex Sodium greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant or compromised in rate and depth. Cheyne-Stokes respiration and apnea have been Open-Label Titration and Stable Dose Periods in Study 1* Concomitant use of sodium oxybate with divalproex sodium results in an increase in disease or other drug therapy. observed. Bradycardia and hypothermia may accompany unconsciousness, as well as systemic exposure to GHB, which was shown to cause a greater impairment on some muscular hypotonia, but tendon reflexes remain intact. Adverse Reaction Open-Label Titration Period + Stable Dose Period 8.6 Hepatic Impairment tests of attention and working memory in a clinical study [see Clinical Pharmacology (14 weeks) Because of an increase in exposure to XYWAV, the starting dose should be reduced by 10.3 Recommended Treatment of Overdose (N=201) (12.3)]. A similar increase in exposure is expected with concomitant use of XYWAV and half in patients with hepatic impairment [see Dosage and Administration (2.5) and Clinical General symptomatic and supportive care should be instituted immediately, and gastric % divalproex sodium; therefore, an initial dose reduction of XYWAV is recommended when Pharmacology (12.3)]. decontamination may be considered if co-ingestants are suspected. Because emesis used concomitantly with divalproex sodium [see Dosage and Administration (2.6)]. 9 DRUG ABUSE AND DEPENDENCE may occur in the presence of obtundation, appropriate posture (left lateral recumbent Headache 20 Prescribers are advised to monitor patient response closely and adjust dose accordingly if position) and protection of the airway by intubation may be warranted. Although the concomitant use of XYWAV and divalproex sodium is warranted. 9.1 Controlled Substance gag reflex may be absent in deeply comatose patients, even unconscious patients Nausea 13 XYWAV is a Schedule III controlled substance under the Federal Controlled Substances may become combative to intubation, and rapid-sequence induction (without the use 8 USE IN SPECIFIC POPULATIONS Act. Non-medical use of XYWAV could lead to penalties assessed under the higher Dizziness 10 of sedative) should be considered. Vital signs and consciousness should be closely 8.1 Pregnancy Schedule I controls. monitored. The bradycardia reported with GHB overdose has been responsive to atropine Decreased appetite 8 Risk Summary 9.2 Abuse intravenous administration. No reversal of the central depressant effects of XYWAV can There are no adequate data on the developmental risk associated with the use of XYWAV The active moiety of XYWAV, oxybate, produces dose-dependent central nervous system be expected from naloxone or flumazenil administration. The use of hemodialysis and Parasomnia† 6 or sodium oxybate in pregnant women. Oral administration of sodium oxybate to effects, including hypnotic and positive subjective reinforcing effects. The onset of effect other forms of extracorporeal drug removal have not been studied in GHB overdose. pregnant rats (0, 150, 350, or 1,000 mg/kg/day) or rabbits (0, 300, 600, or 1,200 mg/kg/ However, due to the rapid metabolism of oxybate, these measures are not warranted. Diarrhea 6 is rapid, enhancing its potential for abuse or misuse. day) throughout organogenesis produced no clear evidence of developmental toxicity; Drug abuse is the intentional non-therapeutic use of a drug product or substance, even 10.4 Poison Control Center Hyperhidrosis‡ 6 however, oral administration to rats throughout pregnancy and lactation resulted in once, for its desirable psychological or physiological effects. Misuse is the intentional use, As with the management of all cases of drug overdosage, the possibility of multiple drug increased stillbirths and decreased offspring postnatal viability and growth, at a clinically ingestion should be considered. The healthcare provider is encouraged to collect urine § for therapeutic purposes of a drug by an individual in a way other than prescribed by Anxiety 5 relevant dose [see Data]. a health care provider or for whom it was not prescribed. Drug misuse and abuse may and blood samples for routine toxicologic screening, and to consult with a regional poison Vomiting 5 In the U.S. general population, the estimated background risk of major birth defects and occur with or without progression to addiction. Drug addiction is a cluster of behavioral, control center (1-800-222-1222) for current treatment recommendations. miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. The cognitive, and physiological phenomena that may include a strong desire to take the 17 PATIENT COUNSELING INFORMATION ¶ drug, difficulties in controlling drug use (e.g., continuing drug use despite harmful Fatigue 4 background risk of major birth defects and miscarriage for the indicated population is Advise the patient and/or caregiver to read the FDA-approved patient labeling consequences, giving a higher priority to drug use than other activities and obligations), unknown. (Medication Guide and Instructions for Use). Dry mouth 4 and possible tolerance or physical dependence. Clinical Considerations Central Nervous System Depression The rapid onset of sedation, coupled with the amnestic features of GHB, particularly when Depressed mood 4 Labor or Delivery combined with alcohol, has proven to be dangerous for the voluntary and involuntary user Inform patients and/or caregivers that XYWAV can cause central nervous system XYWAV has not been studied in labor or delivery. In obstetric anesthesia using an (e.g., assault victim). depression, including respiratory depression, hypotension, profound sedation, syncope, Enuresis 4 injectable formulation of sodium oxybate, newborns had stable cardiovascular and and death. Instruct patients not to engage in activities requiring mental alertness or Illicit GHB is abused in social settings primarily by young adults. Some of the doses respiratory measures but were very sleepy, causing a slight decrease in Apgar scores. motor coordination, including operating hazardous machinery, for at least 6 hours Irritability 3 estimated to be abused are in a similar dosage range to that used for treatment of There was a fall in the rate of uterine contractions 20 minutes after injection. Placental after taking XYWAV. Instruct patients and/or their caregivers to inform their healthcare patients with cataplexy. GHB has some commonalities with ethanol over a limited dose Paresthesia 3 transfer is rapid, and gamma-hydroxybutyrate (GHB) has been detected in newborns providers of all the medications they take [see Warnings and Precautions (5.1)]. range, and some cross tolerance with ethanol has been reported as well. Cases of severe at delivery after intravenous administration of GHB to mothers. Subsequent effects of Abuse and Misuse Depression 3 dependence and craving for GHB have been reported when the drug is taken around sodium oxybate on later growth, development, and maturation in humans are unknown. the clock. Patterns of abuse indicative of dependence include: 1) the use of increasingly Inform patients and/or caregivers that the active ingredient of XYWAV is gamma- Tremor 3 Data large doses, 2) increased frequency of use, and 3) continued use despite adverse hydroxybutyrate (GHB), which is associated with serious adverse reactions with illicit use Animal Data consequences. and abuse [see Warnings and Precautions (5.2)]. Somnolence 2 Oral administration of sodium oxybate to pregnant rats (0, 150, 350, or 1,000 mg/kg/ Because illicit use and abuse of GHB have been reported, physicians should carefully XYWAV and XYREM REMS Muscle spasms 2 day) or rabbits (0, 300, 600, or 1,200 mg/kg/day) throughout organogenesis produced evaluate patients for a history of drug abuse and follow such patients closely, observing XYWAV is available only through a restricted program called the XYWAV and XYREM no clear evidence of developmental toxicity. The highest doses of sodium oxybate them for signs of misuse or abuse of GHB (e.g., increase in size or frequency of dosing, REMS [see Warnings and Precautions (5.3)]. Inform the patient and/or caregiver of the * Adverse reactions related to XYWAV were reported less frequently, as an overall tested in rats and rabbits were approximately 1 and 3 times, respectively, the maximum drug-seeking behavior, feigned cataplexy). Dispose of XYWAV according to state and following notable requirements: incidence, in patients on Xyrem at study entry than in Xyrem-naïve patients. recommended human dose (MRHD) of 9 g per night on a body surface area (mg/m2) federal regulations. It is safe to dispose of XYWAV down the sanitary sewer. • XYWAV is dispensed only by the central pharmacy • XYWAV will be dispensed and shipped only to patients enrolled in the XYWAV and XYREM † Includes abnormal dreams, abnormal sleep-related event, rapid eye movements sleep basis. 9.3 Dependence REMS abnormal, sleep paralysis, sleep talking, sleep terror, sleep-related eating disorder, Additionally, oral administration of sodium oxybate (0, 150, 350, or 1,000 mg/kg/day) to Physical dependence is a state that develops as a result of physiological adaptation in somnambulism rats throughout pregnancy and lactation resulted in increased stillbirths and decreased response to repeated drug use, manifested by withdrawal signs and symptoms after XYWAV is available only from the central pharmacy participating in the program. Therefore, provide patients and/or caregivers with the telephone number and website for ‡Includes hyperhidrosis and night sweats offspring postnatal viability and body weight gain at the highest dose tested. The no- 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 information on how to obtain the product. §Includes anxiety, agitation, panic attack, tension effect dose for pre- and post-natal developmental toxicity in rats is less than the MRHD on a mg/m2 basis. of GHB at frequent repeated doses (18 g to 250 g per day) in excess of the recommended Alcohol or Sedative Hypnotics ¶Includes fatigue and asthenia dosage range. Signs and symptoms of GHB withdrawal following abrupt discontinuation 8.2 Lactation Advise patients and/or caregivers that alcohol and other sedative hypnotics should not Adverse Reactions Observed in Clinical Studies with Xyrem (≥2%), but not in Study 1, and included insomnia, restlessness, anxiety, psychosis, lethargy, nausea, tremor, sweating, be taken with XYWAV [see Contraindications (4)]. Which May Be Relevant for XYWAV Risk Summary muscle cramps, tachycardia, headache, dizziness, rebound fatigue and sleepiness, Sedation Pain, feeling drunk, pain in extremity, cataplexy, disturbance in attention, sleep paralysis, GHB is excreted in human milk after oral administration of sodium oxybate. There confusion, and, particularly in the case of severe withdrawal, visual hallucinations, Inform patients and/or caregivers that the patient is likely to fall asleep quickly after and disorientation. is insufficient information on the risk to a breastfed infant, and there is insufficient 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 taking XYWAV (often within 5 and usually within 15 minutes), but the time it takes to fall Pediatric Patients (7 Years of Age and Older) 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 have not been systematically evaluated in controlled clinical trials. In the clinical trial asleep can vary from night to night. The sudden onset of sleep, including in a standing In the pediatric clinical trial with Xyrem (same active moiety as XYWAV), 104 patients position or while rising from bed, has led to falls complicated by injuries, in some cases XYWAV and any potential adverse effects on the breastfed infant from XYWAV or from experience with Xyrem in narcolepsy/cataplexy patients at recommended doses, two aged 7 to 17 years (37 patients aged 7 to 11 years; 67 patients aged 12 to 17 years) with requiring hospitalization [see Adverse Reactions (6.2)]. Instruct patients and/or caregivers the underlying maternal condition. patients reported anxiety and one reported insomnia following abrupt discontinuation narcolepsy received Xyrem for up to one year [see Clinical Studies (14.2)]. This study at the termination of the clinical trial; in the two patients with anxiety, the frequency of that the patient should remain in bed following ingestion of each dose. Instruct patients included an open-label safety continuation period in which eligible patients received 8.4 Pediatric Use cataplexy had increased markedly at the same time. In the XYWAV clinical trial in adult and/or caregivers that the patient should not take a subsequent nightly dose until at least Xyrem for up to an additional 2 years. The median and maximum exposure across the The safety and effectiveness of XYWAV for the treatment of cataplexy or excessive narcolepsy/cataplexy patients at recommended doses, one patient reported insomnia 2.5 to 4 hours after the previous dose [see Dosage and Administration (2.3)]. entire study were 371 and 987 days, respectively. daytime sleepiness in pediatric patients 7 years of age and older with narcolepsy have following abrupt discontinuation of XYWAV. Administration Instructions Adverse Reactions Leading to Treatment Discontinuation been established. XYWAV has not been studied in a pediatric clinical trial. Use of XYWAV Tolerance Inform patients and/or caregivers that the total nightly dosage of XYWAV is divided into in pediatric patients 7 years of age and older with narcolepsy is supported by evidence In the pediatric clinical trial with Xyrem, 7 of 104 patients reported adverse reactions Tolerance is a physiological state characterized by a reduced response to a drug after two doses and that the first nightly dose of XYWAV should be taken at least 2 hours after from an adequate and well-controlled study of sodium oxybate in pediatric patients 7 that led to withdrawal from the study (hallucination, tactile; suicidal ideation; weight repeated administration (i.e., a higher dose of a drug is required to produce the same eating. decreased; sleep apnea syndrome; affect lability; anger, anxiety, depression; and to 17 years of age, a study in adults showing a treatment effect of XYWAV similar to that effect that was once obtained at a lower dose). Tolerance to XYWAV has not been Respiratory Depression and Sleep-Disordered Breathing observed with sodium oxybate, pharmacokinetic data of sodium oxybate from adult and headache). systematically studied in controlled clinical trials. There have been some case reports Inform patients that XYWAV may impair respiratory drive, especially in patients with pediatric patients, and pharmacokinetic data of XYWAV from healthy adult volunteers Adverse Reactions in the Xyrem Pediatric Clinical Trial of symptoms of tolerance developing after illicit use at dosages far in excess of the compromised respiratory function, and may cause apnea [see Warnings and Precautions [see Adverse Reactions (6.1) and Clinical Studies (14.1, 14.2)]. The most common adverse reactions (≥5%) were nausea (20%), enuresis (19%), vomiting recommended XYWAV dosage regimen. Clinical studies of sodium oxybate in the (5.4)]. (18%), headache (17%), weight decreased (13%), decreased appetite (9%), dizziness (8%), In the pediatric clinical trial with sodium oxybate administration in patients with treatment of alcohol withdrawal suggest a potential cross-tolerance with alcohol. The Depression and Suicidality narcolepsy, serious adverse reactions of central sleep apnea and oxygen desaturation safety and effectiveness of XYWAV in the treatment of alcohol withdrawal have not been and sleepwalking (6%). Instruct patients and/or caregivers to contact a healthcare provider immediately if documented by polysomnography evaluation; depression; suicidal ideation; established. Additional information regarding safety in pediatric patients appears in the following the patient develops depressed mood, markedly diminished interest or pleasure in neuropsychiatric reactions including acute psychosis, confusion, and anxiety; and sections: 10 OVERDOSAGE usual activities, significant change in weight and/or appetite, psychomotor agitation parasomnias, including sleepwalking, have been reported [see Warnings and Precautions • Respiratory Depression and Sleep-Disordered Breathing [see Warnings and Precautions (5.4)] or retardation, increased fatigue, feelings of guilt or worthlessness, slowed thinking or (5.4, 5.5, 5.6, 5.7) and Adverse Reactions (6.1)]. 10.1 Human Experience • Depression and Suicidality [see Warnings and Precautions (5.5)] Information regarding overdose with XYWAV is derived largely from reports in the impaired concentration, or suicidal ideation [see Warnings and Precautions (5.5)]. • Other Behavioral or Psychiatric Adverse Reactions [see Warnings and Precautions (5.6)] Safety and effectiveness of XYWAV in pediatric patients below the age of 7 years have medical literature that describe symptoms and signs in individuals who have ingested Other Behavioral or Psychiatric Adverse Reactions not been established. • Parasomnias [see Warnings and Precautions (5.7)] GHB illicitly. In these circumstances the co-ingestion of other drugs and alcohol was Inform patients and/or caregivers that XYWAV can cause behavioral or psychiatric The overall adverse reaction profile of Xyrem in the pediatric clinical trial was similar to Juvenile Animal Toxicity Data common, and may have influenced the presentation and severity of clinical manifestations adverse reactions, including confusion, anxiety, and psychosis. Instruct them to notify that seen in the adult clinical trial program. The safety profile in pediatric patients with In a study in which sodium oxybate (0, 100, 300, or 900 mg/kg/day) was orally of overdose. their healthcare provider if any of these types of symptoms occur [see Warnings and XYWAV is expected to be similar to that of adult patients treated with XYWAV and to that administered to rats during the juvenile period of development (postnatal days 21 through In adult clinical trials with Xyrem (same active moiety as XYWAV), two cases of overdose Precautions (5.6)]. of pediatric patients treated with Xyrem. 90), mortality was observed at the two highest doses tested. Deaths occurred during were reported. In the first case, an estimated dose of 150 g, more than 15 times the Sleepwalking 6.2 Postmarketing Experience the first week of dosing and were associated with clinical signs (including decreased maximum recommended dose, caused a patient to be unresponsive with brief periods Instruct patients and/or caregivers that XYWAV has been associated with sleepwalking of apnea and to be incontinent of urine and feces. This individual recovered without The following adverse reactions have been identified during postapproval use of sodium activity and respiratory rate) consistent with the pharmacological effects of the drug. and other behaviors during sleep, and to contact their healthcare provider if this occurs sequelae. In the second case, death was reported following a multiple drug overdose oxybate. Because these reactions are reported voluntarily from a population of uncertain Reduced body weight gain in males and females and delayed sexual maturation in males [see Warnings and Precautions (5.7)]. were observed at the highest dose tested. The no-effect dose for adverse effects in consisting of Xyrem and numerous other drugs. No cases of overdose (greater than 9 g) size, it is not always possible to reliably estimate their frequency or establish a causal Distributed By: juvenile rats is associated with plasma exposures (AUC) less than that at the maximum with XYWAV were reported in the XYWAV clinical trial. relationship to drug exposure: Jazz Pharmaceuticals, Inc. Palo Alto, CA 94304 recommended human dose (9 g/night). 10.2 Signs and Symptoms Arthralgia, fall*, fluid retention, hangover, hypersensitivity, hypertension, memory ©2020 Jazz Pharmaceuticals plc or its subsidiaries US-XYW-2000074 Rev1120 impairment, nocturia, and vision blurred. 8.5 Geriatric Use Information about signs and symptoms associated with overdosage with XYWAV derives from reports of illicit use of GHB. Patient presentation following overdose is influenced * The sudden onset of sleep in patients taking sodium oxybate, including in a standing Clinical studies of XYWAV or Xyrem in patients with narcolepsy did not include sufficient by the dose ingested, the time since ingestion, the co-ingestion of other drugs and position or while rising from bed, has led to falls complicated by injuries, in some cases numbers of subjects age 65 years and older to determine whether they respond alcohol, and the fed or fasted state. Patients have exhibited varying degrees of depressed requiring hospitalization. differently from younger subjects.

Sleep_006.indd 2 5/14/21 12:21 PM Adverse Reactions Occurring at an Incidence of 2% or Greater: 7 DRUG INTERACTIONS In clinical studies of sodium oxybate in another population, 39 (5%) of 874 patients were consciousness that may fluctuate rapidly between a confusional, agitated combative Table 1 lists adverse reactions observed in the open-label titration and stable dose periods 7.1 Alcohol, Sedative Hypnotics, and CNS Depressants 65 years or older. Discontinuations of treatment due to adverse reactions were increased state with ataxia and coma. Emesis (even when obtunded), diaphoresis, headache, and in the elderly compared to younger adults (21% vs. 19%). Frequency of headaches was impaired psychomotor skills have been observed. No typical pupillary changes have been of Study 1 that occurred at a frequency of 2% or greater in adult patients treated with XYWAV is contraindicated for use in combination with alcohol or sedative hypnotics. Use markedly increased in the elderly (39% vs. 19%). The most common adverse reactions described to assist in diagnosis; pupillary reactivity to light is maintained. Blurred vision XYWAV. of other CNS depressants may potentiate the CNS-depressant effects of XYWAV [see were similar in both age categories. In general, dose selection for an elderly patient has been reported. An increasing depth of coma has been observed at higher doses. Table 1: Warnings and Precautions (5.1)]. should be cautious, usually starting at the low end of the dosing range, reflecting the Myoclonus and tonic-clonic seizures have been reported. Respiration may be unaffected Adverse Reactions Occurring in ≥2% of Adult Patients Treated with XYWAV in the 7.2 Divalproex Sodium greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant or compromised in rate and depth. Cheyne-Stokes respiration and apnea have been Open-Label Titration and Stable Dose Periods in Study 1* Concomitant use of sodium oxybate with divalproex sodium results in an increase in disease or other drug therapy. observed. Bradycardia and hypothermia may accompany unconsciousness, as well as systemic exposure to GHB, which was shown to cause a greater impairment on some muscular hypotonia, but tendon reflexes remain intact. Adverse Reaction Open-Label Titration Period + Stable Dose Period 8.6 Hepatic Impairment tests of attention and working memory in a clinical study [see Clinical Pharmacology (14 weeks) Because of an increase in exposure to XYWAV, the starting dose should be reduced by 10.3 Recommended Treatment of Overdose (N=201) (12.3)]. A similar increase in exposure is expected with concomitant use of XYWAV and half in patients with hepatic impairment [see Dosage and Administration (2.5) and Clinical General symptomatic and supportive care should be instituted immediately, and gastric % divalproex sodium; therefore, an initial dose reduction of XYWAV is recommended when Pharmacology (12.3)]. decontamination may be considered if co-ingestants are suspected. Because emesis used concomitantly with divalproex sodium [see Dosage and Administration (2.6)]. 9 DRUG ABUSE AND DEPENDENCE may occur in the presence of obtundation, appropriate posture (left lateral recumbent Headache 20 Prescribers are advised to monitor patient response closely and adjust dose accordingly if position) and protection of the airway by intubation may be warranted. Although the concomitant use of XYWAV and divalproex sodium is warranted. 9.1 Controlled Substance gag reflex may be absent in deeply comatose patients, even unconscious patients Nausea 13 XYWAV is a Schedule III controlled substance under the Federal Controlled Substances may become combative to intubation, and rapid-sequence induction (without the use 8 USE IN SPECIFIC POPULATIONS Act. Non-medical use of XYWAV could lead to penalties assessed under the higher Dizziness 10 of sedative) should be considered. Vital signs and consciousness should be closely 8.1 Pregnancy Schedule I controls. monitored. The bradycardia reported with GHB overdose has been responsive to atropine Decreased appetite 8 Risk Summary 9.2 Abuse intravenous administration. No reversal of the central depressant effects of XYWAV can There are no adequate data on the developmental risk associated with the use of XYWAV The active moiety of XYWAV, oxybate, produces dose-dependent central nervous system be expected from naloxone or flumazenil administration. The use of hemodialysis and Parasomnia† 6 or sodium oxybate in pregnant women. Oral administration of sodium oxybate to effects, including hypnotic and positive subjective reinforcing effects. The onset of effect other forms of extracorporeal drug removal have not been studied in GHB overdose. pregnant rats (0, 150, 350, or 1,000 mg/kg/day) or rabbits (0, 300, 600, or 1,200 mg/kg/ However, due to the rapid metabolism of oxybate, these measures are not warranted. Diarrhea 6 is rapid, enhancing its potential for abuse or misuse. day) throughout organogenesis produced no clear evidence of developmental toxicity; Drug abuse is the intentional non-therapeutic use of a drug product or substance, even 10.4 Poison Control Center Hyperhidrosis‡ 6 however, oral administration to rats throughout pregnancy and lactation resulted in once, for its desirable psychological or physiological effects. Misuse is the intentional use, As with the management of all cases of drug overdosage, the possibility of multiple drug increased stillbirths and decreased offspring postnatal viability and growth, at a clinically ingestion should be considered. The healthcare provider is encouraged to collect urine § for therapeutic purposes of a drug by an individual in a way other than prescribed by Anxiety 5 relevant dose [see Data]. a health care provider or for whom it was not prescribed. Drug misuse and abuse may and blood samples for routine toxicologic screening, and to consult with a regional poison Vomiting 5 In the U.S. general population, the estimated background risk of major birth defects and occur with or without progression to addiction. Drug addiction is a cluster of behavioral, control center (1-800-222-1222) for current treatment recommendations. miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. The cognitive, and physiological phenomena that may include a strong desire to take the 17 PATIENT COUNSELING INFORMATION ¶ drug, difficulties in controlling drug use (e.g., continuing drug use despite harmful Fatigue 4 background risk of major birth defects and miscarriage for the indicated population is Advise the patient and/or caregiver to read the FDA-approved patient labeling consequences, giving a higher priority to drug use than other activities and obligations), unknown. (Medication Guide and Instructions for Use). Dry mouth 4 and possible tolerance or physical dependence. Clinical Considerations Central Nervous System Depression The rapid onset of sedation, coupled with the amnestic features of GHB, particularly when Depressed mood 4 Labor or Delivery combined with alcohol, has proven to be dangerous for the voluntary and involuntary user Inform patients and/or caregivers that XYWAV can cause central nervous system XYWAV has not been studied in labor or delivery. In obstetric anesthesia using an (e.g., assault victim). depression, including respiratory depression, hypotension, profound sedation, syncope, Enuresis 4 injectable formulation of sodium oxybate, newborns had stable cardiovascular and and death. Instruct patients not to engage in activities requiring mental alertness or Illicit GHB is abused in social settings primarily by young adults. Some of the doses respiratory measures but were very sleepy, causing a slight decrease in Apgar scores. motor coordination, including operating hazardous machinery, for at least 6 hours Irritability 3 estimated to be abused are in a similar dosage range to that used for treatment of There was a fall in the rate of uterine contractions 20 minutes after injection. Placental after taking XYWAV. Instruct patients and/or their caregivers to inform their healthcare patients with cataplexy. GHB has some commonalities with ethanol over a limited dose Paresthesia 3 transfer is rapid, and gamma-hydroxybutyrate (GHB) has been detected in newborns providers of all the medications they take [see Warnings and Precautions (5.1)]. range, and some cross tolerance with ethanol has been reported as well. Cases of severe at delivery after intravenous administration of GHB to mothers. Subsequent effects of Abuse and Misuse Depression 3 dependence and craving for GHB have been reported when the drug is taken around sodium oxybate on later growth, development, and maturation in humans are unknown. the clock. Patterns of abuse indicative of dependence include: 1) the use of increasingly Inform patients and/or caregivers that the active ingredient of XYWAV is gamma- Tremor 3 Data large doses, 2) increased frequency of use, and 3) continued use despite adverse hydroxybutyrate (GHB), which is associated with serious adverse reactions with illicit use Animal Data consequences. and abuse [see Warnings and Precautions (5.2)]. Somnolence 2 Oral administration of sodium oxybate to pregnant rats (0, 150, 350, or 1,000 mg/kg/ Because illicit use and abuse of GHB have been reported, physicians should carefully XYWAV and XYREM REMS Muscle spasms 2 day) or rabbits (0, 300, 600, or 1,200 mg/kg/day) throughout organogenesis produced evaluate patients for a history of drug abuse and follow such patients closely, observing XYWAV is available only through a restricted program called the XYWAV and XYREM no clear evidence of developmental toxicity. The highest doses of sodium oxybate them for signs of misuse or abuse of GHB (e.g., increase in size or frequency of dosing, REMS [see Warnings and Precautions (5.3)]. Inform the patient and/or caregiver of the * Adverse reactions related to XYWAV were reported less frequently, as an overall tested in rats and rabbits were approximately 1 and 3 times, respectively, the maximum drug-seeking behavior, feigned cataplexy). Dispose of XYWAV according to state and following notable requirements: incidence, in patients on Xyrem at study entry than in Xyrem-naïve patients. recommended human dose (MRHD) of 9 g per night on a body surface area (mg/m2) federal regulations. It is safe to dispose of XYWAV down the sanitary sewer. • XYWAV is dispensed only by the central pharmacy • XYWAV will be dispensed and shipped only to patients enrolled in the XYWAV and XYREM † Includes abnormal dreams, abnormal sleep-related event, rapid eye movements sleep basis. 9.3 Dependence REMS abnormal, sleep paralysis, sleep talking, sleep terror, sleep-related eating disorder, Additionally, oral administration of sodium oxybate (0, 150, 350, or 1,000 mg/kg/day) to Physical dependence is a state that develops as a result of physiological adaptation in somnambulism rats throughout pregnancy and lactation resulted in increased stillbirths and decreased response to repeated drug use, manifested by withdrawal signs and symptoms after XYWAV is available only from the central pharmacy participating in the program. Therefore, provide patients and/or caregivers with the telephone number and website for ‡Includes hyperhidrosis and night sweats offspring postnatal viability and body weight gain at the highest dose tested. The no- 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 information on how to obtain the product. §Includes anxiety, agitation, panic attack, tension effect dose for pre- and post-natal developmental toxicity in rats is less than the MRHD on a mg/m2 basis. of GHB at frequent repeated doses (18 g to 250 g per day) in excess of the recommended Alcohol or Sedative Hypnotics ¶Includes fatigue and asthenia dosage range. Signs and symptoms of GHB withdrawal following abrupt discontinuation 8.2 Lactation Advise patients and/or caregivers that alcohol and other sedative hypnotics should not Adverse Reactions Observed in Clinical Studies with Xyrem (≥2%), but not in Study 1, and included insomnia, restlessness, anxiety, psychosis, lethargy, nausea, tremor, sweating, be taken with XYWAV [see Contraindications (4)]. Which May Be Relevant for XYWAV Risk Summary muscle cramps, tachycardia, headache, dizziness, rebound fatigue and sleepiness, Sedation Pain, feeling drunk, pain in extremity, cataplexy, disturbance in attention, sleep paralysis, GHB is excreted in human milk after oral administration of sodium oxybate. There confusion, and, particularly in the case of severe withdrawal, visual hallucinations, Inform patients and/or caregivers that the patient is likely to fall asleep quickly after and disorientation. is insufficient information on the risk to a breastfed infant, and there is insufficient 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 taking XYWAV (often within 5 and usually within 15 minutes), but the time it takes to fall Pediatric Patients (7 Years of Age and Older) 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 have not been systematically evaluated in controlled clinical trials. In the clinical trial asleep can vary from night to night. The sudden onset of sleep, including in a standing In the pediatric clinical trial with Xyrem (same active moiety as XYWAV), 104 patients position or while rising from bed, has led to falls complicated by injuries, in some cases XYWAV and any potential adverse effects on the breastfed infant from XYWAV or from experience with Xyrem in narcolepsy/cataplexy patients at recommended doses, two aged 7 to 17 years (37 patients aged 7 to 11 years; 67 patients aged 12 to 17 years) with requiring hospitalization [see Adverse Reactions (6.2)]. Instruct patients and/or caregivers the underlying maternal condition. patients reported anxiety and one reported insomnia following abrupt discontinuation narcolepsy received Xyrem for up to one year [see Clinical Studies (14.2)]. This study at the termination of the clinical trial; in the two patients with anxiety, the frequency of that the patient should remain in bed following ingestion of each dose. Instruct patients included an open-label safety continuation period in which eligible patients received 8.4 Pediatric Use cataplexy had increased markedly at the same time. In the XYWAV clinical trial in adult and/or caregivers that the patient should not take a subsequent nightly dose until at least Xyrem for up to an additional 2 years. The median and maximum exposure across the The safety and effectiveness of XYWAV for the treatment of cataplexy or excessive narcolepsy/cataplexy patients at recommended doses, one patient reported insomnia 2.5 to 4 hours after the previous dose [see Dosage and Administration (2.3)]. entire study were 371 and 987 days, respectively. daytime sleepiness in pediatric patients 7 years of age and older with narcolepsy have following abrupt discontinuation of XYWAV. Administration Instructions Adverse Reactions Leading to Treatment Discontinuation been established. XYWAV has not been studied in a pediatric clinical trial. Use of XYWAV Tolerance Inform patients and/or caregivers that the total nightly dosage of XYWAV is divided into in pediatric patients 7 years of age and older with narcolepsy is supported by evidence In the pediatric clinical trial with Xyrem, 7 of 104 patients reported adverse reactions Tolerance is a physiological state characterized by a reduced response to a drug after two doses and that the first nightly dose of XYWAV should be taken at least 2 hours after from an adequate and well-controlled study of sodium oxybate in pediatric patients 7 that led to withdrawal from the study (hallucination, tactile; suicidal ideation; weight repeated administration (i.e., a higher dose of a drug is required to produce the same eating. decreased; sleep apnea syndrome; affect lability; anger, anxiety, depression; and to 17 years of age, a study in adults showing a treatment effect of XYWAV similar to that effect that was once obtained at a lower dose). Tolerance to XYWAV has not been Respiratory Depression and Sleep-Disordered Breathing observed with sodium oxybate, pharmacokinetic data of sodium oxybate from adult and headache). systematically studied in controlled clinical trials. There have been some case reports Inform patients that XYWAV may impair respiratory drive, especially in patients with pediatric patients, and pharmacokinetic data of XYWAV from healthy adult volunteers Adverse Reactions in the Xyrem Pediatric Clinical Trial of symptoms of tolerance developing after illicit use at dosages far in excess of the compromised respiratory function, and may cause apnea [see Warnings and Precautions [see Adverse Reactions (6.1) and Clinical Studies (14.1, 14.2)]. The most common adverse reactions (≥5%) were nausea (20%), enuresis (19%), vomiting recommended XYWAV dosage regimen. Clinical studies of sodium oxybate in the (5.4)]. (18%), headache (17%), weight decreased (13%), decreased appetite (9%), dizziness (8%), In the pediatric clinical trial with sodium oxybate administration in patients with treatment of alcohol withdrawal suggest a potential cross-tolerance with alcohol. The Depression and Suicidality narcolepsy, serious adverse reactions of central sleep apnea and oxygen desaturation safety and effectiveness of XYWAV in the treatment of alcohol withdrawal have not been and sleepwalking (6%). Instruct patients and/or caregivers to contact a healthcare provider immediately if documented by polysomnography evaluation; depression; suicidal ideation; established. Additional information regarding safety in pediatric patients appears in the following the patient develops depressed mood, markedly diminished interest or pleasure in neuropsychiatric reactions including acute psychosis, confusion, and anxiety; and sections: 10 OVERDOSAGE usual activities, significant change in weight and/or appetite, psychomotor agitation parasomnias, including sleepwalking, have been reported [see Warnings and Precautions • Respiratory Depression and Sleep-Disordered Breathing [see Warnings and Precautions (5.4)] or retardation, increased fatigue, feelings of guilt or worthlessness, slowed thinking or (5.4, 5.5, 5.6, 5.7) and Adverse Reactions (6.1)]. 10.1 Human Experience • Depression and Suicidality [see Warnings and Precautions (5.5)] Information regarding overdose with XYWAV is derived largely from reports in the impaired concentration, or suicidal ideation [see Warnings and Precautions (5.5)]. • Other Behavioral or Psychiatric Adverse Reactions [see Warnings and Precautions (5.6)] Safety and effectiveness of XYWAV in pediatric patients below the age of 7 years have medical literature that describe symptoms and signs in individuals who have ingested Other Behavioral or Psychiatric Adverse Reactions not been established. • Parasomnias [see Warnings and Precautions (5.7)] GHB illicitly. In these circumstances the co-ingestion of other drugs and alcohol was Inform patients and/or caregivers that XYWAV can cause behavioral or psychiatric The overall adverse reaction profile of Xyrem in the pediatric clinical trial was similar to Juvenile Animal Toxicity Data common, and may have influenced the presentation and severity of clinical manifestations adverse reactions, including confusion, anxiety, and psychosis. Instruct them to notify that seen in the adult clinical trial program. The safety profile in pediatric patients with In a study in which sodium oxybate (0, 100, 300, or 900 mg/kg/day) was orally of overdose. their healthcare provider if any of these types of symptoms occur [see Warnings and XYWAV is expected to be similar to that of adult patients treated with XYWAV and to that administered to rats during the juvenile period of development (postnatal days 21 through In adult clinical trials with Xyrem (same active moiety as XYWAV), two cases of overdose Precautions (5.6)]. of pediatric patients treated with Xyrem. 90), mortality was observed at the two highest doses tested. Deaths occurred during were reported. In the first case, an estimated dose of 150 g, more than 15 times the Sleepwalking 6.2 Postmarketing Experience the first week of dosing and were associated with clinical signs (including decreased maximum recommended dose, caused a patient to be unresponsive with brief periods Instruct patients and/or caregivers that XYWAV has been associated with sleepwalking of apnea and to be incontinent of urine and feces. This individual recovered without The following adverse reactions have been identified during postapproval use of sodium activity and respiratory rate) consistent with the pharmacological effects of the drug. and other behaviors during sleep, and to contact their healthcare provider if this occurs sequelae. In the second case, death was reported following a multiple drug overdose oxybate. Because these reactions are reported voluntarily from a population of uncertain Reduced body weight gain in males and females and delayed sexual maturation in males [see Warnings and Precautions (5.7)]. were observed at the highest dose tested. The no-effect dose for adverse effects in consisting of Xyrem and numerous other drugs. No cases of overdose (greater than 9 g) size, it is not always possible to reliably estimate their frequency or establish a causal Distributed By: juvenile rats is associated with plasma exposures (AUC) less than that at the maximum with XYWAV were reported in the XYWAV clinical trial. relationship to drug exposure: Jazz Pharmaceuticals, Inc. Palo Alto, CA 94304 recommended human dose (9 g/night). 10.2 Signs and Symptoms Arthralgia, fall*, fluid retention, hangover, hypersensitivity, hypertension, memory ©2020 Jazz Pharmaceuticals plc or its subsidiaries US-XYW-2000074 Rev1120 impairment, nocturia, and vision blurred. 8.5 Geriatric Use Information about signs and symptoms associated with overdosage with XYWAV derives from reports of illicit use of GHB. Patient presentation following overdose is influenced * The sudden onset of sleep in patients taking sodium oxybate, including in a standing Clinical studies of XYWAV or Xyrem in patients with narcolepsy did not include sufficient by the dose ingested, the time since ingestion, the co-ingestion of other drugs and position or while rising from bed, has led to falls complicated by injuries, in some cases numbers of subjects age 65 years and older to determine whether they respond alcohol, and the fed or fasted state. Patients have exhibited varying degrees of depressed requiring hospitalization. differently from younger subjects.

Sleep_007.indd 3 5/14/21 12:22 PM Sleep problems likely to become more common because of pandemic

BY RUTH M. BENCA, MD, PHD from the pandemic lockdown has Virtual Rounds at the Center for made smartphones the predominant Women’s Health at Massachusetts n the midst of the COVID-19 form of communication and has General Hospital in Boston, which pandemic, we also face a dramat- only heightened youths’ dependen- provides a forum to discuss cases ic increase in psychiatric disorders cy on them. and treatment approaches for preg- and behavioral issues that it has “Nomophobia,” or the fear and nant and postpartum women. (See Itriggered, including insomnia, mood anxiety of being without access to a page 17.) The prospective study by and anxiety disorders, smartphone, describes Robbins and colleagues demon- and suicide. While the psychological ef- strated that those aged 65 years and most of the studies fects of loss of a ma- older who report sleeping less than reported in this issue jor means of social 5 hours per night were more likely were not performed interaction and, as to develop Alzheimer’s disease or during the pandemic, reported in the study die over the next 5 years. (See page they all describe issues by Peszka, results in 25.) Health risks related to insuffi- that are likely to be- sleep disturbance. cient sleep in the elderly could be come even more com- Similarly, e-cigarette exacerbated during the pandemic, mon both during the use has been increas- because sleep loss is associated with pandemic as well as in ing dramatically in increased risk of infections as well its aftermath. adolescents and young as decreased responsivity to immu- Two of the reports Dr. Benca adults. The study by nization. describe addictive be- Kianarsi, which surveyed Finally, the study by Skobic and haviors and their sequelae that are almost 19,000 young adults, found colleagues reports that, in a group particularly common in adolescents: that greater use of e-cigarettes was of subjects who had experienced job excessive use of smartphones (see associated with a significantly greater loss, those who had insomnia had page 10) and vaping e-cigarettes (see degree of sleep deprivation. Both increased experiences of subsequent page 13). Both are associated with smartphones and e-cigarettes have stress, compared with those who sleep deprivation and delayed sleep also been associated with increased did not have insomnia following job patterns. Smartphone use often risk of anxiety and depression in loss. This suggests that people who increases at night and exposure to those who use them most frequently. tend to react to stress by developing screen lighting may promote a phase Pregnant women and the elder- insomnia are more likely to expe- shift, whereas nicotine from e-cig- ly are particularly at risk for sleep rience continued stress, setting up arettes, particularly when used in problems and additional health a vicious cycle between stress and the evening, can interfere with sleep issues secondary to sleep problems. insomnia. This is particularly con- through its stimulant properties. In pregnant women, economic concerning given the dramatic increase Younger generations who have cerns and fears about contracting in multiple, severe stressors caused grown up with smartphones have the virus by mother and baby have by the pandemic. (See page 15.) become highly dependent on them led to increased rates of COVID-in- In summary, the reports in this for many activities in their daily duced insomnia, anxiety, and depres- issue describe at-risk groups for in- lives. The social isolation resulting sion. The article by Cohen describes Continued on following page }

Sleep Medicine A Special Report Editor / Katie Lennon Sleep Medicine is a special report to Clinical Publisher. Frontline Medical Communications Inc. Vice President, Sales / Mike Guire Psychiatry News, Family Practice News, Internal will not assume responsibility for damages, loss, Vice President, Sales, Medicine News, Pediatric News, and Neurology or claims of any kind arising from or related to the Strategy & Partnerships / JoAnn Wahl Reviews, independent newspapers that provide the information contained in this publication, including practicing physician with timely and relevant news any claims related to the products, drugs, or ser- Production Specialist / Mike Wendt and commentary about clinical developments in vices mentioned herein. Art Director / Elizabeth Byrne Lobdell their field and about the impact of health care Cover image / Geber86/E+ policy on the specialty and the physician’s practice. The ideas and opinions expressed in this spe- ©Copyright 2021, by Frontline Medical Communi- cial report do not necessarily reflect those of the cations Inc. All rights reserved.

8 June 2021 • Sleep Medicine

08_9ASUPP21Sleep.indd 8 5/17/2021 3:40:12 PM Dementia’s link to sleep-related conditions, problems with daylight saving time addressed

BY KRISHNA M. SUNDAR, MD cussing the American Academy and sleep medicine at the University of Sleep Medicine’s recent call to of Utah. he impact of a number of eliminate daylight saving time in a He is a full-time associate professor sleep-related conditions on the statement. (See page 14.) at the University of Utah, where he has occurrence of dementia is one Other articles continue to high- expanded the school’s sleep program of the most topical subjects light the variation of OSA ex- in terms of its clinical, research, and addressedT in this publication. pression with race and increasing teaching opportunities. He also directs The incidence of burden of disease a multidisciplinary chronic cough clinic dementia is an in- stemming from co- at the Voice Disorders Center, University creasing problem morbid insomnia in of Utah. worldwide as people frequently encoun- Dr. Sundar has authored more continue to live lon- tered chronic diseases than 50 peer-reviewed publications ger. Inside is a note- such as chronic ob- in pulmonary, critical care, and sleep worthy article on the structive pulmonary medicine. He is actively involved in relationship between disorder. clinical and translational research in a adherence to therapy number of areas, including the basis for obstructive sleep Dr. Sundar is currently of sleep-disordered breathing, chronic apnea (OSA) with the medical director of cough, patterns of chronic hypoxia, continuous positive the Sleep-Wake Center and outcomes from sleep apnea. He airway pressure and Dr. Sundar and clinical professor in has mentored a number of residents the risk of incident the department of medicine, and fellows and has been recognized dementia. (See page 22.) You can University of Utah, Salt Lake City. He for teaching and clinical excellence. He also read about dementia risk in is board certified in sleep medicine, serves on the editorial advisory board older adults being magnified with pulmonary disease, critical care of CHEST Physician and has lectured on sleep medication use. (See page medicine, and internal medicine. a wide range of topics at international 25.) Following his medical training in conferences. Despite the changes in sleep and Delhi University and postgraduate Dr. Sundar serves on the advisory work schedules caused by COVID, training in PGIMER, Chandigarh, board to Merck. He is a cofounder the biannual change of clocks to India, Dr. Sundar completed his of Hypnoscure, created through accommodate daylight saving time residency in internal medicine at St. the University of Utah Technology continues to have an impact on Luke’s-Roosevelt Hospital, Columbia Commercialization Office, aimed health. One of the articles draws University, New York, and a fellowship at software creation for population attention to this problem by dis- in pulmonary, critical care medicine, management of sleep disorders.

| Continued from previous page Irvine. She received her bachelor of arts across the life span, and the role of somnia, behaviors that contribute to degree from Harvard University and her sleep and sleep disorders on Alzheimer’s sleep disturbance, and health risks MD and PhD degrees from the University disease. She has served as principal associated with sleep disturbance. of Chicago. She has been a faculty investigator for studies funded by All of the reports are particularly member at the University of Chicago agencies, including the National Institutes relevant during the COVID-19 pan- and the University of Wisconsin– of Health and the Department of Defense. demic, as insomnia and psychiatric Madison, where she was associate Her work has spanned basic research in illnesses have increased dramatically, chair of the psychiatry department and animal models to clinical research and largely related to the multitude of director of the UW Center for Sleep clinical trials. Dr. Benca has authored over pandemic-related stressors. They Medicine and Sleep Research. 150 articles, reviews, and book chapters. highlight the importance of assess- Dr. Benca moved to UC Irvine in She currently is editor-in-chief of Current ing and treating sleep problems in 2016, where she has established a Sleep Medicine Reports and insomnia our patients, now more than ever. sleep medicine center, which provides section editor for UpToDate. clinical care for sleep disorders and Dr. Benca has served as a consultant Dr. Benca is professor and chair of the promotes translational research. to Eisai, Idorsia Pharmaceuticals, department of psychiatry and human Her research focuses on the interface Genomind, Jazz Pharmaceuticals, Merck, behavior at the University of California, between sleep and psychiatric disorders and Sunovion.

A Special Report • June 2021 9

08_9ASUPP21Sleep.indd 9 5/17/2021 3:40:21 PM ‘No mobile phone’ phobia tied to sleep problems in college students

BY MEGAN BROOKS Commentary by Dr. Benca omophobia” – the fear of being without Use of smartphones has become almost ubiquitous in modern a mobile phone or out of mobile phone society. These devices are used for an ever-increasing range of contact – is extremely prevalent among activities, including social interaction, entertainment, learning, college students and is associated with shopping, and so on, raising the question of whether distress “Npoor sleep habits and fatigue. In a study of more upon disconnection from such a vital communication tool than 300 college students, nearly 9 in 10 (89%) were should be considered a psychological disorder or a predict- classified as having moderate to severe nomophobia. able response to sudden social isolation! Greater levels of nomophobia were significantly Nomophobia, or fear of being without a mobile phone, is linked to daytime sleepiness and more behaviors as- understandably increased when there is extreme reliance on sociated with poor sleep hygiene. its use. The study by Peszka and colleagues found a high “My undergraduate research team came up with prevalence of moderate to severe nomophobia (89%) in a the idea for this study,” said study investigator Jenni- survey of undergraduate college students; several other stud- fer Peszka, PhD, professor of psychology at Hendrix ies have similarly found adolescents and young adults to have College, Conway, Ark. She explained that her students reported rates of at least 80%. Factors that are consistently had been looking at the impact of technology use in associated with higher levels of nomophobia include younger the 2 hours before bed, and hypothesized that “cell age and more hours of daily phone use. This suggests again phone addiction” might play a role in sleep problems. that greater reliance on mobile phones as a primary route Incidentally, “that group of students were all pret- of communication results in more severe distress upon the ty high on nomophobia themselves so they were re- threat of losing them. ally interested in the outcome,” Dr. Peszka said. Not surprisingly, excessive phone use and nomophobia are The study findings were presented at the virtual strongly related to sleep problems. Excessive use of smart- annual meeting of the Associated Professional Sleep phones is associated with insomnia, reduced sleep quality, Societies. and sleep loss. Teenagers and young adults who already have a tendency to be “night owls” often use smartphones late A likely suspect into the night. The results of the study reported here further The study involved 327 undergraduates (mean age, 19.7 support these associations, with increased use of the phone Continued on following page } during sleep time and more daytime sleepiness associated with greater nomophobia. More severe nomophobia occurs in those with greater anxiety or depression, both of which in turn are strongly associated with disturbed sleep; in the current study, decreased motivation – a symptom of depression – was also associated with nomophobia. Other potential health risks have been linked with nomophobia. Increased rates of both prohibited (that is, using a cell phone in a restricted area) and dangerous (that is, using a cell phone while driving) use of cell phones have been reported in younger individuals, with increased hours of daily phone use, increased nomophobia, and in males, higher concerns for more accidents and injuries. Clearly, extreme nomophobia might identify individuals with psychological characteristics that can put them at risk for other disorders. Further work is needed to identify risk factors for nomophobia, particularly in young people. How does living a significant portion of waking life virtually through cell phones affect psychological development during the critical period of adolescence? These issues are further intensified during the COVID-19 pandemic, which has led to severe social isolation for young people due to school closures and elimination of sports and social activities. Cade/Stone/Getty Images Peter

10 June 2021 • Sleep Medicine

10to12ASUPP21Sleep.indd 10 5/17/2021 3:41:48 PM Smartphone ‘addiction’ tied to poor sleep in young adults

BY MEGAN BROOKS lead investigator Ben Carter, PhD, King’s College London, noted in the martphone “addiction” may report. explain poor sleep quality in In a cross-sectional survey, a significant proportion of 1,043 college students (aged 18-30 young adults, new research years, 73% women) completed the Ssuggests. 10-question validated Smartphone Investigators found that almost Addiction Scale Short Version (SAS- 40% of adults aged 18-30 years who SV) and the adapted Pittsburgh self-reported excessive smartphone Sleep Quality Score Index. use also reported poor sleep. On the SAS-SV, 406 students “Our study provides further (38.9%) reported “addiction” to support to the growing body of their smartphones. This estimated evidence that smartphone addiction Dr. Carter prevalence is consistent with other has a deleterious impact on sleep,” reported studies in young adult wrote the researchers. Not a clinical diagnosis populations globally, which is in the The study was published on- Smartphone addiction is not formal- range of 30%-45%, the researchers line March 2 in Frontiers of Psychia- ly recognized as a clinical diagnosis, noted. try (doi: 10.3389/fpsyt.2021.629407). but it’s an “active” area of research, Continued on following page }

| Continued from previous page Dasgupta, MD, University of South- years) recruited from introductory For now, ern California, Los Angeles, said this is psychology courses and campus news- a “very timely study with COVID-19. letters. They completed several ques- technology is the Right now, more than ever, technol- tionnaires, including the Nomophobia ogy is a double-edged sword. I’m a Questionnaire, the Epworth Sleepiness only way some father of three kids and, for now, tech- Scale, and the Sleep Hygiene Index. nology is the only way some kids are Nomophobia was prevalent, with kids are going to going to be socializing and learning.” mild, moderate, and severe nomopho- be socializing and Yet a foundation of good sleep bia reported by 10%, 83%, and 7% hygiene is keeping a nightly sleep of students, respectively. Only one learning. routine, said Dr. Dasgupta, who was student reported no nomophobia at not involved in the study. “Right all. Dr. Peszka said the fact that 89% using technology during sleep time, now, it seems like all my sleep pa- of students had moderate or severe long daytime naps, inconsistent wake tients are becoming night owls and nomophobia is “concerning,” given a and bed times, using bed for non sleep time is becoming more and 2012 study suggesting that 77% of 18- sleep purposes, uncomfortable bed, more delayed because there is so to 24-year-olds had nomophobia. This and bedtime cognitive rumination). much news to keep up with. Also, phobia “very well may be on a rapid Prior research has shown that you may be stressed at night and rise,” she lamented. smartphones may lead to compulsive you may not have the motivation to Greater severity of nomophobia “checking” habits, compulsive usage, wake up early in the morning.” was significantly correlated with increased distress, and potentially ad- He said it is important to counsel greater sleepiness measured by both dictive behaviors. Active phone use at patients to “put technology away at the Epworth Sleepiness Scale (P < bedtime has also been implicated in night. That goes for kids and adults.” .05) and the Associated Features of disrupted sleep. Nomophobia is like- Support for the study was pro- Poor Sleep Hygiene daytime sleep- ly to be an important consideration vided by Hendrix College Charles iness item (P < .05). More severe when treating sleep disorders and/ Brewer Fund for Psychology. Dr. nomophobia was also related to or making any sleep hygiene recom- Peszka and Dr. Dasgupta disclosed decreased motivation (a commonly mendations, Dr. Peszka said. no relevant financial relationships. reported symptom of insufficient sleep) and with more maladaptive Proliferation of ‘night owls’ A version of this article originally sleep hygiene behaviors (including Reached for comment, Rajkumar (Raj) appeared on Medscape.com.

A Special Report • June 2021 11

10to12ASUPP21Sleep.indd 11 5/17/2021 3:41:53 PM | Continued from previous page lescent Psychiatry, said the finding phone in another room, “the sleep Overall, 61.6% of participants sur- of a relationship between addictive problem resolves,” Dr. Weigle said. veyed reported poor sleep; among smartphone usage and poor sleep One caveat, he said, is that it’s those who reported smartphone ad- quality is not surprising. “somewhat unclear whether this diction, 68.7% had poor sleep qual- “Great increases in adolescent is best classified as an addiction ity, vs. 57.1% of those who did not screen media habits in recent decades or simply a seriously problematic report smartphone addiction. have seen a concurrent increase in habit. Either way, this type of habit In multivariable analysis that ad- rates of insomnia among this popula- causes a great deal of distress and justed for a variety of relevant fac- tion,” he said in an interview. dysfunction in the lives of those it tors, among those for whom there Dr. Weigle also noted that young affects, so it is important to under- was evidence of smartphone addic- people who use the phone exces- stand,” he said. tion, the odds of poor sleep were sively often do so in bed, “which In a statement, Bob Patton, PhD, increased by 41% (adjusted odds decreases sleep onset by disrupting lecturer in clinical psychology, University of Surrey, Guildford, En- gland, noted that this is a cross-sectional study “and as such cannot lead to any firm conclusions about phone usage as the cause of reduced sleep quality. “It does, however, provide some compelling evidence,” Dr. Patton said, “that the nature of smartphone usage and its related consequences are important considerations in addressing the emerging phenomenon of ‘smartphone addiction.’ ” Also weighing in, Andrew Przy- bylski, PhD, director of research, Oxford (England) Internet Institute, University of Oxford, said the study is “the latest, among many dozens of others, to study so-called ‘smartphone addiction,’ a condition which is not recognized by any global health body

maewjpho/Thinkstock and is not a psychiatric disorder. “The study is a correlational anal- ratio [aOR] = 1.41; 95% confidence conditioning (the tendency for our ysis of a sample of participants re- interval, 1.06-1.87; P = .018). bodies to relate bed with sleep) and cruited on university campuses and The findings also suggest that a by increasing physiological arousal, therefore only reflects the experienc- greater amount of time spent using which makes it more difficult to fall es of those who had the purpose of the phone and greater use late at asleep. The blue light from smart- the study explained to them. It can night can raise the risk for smartphones used at night disrupts our say nothing about behaviors in the phone addiction. body’s natural circadian rhythms, general population,” Dr. Przybylski “Should smartphone addiction confusing our brains regarding said in a statement. become firmly established as a focus whether it is night or day, and fur- “Readers should be cautious of of clinical concern, those using their ther worsens sleep.” making any firm conclusions about phones after midnight or using their Dr. Weigle said in an inter- the impact of smartphone use in the phones for four or more hours per view that some of his patients come general population, or the idea that day are likely to be at high risk, and to him seeking sleep medications, they’re addictive in any objective should guide administration of the although the best treatment is to sense, on the basis of this work,” he SAS-SV,” the researchers wrote. perform a “smartphone-ectomy” added. every evening. The study had no specific funding. Caveats, cautions, and concerns Teenage patients will “beg, bor- Dr. Carter, Dr. Weigle, Dr. Patton, Reached for comment, Paul Wei- row, or steal” to be allowed to keep and Dr. Przybylski have disclosed no gle, MD, psychiatrist with Hartford their phones by the bed with the relevant financial relationships. HealthCare and Hartford (Conn.) promise not to use them overnight. Hospital, and member of the Amer- Three-quarters of the time, when A version of this article originally ican Academy of Child and Ado- the parents are able to charge the appeared on Medscape.com.

12 June 2021 • Sleep Medicine

10to12ASUPP21Sleep.indd 12 5/17/2021 3:42:00 PM Use of e-cigarettes may be linked to sleep deprivation

BY RICHARD FRANKI Sleep deprivation more common in e-cigarette users FROM ADDICTIVE BEHAVIORS 1.49 Never used, 1.0 (reference) urrent and former users of 1.42 e-cigarettes are more likely to 1.31 1.25 report sleep deprivation, com- 1.17 pared with those who have 1.08 Cnever used e-cigarettes, according to the first study to evaluate the association in a large, nationally represen- Bivariate model* Fully adjusted model** tative population of young adults. * E-cigarette exposure and sleep deprivation Prevalence ratio “The e-cigarette use and sleep ** Also includes 12 confounders, such as gender, body mass index, deprivation association seems to race, employment status, marital status, and cigarette smoking status have a dose-response nature as the point estimate of the association in- MDedge News creased with increased exposure to Every day Some days Former e-cigarettes,” Sina Kianersi, DVM, Level of e-cigarette use and associates at Indiana University, Bloomington, said in Addictive Be- Note: Based on data for 18,945 (bivariate) and 16,427 (fully adjusted) young adults who haviors. responded to the 2017 and 2018 Behavioral Risk Factor Surveillance System surveys. Sleep deprivation was 49% more Source: Addict Behav. 2020 Sep 6. doi: 10.1016/j.addbeh.2020.106646 prevalent among everyday users of e-cigarettes, compared with non- (1.31) and occasional users (1.25) analysis of data from young adults users. also showed significantly higher aged 18-24 years who participated The investigators found that sleep deprivation, compared with in the 2017 and 2018 Behavioral prevalence ratios for former users nonusers, based on a bivariate Continued on following page }

Commentary by Dr. Benca comes, including those with obesity, poor mental health and Use of e-cigarettes in adolescents and young adults is in- depression, and alcohol abuse, which may further compound creasing dramatically. In the current study, use among the the risks of nicotine use in young people. population of 18- to 24-year-olds sampled jumped from 10% The current study demonstrated that in a study of more than in 2017 to 15.7% in 2018. Rates are even higher among 19,000 young adults, sleep amounts were significantly lower younger individuals, with more than 1 in 5 high school stu- in those who used e-cigarettes and were lowest in those who dents reporting current use of e-cigarettes. reported daily use. Users were more likely to report a diagnosis Nicotine is a stimulant that has significant negative impacts of depression, which is also associated with sleep disturbance, on sleep, leading to insomnia, both at the beginning of the but even after controlling for depression and other health and night (prolonged latency to sleep onset) as well as during the demographic confounders, daily use of e-cigarettes was associ- night (increased fragmentation of sleep and decreased sleep ated with a 42% increased prevalence rate of obtaining less than efficiency). It also can decrease the amount of deep slow- 7 hours of sleep per night. Seven hours per night is even a likely wave sleep. These sleep-disruptive effects can lead to sleep underestimation of the average amount of sleep needed by this deprivation with resulting daytime sleepiness. Withdrawal from age group, because the recommended range is 7-9 hours per nicotine also leads to decreased sleep quality and daytime night! The additional effects of sleep deprivation in young people sleepiness, as well as increased depression. can further add to health risks, particularly because adolescents Given that brain development continues to the middle of and young adults are even more vulnerable to the effect of sleep the third decade of life, effects of nicotine in adolescents and loss than older adults. Chronic insufficient sleep can lead to young adults are particularly concerning, and can lead to increased risk of accidents and injuries, mood dysregulation, problems with attention, impulsivity, and anxiety. Furthermore, problems with attention and memory, obesity, cardiovascular nicotine is a gateway drug to the use of other addictive sub- disease, metabolic syndrome, and – particularly relevant during stances. Even more alarming is that e-cigarette use is greater this time of the COVID-19 pandemic – increased susceptibility in individuals who are already at risk for poorer health out- to infections and decreased immune response to vaccination.

A Special Report • June 2021 13

13to16ASUPP21Sleep.indd 13 5/17/2021 3:46:22 PM Experts advocate for the elimination of daylight saving time

BY MEGAN BROOKS Significant health risks FROM SLEEP 2020 In the United States, the annual “spring forward” to n the interest of public health daylight saving time and and safety, the American Acade- “fall back” to standard my of Sleep Medicine is calling time is required by law, for the elimination of daylight although under the statute Isaving time in favor of permanent some exceptions are per- year-round standard time – a recom- mitted. mendation that has garnered strong There has been intense support from multiple medical and debate over the last sever- other high-profile organizations. al years about transitioning “Permanent, year-round standard between standard and daylight time is the best choice to most saving time. The AASM says there closely match our circadian sleep- is “an abundance of evidence” to wake cycle,” M. Adeel Rishi, MD, indicate that quick transition from lead author of the AASM position standard time to daylight saving Francesca Bellini/iStock/Getty Images statement, said in a news release. time incurs significant public health A recent study also showed an in- “Daylight saving time results in and safety risks, including increased crease in medical errors in the week more darkness in the morning and risk of heart attack, stroke, mood after switching to daylight saving time. more light in the evening, disrupt- disorders, and car crashes. “Because the adoption of perma- ing the body’s natural rhythm,” “Although chronic effects of re- nent standard time would be benefi- said Dr. Rishi, of the department of maining in daylight saving time year- cial for public health and safety, the pulmonology, critical care, and sleep round have not been well studied, AASM will be advocating at the fed- medicine, Mayo Clinic, Eau Claire, daylight saving time is less aligned eral level for this legislative change,” Wis., and vice chair of the AASM with human circadian biology – said AASM President Kannan Ra- Public Safety Committee. which, because of the impacts of mar, MBBS, MD, with the Mayo The position statement was the delayed natural light/dark cycle Clinic in Rochester, Minn. published Aug. 26 in the Journal on human activity, could result in It seems that many Americans are of Clinical Sleep Medicine (doi: circadian misalignment, which has in favor of the change. In July, an 10.5664/jcsm.8780) to coincide been associated in some studies with AASM survey of roughly 2,000 U.S. with the virtual annual meeting of increased cardiovascular disease adults showed that two-thirds sup- the Associated Professional Sleep risk, metabolic syndrome, and other port doing away with the seasonal Societies. health risks,” the authors wrote. Continued on following page }

| Continued from previous page a significant 1.17, the investigators hand, has been found to increase Risk Factor Surveillance System said. sleep duration in a dose-dependent surveys. “The nicotine in the inhaled e-cig- manner, which “could explain the After adjustment for multiple arette aerosols may have negative smaller [prevalence ratios] observed confounders, young adults who effects on sleep architecture and for the association between e-cig- currently used e-cigarettes every disturb the neurotransmitters that arette use and sleep deprivation day were 42% more likely to re- regulate sleep cycle,” they suggest- among former and some days e-cig- port sleep deprivation than those ed, and because higher doses of arette users,” Dr. Kianersi and asso- who never used e-cigarettes, a nicotine produce greater reductions ciates added. difference that was statistically sig- in sleep duration, “those who use The bivariate analysis involved nificant. The prevalence of sleep e-cigarette on a daily basis might 18,945 survey respondents, of deprivation among those who used consume higher doses of nicotine, whom 16,427 were included in the e-cigarettes on some days was not compared to some days, former, fully adjusted model using 12 con- significantly higher (prevalence and never users, and therefore get founding factors. ratio, 1.08), but the ratio between fewer hours of sleep.” The authors of the paper dis- former users and never users was Nicotine withdrawal, on the other closed no conflicts of interest.

14 June 2021 • Sleep Medicine

13to16ASUPP21Sleep.indd 14 5/17/2021 3:46:30 PM Insomnia may have a role in generation of stressful life events

BY CHRISTINE KILGORE events that create family conflict or ing commitments, and other sources FROM SLEEP 2020 disrupt careers, for instance – than [of stressful life events],” she said. individuals who are not depressed. “This extension of the stress-genera- nsomnia disorder appears to play The new analysis of individuals tion hypothesis has important implica- a causal role in the development with involuntary job loss suggests that tions for harm reduction interventions of new stressful life events, es- the same can be said of insomnia. for insomnia disorder.” pecially “dependent” events for “Insomnia disorder is associated with Investigators conducted a cross- Iwhich individuals are at least partly fatigue, daytime sleepiness, impaired lagged panel analysis using baseline responsible, said the investigators concentration, and difficulties in emo- and 3-month follow-up data from of an ongoing longitudinal study of tional regulation,” Iva Skobic, MSPH, 137 individuals who completed a people who have experienced invol- MA, a PhD student at the University standardized, textual life event mea- untary job loss. of Arizona, Tucson, said at the virtual sure called the Life Events and Dif- The “stress-generation hypothe- annual meeting of the Associated Pro- ficulties Schedule after having lost sis” has been applied for several de- fessional Sleep Societies. their jobs involuntarily. Participants cades in the context of depression. “These may lead to impaired deci- were interviewed and their events It posits that depressed individuals sion-making, interpersonal conflicts, were rated for severity by a consen- generate more stressful life events – difficulty meeting deadlines and keep- Continued on following page }

| Continued from previous page Sleep Medicine, and the Society of ated consequences,” he added. time change. Only 11% opposed it. Behavioral Sleep Medicine. In light of this research, the rec- In addition, the academy’s 2019 sur- Weighing in on the issue, Saul ommendation to dispense with vey showed more than half of Rothenberg, PhD, from the Sleep daylight saving time seems “quite adults feel extremely, or somewhat, Center at Greenwich Hospital, reasonable” from a public health tired after the springing ahead to Conn., said the literature on day- perspective. “I am left with a daylight saving time. light saving time has grown over the strengthened view on the impor- past 20 years. He said he was ”hum- tance of regular adequate sleep Strong support bled” by the research that shows as a way to enhance health, per- The position statement has been that a “relatively small” misalign- formance, and quality of life,” he endorsed by 19 organizations, in- ment of biological and social clocks added. cluding the American Academy has a measurable impact on human This research had no commercial of Cardiovascular Sleep Medicine, health and behavior. funding. Dr. Rishi and Dr. Rothen- American College of Chest Physi- “Because misalignment is associat- berg have disclosed no relevant fi- cians, American College of Occupa- ed with negative health and perfor- nancial relationships. tional and Environmental Medicine, mance outcomes, keeping one set National PTA, National Safety of hours year-round is promoted to A version of this article originally Council, Society of Anesthesia and minimize misalignment and associ- appeared on Medscape.com.

Commentary by Dr. Sundar shift to daylight saving time (DST) in not unexpected. Even a Living creatures have developed biological rhythms that are 1-hour shift in time change is associated with increased risk adapted to the 24-hour rotation of the earth. The sleep-wake of myocardial infarctions and strokes in the first few days after cycle is the dominant circadian and, like all biological and DST begins (Int Emerg Med. 2018;13:641-6) and worsening behavioral rhythms, sleep is regulated by transcriptional-trans- of inflammatory bowel disease and depression in the fall lational feedback loops. In fact, up to 43% of protein-coding (Front Med. 2019;6:103). There is now widespread recognition genes in mammals show circadian rhythms (Proc Natl Acad of adverse health effects of DST amongst health professionals Sci USA. 2014;111[45]:16219-24) and changes in sleep and societies along with increasing advocacy for a need for duration and timing can have profound effects on both central legislative change for public health and safety. This statement and peripheral clock genes (J Sleep Res. 2015;24:476-93). by the American Academy of Sleep Medicine is timely and Given the widespread effects of clock gene outputs on both medical professionals and lay public should vigorously protein expression, the effects of clock misalignment from support the push to eliminate DST.

A Special Report • June 2021 15

13to16ASUPP21Sleep.indd 15 5/17/2021 3:46:34 PM | Continued from previous page sus panel using operationalized criteria. The analysis Commentary by Dr. Benca employed linear regression controlling for covariates Job loss is one of the 10 most stressful life events, and (age, gender, and race) and logistic regression that more than 20 million Americans have lost their jobs as a controlled for insomnia at baseline. Insomnia disor- result of the COVID-19 pandemic. It is, unfortunately, only der was defined as meeting ICSD-2/3 criteria using one of many stressors affecting the population during the the Duke Structured Interview for Sleep Disorders. current pandemic and leading to widespread insomnia, or The findings: Insomnia disorder at baseline predicted “coronasomnia.” the number of stressful life events (either dependent or Most of us have experienced how a stressful event can dis- interpersonal) generated within 3 months (beta, 0.70; rupt our sleep, and how we are more irritable and vulnerable standard error, 0.31; T score, 2.27; P = .03). Conversely, to stress following a bout of insomnia. That is because one of the number of stressful events at baseline did not pre- the functions of sleep is to downregulate our experiences of dict insomnia (odds ratio, 0.97; 95% confidence inter- emotional distress, and both insomnia and sleep loss lead to val, 0.73-1.29). There also was a trend toward increased a decrease in our ability to have a more positive emotional generation of dependent events specifically among response to a positive event. those with insomnia disorder. To make matters worse, individuals prone to insomnia tend Participants were a mean age of 42 years, and all to have greater sleep disruption during stressful situations, had been in their previous place of employment for at and show physiological evidence of hyperarousal during both least 6 months. Nearly 60% met the diagnostic thresh- waking and sleep, as well as increased emotional reactivity. old for insomnia at baseline. They were part of a larg- Insomnia is also closely linked to depression, with individuals er ongoing study examining the linkages between job experiencing chronic insomnia having a significantly greater loss and sleep disturbances, obesity, and mental health risk of developing depression. Furthermore, like those with – the Assessing Daily Activity Patterns through Occu- insomnia, depressed individuals also show increased stress pational Transitions (ADAPT) study, supported by the reactivity, which could also be contributing to the findings National Heart, Lung, and Blood Institute. noted in this study, as the analysis did not control for de- This analysis on insomnia was completed before the pressive symptoms. COVID-19 pandemic began, but it and other analyses The important finding in this study, however, is that baseline soon to be reported are highly relevant to the eco- insomnia predicted increased stressful life events, particularly nomic climate, said Patricia Haynes, PhD, principal in- those that were “dependent” and thus presumably somewhat vestigator of ADAPT and a coauthor of the insomnia under subjects’ control. This is consistent with other studies study, in an interview after the meeting. that have reported that poor sleep was predictive of more work Insomnia is a frequent comorbidity of depression and family conflict the following day. and shares many of its symptoms, from increased The interesting thing about the design of the current study is fatigue to emotional dysregulation and an increased that all the subjects had recently experienced involuntary job risk of maladaptive coping strategies. “Interestingly, loss, a major life stressor, but not all of them had insomnia. the literature on the stress-generation hypothesis Those with insomnia at the time of study entry reported signifi- posits that these very symptoms are on the casu- cantly more stressful life events in the subsequent 3 months. al pathway between depression and stressful life This suggests that the lack of insomnia in some individuals events,” said Ms. Skobic at the meeting. after job loss indicated a greater level of resilience and thus In commenting on the study, Krishna M. Sundar, better ability to cope with ongoing life challenges. There is also MD, medical director of the Sleep-Wake Center at evidence that better sleep and/or successful treatment of in- the University of Utah, Salt Lake City, noted that somnia may improve daytime emotional function and decrease the analysis did not include any measure of the the likelihood of becoming entangled in stressful interactions severity of insomnia. Still, he said, “finding an as- and events. Thus the findings overall suggest a bidirectional sociation [with stress generation] at [just] 3 months relationship between stress and insomnia, whereby increasing with the presence of insomnia disorder is quite either component exacerbates the other, and conversely, de- interesting.” creasing either component can improve the other. There were higher rates of insomnia in the sample In the current pandemic, there has been a dramatic increase than depression, Dr. Haynes said, but the analysis in major life stressors experienced by a large segment of the did not control for depression or take it into account. population. Not surprisingly, those living and working in more “We know [from prior research] that stress clearly stressful situations (for example, essential workers, those leads to insomnia. The big [takeaway] here is that in- from lower socioeconomic levels, and minorities) have shown somnia can also lead to more stress,” she said. “It’s im- increased rates of insomnia. Results from this study suggest portant to think of it as a reciprocal relationship. If we that they may be more vulnerable to experiencing increased can potentially treat insomnia, we may be able to stop stressful life events and more vulnerable to psychiatric disor- that cycle of other stressful events that affect both [the ders, highlighting the need for health care providers to assess individuals] and others as well.” sleep problems routinely. Ms. Skobic had no disclosures.

16 June 2021 • Sleep Medicine

13to16ASUPP21Sleep.indd 16 5/17/2021 3:46:38 PM Treating insomnia, anxiety in pregnancy and postpartum period in pandemic

BY LEE S. COHEN, MD a review of the risks and benefits of treatment before, during, and after ince the start of the pandem- pregnancy. ic, we have been conducting Seemingly, week to week, more an extra hour of Virtual and more colleagues raise questions Rounds at the Center for about the treatment of anxiety and SWomen’s Mental Health. Virtual insomnia during pregnancy and Rounds has been an opportunity the postpartum period. I’ve spoken to discuss cases around a spectrum in previous columns about the en- of clinical management issues with hanced use of telemedicine. Tele- respect to depression, bipolar disor- medicine not only facilitates efforts der, and a range of anxiety disorders like Virtual Rounds and our ability like obsessive-compulsive disorder to reach out to colleagues across the (OCD), posttraumatic stress disor- country and share cases, but also Dr. Cohen is the director of the Ammon- der (PTSD), and generalized anxiety has allowed us to keep even closer Pinizzotto Center for Women’s Mental disorder. How to apply the calculus tabs on the emotional well-being of Health at Massachusetts General of risk-benefit decision-making our pregnant and postpartum wom- Hospital (MGH) in Boston, which around management of psychiatric en during COVID-19. provides information resources and disorders during pregnancy and the The question is not just about the conducts clinical care and research postpartum period has been the cor- effects of a medicine that a woman in reproductive mental health. He has nerstone of the work at our center might take to treat anxiety or in- been a consultant to manufacturers of for over 2 decades. somnia during pregnancy, but the psychiatric medications. When we went virtual at our cen- experience of the pandemic per se, ter in the early spring, we decided which we are measuring in multiple to keep the format of our faculty studies now using a variety of psy- insomnia can be part and parcel of an rounds the way they have been for chological instruments that patients underlying mood disorder. years and to sustain cohesiveness of complete. The pandemic is unequiv- With that in mind, what are the our program during the pandemic. ocally taking a still unquantified toll options? During the pandemic, we’ve But we thought the needs of preg- on the mental health of Americans seen an increased use of digital cog- nant and postpartum women war- and potentially on the next genera- nitive behavioral therapy for insom- ranted being addressed in a context tion to come. nia (CBT-I) for patients who cannot more specific to COVID-19, and also initiate sleep, which has a very strong that reproductive psychiatrists and Midcycle awakening evidence base for effectiveness as a other clinicians could learn from during pregnancy first-line intervention for many. each other about novel issues coming Complaints of insomnia and midcy- If a patient has an incomplete up for this group of patients during cle awakening during pregnancy are response to CBT-I, what might be the pandemic. With that backdrop, not new – it is the rule, rather than pursued next? In our center, we Marlene Freeman, MD, and I found- the exception for many pregnant have a low threshold for using low ed “Virtual Rounds at the Center” women, particularly later in preg- doses of benzodiazepines, such as to respond to queries from our col- nancy. We have unequivocally seen a lorazepam or clonazepam, because leagues across the country; we do worsening of complaints of sleep dis- the majority of data do not support this just after our own rounds on ruption including insomnia and mid- an increased risk of major con- Wednesdays at 2:00 p.m. cycle awakening during the pandemic genital malformations even when As the pandemic has progressed, that is greater than what we have used in the first trimester. It is quite Virtual Rounds has blossomed into seen previously. Both patients and col- common to see medicines such as a virtual community on the Zoom leagues have asked us the safest ways newer nonbenzodiazepine sedative platform, where social workers, to manage it. One of the first things hypnotics such as Ambien CR (zolp- psychologists, nurse prescribers, psy- we consider when we hear about idem) or Lunesta (eszopiclone) used chiatrists, and obstetricians discuss insomnia is whether it is part of an by our colleagues in ob.gyn. The the needs of pregnant and postpar- underlying mood disorder. While reproductive safety data on those tum women specific to COVID-19. we see primary insomnia clinically, it medicines are particularly sparse, Frequently, our discussions involve really is important to remember that Continued on following page }

A Special Report • June 2021 17

17to19ASUPP21Sleep.indd 17 5/17/2021 3:48:03 PM data on biobehavioral intervention for anxiety is enormous, and this should be used as first-line treatment for patients with mild to moderate symptoms; so many women would prefer to avoid pharmacological intervention during pregnancy, if possible, to avoid fetal drug exposure. For patients who meet criteria for frank anxiety disorder, other nonpharmacologic interventions such as CBT have been shown to be effective. Frequently, we see women who are experiencing levels of anxiety where nonpharmacological interventions have an incomplete response, and colleagues have asked about the safest way to treat these patients. As has been discussed in multiple previous columns, selective

becon/E+ serotonin reuptake inhibitors (SS- RIs) should be thought of sooner | Continued from previous page safe. Over time, anxiety has shifted rather than later, particularly with and they may have greater risk of to still staying safe during the pan- medicines with good reproductive cognitive side effects the next day, so demic and the potential impact of safety data such as sertraline, citalo- we tend to avoid them. SARS-CoV-2 infection on pregnancy pram, or fluoxetine (N Engl J Med. Another sometimes-forgotten op- outcomes. The No. 1 concern is 2014 Jun 19; 370(25):2397-407). tion to consider is using low doses of what the implications of COVID-19 We also reported over 15 years tricyclic antidepressants (that is, 10-25 disease are on mother and child. ago that at least 30%-40% of wom- mg of nortriptyline at bedtime), with New mothers also are anxious en presenting with histories of tricyclics having a 40-year history and about how they will practically recurrent major depression at the at least one pooled analysis showing navigate life with a newborn in the beginning of pregnancy had co- the absence of increased risk for ma- postpartum setting. morbid anxiety disorders, and that jor congenital malformations when Early on in the pandemic, some the use of benzodiazepines in that used. This may be a very easy way of hospital systems severely limited population in addition to SSRIs was managing insomnia, with low-dose who was in the room with a woman exceedingly common, with doses tricyclics having an anxiolytic effect during labor, potentially impeding of approximately 0.5-1.5 mg of as well. the wishes of women during deliv- clonazepam or lorazepam being ery who would have wanted their standard fare. Again, this is very Anxiety during pregnancy loved ones and/or a doula present, appropriate treatment to mitigate The most common rise in symp- as an example. With enhanced test- anxiety symptoms because now toms during COVID-19 for women ing available now, protocols have have enough data as a field that who are pregnant or post partum since relaxed in many hospitals to support the existence of adverse has been an increase in anxiety. allow partners – but not a team – to outcomes associated with untreated Women present with a spectrum remain in the hospital during the anxiety during pregnancy in terms of concerns leading to anxiety labor process. Still, the prospect of both adverse obstetric and neo- symptoms in the context of the of delivering during a pandemic is natal outcomes, higher rates of pandemic. Earlier on in the pan- undoubtedly a source of anxiety for preterm birth, and other obstetric demic, concerns focused mostly some women. complications. Hence, managing on how to stay healthy, and how to This sort of anxiety, particularly anxiety during pregnancy should mitigate risk and not catch SARS- in patients with preexisting anxiety be considered like managing a toxic CoV-2 during pregnancy, as well as disorders, can be particularly chal- exposure – the same way that one the very complex issues that were lenging. Fortunately, there has been would be concerned about anything playing out in real time as hospital a rapid increase over the last several else that a pregnant woman could systems were figuring out how to years of digital apps to mitigate be exposed to. manage pregnant women in labor anxiety. While many of them have Lastly, although no atypical anti- and to keep both them and staff not been systematically studied, the psychotic has been approved for the

18 June 2021 • Sleep Medicine

17to19ASUPP21Sleep.indd 18 5/17/2021 3:48:11 PM treatment of anxiety, its use off label atypical antipsychotics, SSRIs, lith- would not be used as a first-line is extremely common. More and ium, and pharmacovigilance inves- treatment for the management of more data support the absence of tigations among other important anxiety or insomnia during preg- a signal of teratogenicity across the topics. In this study, the database nancy. But these new data still are family of molecules including atypi- was used to look specifically at 4,642 reassuring for patients who come cal antipsychotics. Beyond potential pregnancies with gabapentin expo- in, frequently with unplanned use of atypical antipsychotics, at Vir- sure relative to 1,744,447 unexposed pregnancies. It is an important re- tual Rounds last week, a colleague pregnancies, without a significant minder to those of us taking care asked about the use of gabapentin finding for increased risk for major of patients during the pandemic in a patient who was diagnosed with congenital malformations (PLOS to review use of contraception, substance use disorder and who Med. 2020 Sep 1;17(9):e1003322). because although data are unavail- had inadvertently conceived on ga- The question of an increased able specific to the period of the bapentin, which was being used to risk of cardiac malformations pandemic, what is clear is that, even treat both anxiety and insomnia. We and of increased risk for obstet- prior to COVID-19, 50% of preg- have typically avoided the use of ga- ric complications are difficult to nancies in America were unplanned. bapentin during pregnancy because untangle from anxiety and depres- Addressing issues of reliable use of prospective data have been limited to sion, as they also are associated contraception, particularly during relatively small case series and one with those same outcomes. With the pandemic, is that much more report, with a total of exposures in that said, the analysis is a welcome important. roughly the 300 range. addition to our knowledge base In this particular case, our clini- However, our colleagues at the for a medicine used more widely cian colleague in Virtual Rounds Harvard School of Public Health to treat symptoms such as anxi- decided to continue gabapentin have recently published an article ety and insomnia in the general across pregnancy in the context of that looked at the United States population, with a question mark these reassuring data, but others Medicaid Analytic eXtract (MAX) around where it may fit into the may choose to discontinue or pur- dataset, which has been used to algorithm during pregnancy. sue some of the other treatment publish other articles addressing In our center, gabapentin still options noted above.

Commentary by Dr. Benca gestational hypertension, preeclampsia, miscarriage, preterm The COVID-19 pandemic has had a significant impact on birth, low birth weight, as well as worse cognitive and emo- sleep and mental health in people worldwide. COVID-19 tional development in infants and children. infection can lead to insomnia and new onset of psychiatric Pregnancy is thus a time of increased risk for both sleep illness. But the effects of the pandemic go far beyond those and psychiatric problems that can significantly impact the who have been infected – multiple studies have shown per- health of both mother and baby. Women receiving prenatal sistently increased rates of insomnia, anxiety, and depression care potentially results in more of these disorders being in the worldwide population at large. Young people; essential identified and treated. The Virtual Rounds at the Center for workers; underrepresented minorities; and those who have Women’s Mental Health developed by Dr. Cohen is a model experienced job loss, financial loss, or loss of a loved one that can hopefully be adopted in other medical centers to help from COVID-19 are especially at risk. health care providers identify and manage psychiatric care Not surprisingly, rates of insomnia and psychological dis- during pregnancy, particularly during this time of the COVID-19 tress have also increased in pregnant women during the pandemic. A major issue in treating psychiatric disorders in COVID-19 pandemic, possibly even more so than in the gener- pregnant women is that there are essentially no controlled al population. A recent meta-analysis of 23 studies estimated studies on the safety and efficacy of psychotropic medications rates of anxiety (37%), depression (31%), psychological in this population. The Virtual Rounds gives experts the ability distress (70%), and insomnia (49%) in pregnant women, as to share valuable information about their experiences treating well as postpartum depression (22%) during the pandemic anxiety and insomnia in pregnant patients. (Front Psychol. 2020 Nov 25;11:617001. doi: 10.3389/ Dr. Cohen makes the important point that, for mothers and fpsyg.2020.617001). Given these numbers, it is imperative infants, it’s far less dangerous for mothers to use pharma- that pregnant and postpartum women are regularly screened cologic treatments for major psychiatric disorders than for for sleep problems and psychiatric symptoms. mothers to not take them, because of the potential effects of Insomnia during pregnancy not only increases the likeli- the disorders themselves. Finally, the use of video telemedicine hood for postpartum depression but also is associated with and digital cognitive-behavioral therapy, not only for insomnia other poor health outcomes in mothers and infants, including but also for depression, has increased dramatically during increased rates of preterm birth and large-for-gestational-age the pandemic, has generally good patient acceptance, and is infants. Anxiety and depression during pregnancy are asso- likely to become a major component of the “new normal” in ciated with threats to maternal and fetal health, including behavioral health care.

A Special Report • June 2021 19

17to19ASUPP21Sleep.indd 19 5/17/2021 3:48:14 PM Insomnia + COPD tied to more health care use

BY CHRISTINE KILGORE without comorbid insomnia, those graphic and other medical condi- FROM SLEEP 2020 who had both COPD and insomnia tions, COPD patients with insomnia (575,539 of the total 1,542,642) were had greater rates of health care nsomnia is “highly prevalent” older (69 vs. 64 years), more likely utilization relative to COPD patients in veterans with chronic pul- to be female (6.3% vs. 3.7%), more without insomnia,” Dr. Luyster said monary obstructive disease and likely to be Black (14% vs. 11%), in the interview. is significantly associated with and more likely to be a current Prior studies have suggested that Igreater COPD-related health care smoker (46.1% vs. 35.5%). disturbed sleep is a predictor of utilization, according to an analysis Those with both COPD and in- poorer longitudinal outcomes in of national Veterans Health Admin- somnia were also more likely to COPD, even after controlling for istration data. have a service-connected disability COPD severity, but have not looked “The study highlights the impor- rating of 50% of greater; specifically at insomnia, tance of exploring potential sleep use supplemental oxygen; she said. disturbances and disorders in this be divorced, widowed, or Commenting on the population and suggests that a tar- separated; have a high- study Octavian C. Ioa- geted treatment for insomnia may er body mass index; or chimescu, MD, PhD, of help to improve COPD outcomes have other medical or Emory University, Atlanta, in veterans with COPD and insom- psychiatric conditions – and the Atlanta VA Medi- nia,” said Faith Luyster, PhD, assis- in particular obstructive cal Center in Decatur, said tant professor at the University of sleep apnea (39% vs. 7%), the criteria used to define Pittsburgh, in an interview after the depression (21% vs. 5%), Dr. Ioachimescu insomnia – unadjudicated virtual annual meeting of the Asso- and PTSD (33% vs. 3%). ICD diagnoses as well as ciated Professional Sleep Societies, P values were < .001 for all of sedative-hypnotic prescriptions – where she presented the findings. these demographic and clinical vari- may explain part of the reported Dr. Luyster and coinvestigators ables, Dr. Luyster reported at the prevalence of insomnia. Even so, used an administrative database from meeting. the findings add to existing litera- the Veterans Affairs Corporate Data Comorbid insomnia clearly affect- ture demonstrating that COPD and Warehouse to identify more than ed health care utilization, she said. insomnia are both common disor- 1.5 million patients with COPD who Veterans with insomnia in addition ders among VHA patients, and that used VHA services over a 6-year peri- to COPD had more outpatient and their frequent coexistence “could od (fiscal years 2011-2017). Insomnia ED visits (10.5 vs. 6.9, and 1.6 vs. have adverse consequences on the was defined by ICD-9/10 diagnostic 1.4, respectively) and more hospital- overall health, functional status, codes and/or a sedative-hypnotic izations (2.2 vs. 1.8) with a primary long-term outcomes, and quality of prescription for at least 30 doses diagnostic code for COPD or COPD life of these patients.” during any of these years. exacerbation (P < .001). Questions of causation are yet Insomnia with COPD was prev- A negative binomial regression to be answered, he said. “Is it that alent in this sample of veterans at analysis (P < .001) showed that uncontrolled or severe airflow ob- 37.3%. Compared with veterans “even after controlling for demo- Continued on following page }

Commentary by Dr. Sundar and psychiatric comorbidities but also with increased health A number of studies have highlighted the importance of sleep care utilization. disturbances in patients with chronic obstructive pulmonary While causative factors for insomnia in COPD are many, poor disease (COPD) and linked it to health status, quality of life sleep quality as assessed by validated questionnaires such scores, symptoms of dyspnea and fatigue, and risk of COPD as the Pittsburgh sleep quality index has been consistently exacerbations. Whereas there has been focus on comorbid shown to be associated with an increased risk of exacerba- obstructive sleep apnea (McNicholas WT et al. Eur Respir tions (Shorofsky M et al. Chest. 2019:156:852-63). Therefore, Rev. 2019;28:190064), the prevalence of insomnia in COPD frequent nighttime symptom burden coupled with sleep dis- patients is significant, affecting at least a quarter or more pa- turbance represents a modifiable risk factor in patients with tients with COPD (Budhiraja R et al. Sleep. 2012;35(3):369- COPD (Zeidler MR et al. Sleep. 2018;1:41(5);zsy044). Routine 75). Luyster and colleagues’ study on a large sample of evaluation for sleep quality and assessment for factors driving veterans with COPD over a 6-year period confirms the high insomnia should be done in patients with COPD. Addressing prevalence of insomnia in patients with COPD. It also shows insomnia in conjunction with sleep-disordered breathing offers that insomnia in COPD was associated not only with medical the opportunity to improve COPD outcomes.

20 June 2021 • Sleep Medicine

20to23ASUPP21Sleep.indd 20 5/17/2021 3:50:57 PM Study validates OSA phenotypes in Latinos

BY CHRISTINE KILGORE REPORTING FROM SLEEP 2020

hree previously described clinical phenotypes of obstructive sleep apnea (OSA) have been validated in a large and diverse Hispanic/LatinoT community-based population for the first time, according to findings presented at the virtual annual meeting of the As- sociated Professional Sleep Societies. The three OSA symptom profiles present in this population – labeled “minimally symptomatic,” “disturbed sleep,” and “daytime sleepiness” – are consistent with recent findings from

the Sleep Apnea Global Interdisci- Juanmonino/E+/Getty Images plinary Consortium, which were published in Sleep (2018 Mar. doi: Hispanic/Latino health and disease clusters offering the “best” fit for 10.1093/sleep/zsx214), but there are in the United States. Their respirato- the data aligned with the previously notable differences in the prevalence ry events were measured overnight reported phenotypes and identi- of these clusters, with the minimally in HCHS/SOL sleep reading cen- fied daytime sleepiness in 15.3%, symptomatic cluster much more prev- ters with an ARES Unicorder 5.2, disturbed sleep (insomnia-like alent than in prior research, reported B-Alert. Sleep patterns and risk fac- symptoms) in 37.7%, and minimally Kevin Gonzalez, of the University of tors were assessed using the Sleep symptomatic (a low symptom pro- California, San Diego. Heart Health Study Sleep Habits file) in 46.9%. “Other biopsychosocial factors Questionnaire and the Epworth These phenotypes were reported may be contributing to OSA phe- Sleepiness Scale. in the European Respiratory Jour- notypes among Hispanics and Participants meeting the criteria for nal in 2014 in a cluster analysis of Latinos,” Mr. Gonzalez said in his moderate to severe OSA (with an Ap- data from a sleep apnea cohort in presentation. Prior research to char- nea Hypopnea Index of 15 or above) Iceland (2014 Dec;44[6]:1600-7) and acterize the heterogeneity of sleep were included in the analysis (n = later replicated in the analysis of apnea has not included a diverse 1,623). Their average age was 52.4 ± data from the Sleep Apnea Glob- Latino population, he emphasized. 13.9 years, and 34.1% were female. al Interdisciplinary Consortium The adults studied were aged 18- To identify phenotype clusters, in- published in Sleep in 2018. The 74 years and participants in the mul- vestigators performed a latent class consortium study also added two tisite Hispanic Community Health analysis using 15 common OSA additional phenotypes, labeled “up- Study/Study of Latinos (HCHS/ symptoms and a survey weighted to per airway symptoms dominant” SOL), a comprehensive study of adjust for selection bias. The three Continued on following page }

| Continued from previous page chymal lung disease, making the or probably more ideally through struction causing frequent noctur- latter diagnosis more overt than in [cognitive behavioral therapy] for nal arousals, dyspnea, orthopnea, others? insomnia.” overuse of inhaled sympathomi- “My bet is on a bidirectional The study did not control for metics and heightened anxiety causal relationship,” said Dr. Ioachi- COPD severity, she said, because of leads to insomnia? Or is it that mescu, an editorial board advisor of the difficulty of extracting this data insomnia – possibly in a cluster CHEST Physician. from the VA Corporate Data Ware- with other affective disorders such “Regardless of the etiology [of house. The study was funded by the as depression, anxiety disorders, insomnia in veterans with COPD],” VA Competitive Career Develop- or PTSD – elicits more frequent Dr. Luyster said, “it’s important that ment Fund. or more severe symptoms of [insomnia] be addressed and treat- Dr. Luyster reported that she had shortness of breath in those with ed appropriately, whether that be no disclosures. Dr. Ioachimescu also smoking-induced airway and paren- through pharmacological treatment, said he had no relevant disclosures.

A Special Report • June 2021 21

20to23ASUPP21Sleep.indd 21 5/17/2021 3:51:07 PM Study confirms link between PAP apnea treatment and dementia onset

BY CHRISTINE KILGORE of a 5% random sample of Medicare a month, said Galit Levi Dunietz, FROM SLEEP 2020 beneficiaries (more than 2.7 million) PhD, MPH, at the virtual annual and their claims data, investigators meeting of the Associated Profes- bstructive sleep apnea (OSA) identified approximately 53,000 who sional Sleep Societies. treatment with positive air- had an OSA diagnosis prior to 2011. Dr. Dunietz and her coinvestiga- way pressure (PAP) therapy Of these Medicare beneficiaries, tors used logistic regression to ex- was associated with lower 78% with OSA were identified as amine the associations between PAP Oodds of incident Alzheimer’s disease “PAP-treated” based on having at treatment and PAP treatment adher- and other dementia in a large retro- least one durable medical equip- ence, and incident ICD-9 diagnoses spective cohort study of Medicare ment claim for PAP equipment. And of Alzheimer’s disease (AD), mild patients with the sleep disorder. of those treated, 74% were iden- cognitive impairment (MCI), and The study builds on research link- tified as “PAP adherent” based on dementia not otherwise specified ing OSA to poor cognitive outcomes having more than two PAP equip- (DNOS) over the period 2011-2013. and dementia syndromes. With use ment claims separated by at least Continued on following page }

| Continued from previous page phenotype in prior research – con- underrecognized in Hispanics and and “sleepiness dominant.” stituted only a minority in the His- Latinos and that there is more re- The prevalence of a “minimally panic/Latino population, he said. search to be done to better identify symptomatic group” in the new anal- Alberto Ramos, MD, of the Uni- and stratify patients with varying ysis of the Hispanics/Latinos in the versity of Miami and the principal symptomatology for more person- United States is much higher than re- investigator, said in an interview alized treatment and for clinical trial ported in these prior studies, at least that the research team is currently selection. “Maybe we should expand partly, the investigators believed, be- analyzing “if and how these different our criteria ... broaden our [recog- cause the “prior studies were clinical [phenotypic] clusters could affect the nition] of the presentation of sleep samples, and the people who were incidence of comorbidities” recorded apnea and the symptoms associated minimally symptomatic didn’t get to in the HCHS/SOL study, such as hy- with it, not only in Hispanics but the sleep centers,” Mr. Gonzalez said pertension, diabetes, cardiovascular maybe in the general population,” in an interview after the meeting. disease, and cognitive decline. Dr. Ramos said. Patients with a phenotype of day- For now, he said, the findings The investigators reported no rel- time sleepiness – the most common suggest that OSA may be especially evant disclosures.

Commentary by Dr. Sundar: breathing, only 1.3% had a sleep apnea diagnosis (Redline Obstructive sleep apnea is a condition with a high prevalence S et al. Am J Respir Crit Care Med. 2014;189:335-44). The in the general population, and given its protean effects on finding of the current cluster analysis further expands upon health, its recognition across populations is important. While prior studies showing that the “minimally symptomatic” clus- clinical assessments are aimed at predicting how likely ter in the HCHS/SOL study was higher in the Hispanic/Latino someone is to have OSA on objective testing, the pattern population as compared to the Icelandic and different SAGIC of symptoms from untreated OSA can also be predictive population studies. This has implications for both outcomes of outcomes. This was first reported in an Icelandic study and treatment of OSA in this population. (Ye et al. Eur Respir J. 2014;44:1600-7), following which In terms of outcomes, there were differences between as- the applicability of using symptom-based clustering to look sociation with comorbidities in the “minimally symptomatic” at outcomes has been expanded to a number of different cluster noted between Icelandic and SAGIC studies – such populations (Sleep Apnea Global International Consortium relationship needs to be derived from the HCHS/SOL cohort. In (SAGIC) cluster analysis – Keenan et al. Sleep. 2018;1-14). terms of treatment, while all clusters respond to treatment with This has allowed the appreciation of cultural and psycho- CPAP, there may be variations in treatment adherence between social factors critical in expression and detection of OSA. different clusters with the “excessively sleepy” cluster being Initial data on OSA prevalence from the Hispanic Community more adherent compared to the “disturbed sleep” cluster, Health Study/Study of Latinos (HCHS/SOL) have shown that further highlighting the need to understand the distribution of while a quarter of patients met criteria for sleep-disordered symptom clusters in individual ethnic groups.

22 June 2021 • Sleep Medicine

20to23ASUPP21Sleep.indd 22 5/17/2021 3:51:11 PM | Continued from previous page After adjustments for potential Commentary by Dr. Sundar confounders (age, sex, race, stroke, A number of studies have highlighted the importance of sleep disturbances in pa- hypertension, cardiovascular disease, tients with chronic obstructive pulmonary disease (COPD) and linked it to health and depression), OSA treatment was status, quality of life scores, symptoms of dyspnea and fatigue, and risk of COPD associated with a significantly lower exacerbations. Whereas there has been focus on comorbid obstructive sleep odds of a diagnosis of AD (odds apnea (McNicholas WT et al. Eur Respir Rev. 2019;28:190064), the prevalence ratio, 0.78; 95% confidence interval of insomnia in COPD patients is significant, affecting at least a quarter or more 0.69-0.89) or DNOS (OR, 0.69; 95% patients with COPD (Budhiraja R et al. Sleep. 2012;35(3):369-75). Luyster and CI, 0.55-0.85), as well as nonsignifi- colleagues’ study on a large sample of veterans with COPD over a 6-year period cantly lower odds of MCI diagnosis confirms the high prevalence of insomnia in patients with COPD. It also shows (OR, 0.82; 95% CI, 0.66-1.02). that insomnia in COPD was associated not only with medical and psychiatric “People who are treated for OSA comorbidities but also with increased health care utilization. have a 22% reduced odds of being di- While causative factors for insomnia in COPD are many, poor sleep quality as agnosed with AD and a 31% reduced assessed by validated questionnaires such as the Pittsburgh Sleep Quality Index odds of getting DNOS,” said Dr. Du- has been consistently shown to be associated with an increased risk of exacerba- nietz, from the University of Mich- tions (Shorofsky M et al. Chest. 2019:156:852-63). Therefore, frequent nighttime igan in Ann Arbor, in an interview symptom burden coupled with sleep disturbance represents a modifiable risk after the meeting. “The 18% reduced factor in patients with COPD (Zeidler MR et al. Sleep. 2018;1:41(5);zsy044). odds of mild cognitive disorder is not Routine evaluation for sleep quality and assessment for factors driving insomnia really significant because the upper should be done in patients with COPD. Addressing insomnia in conjunction with bound is 1.02, but we consider it ap- sleep-disordered breathing offers the opportunity to improve COPD outcomes. proaching significance.” Adherence to treatment was sig- of Medicine at Mount Sinai and the ga, a coauthor of that study. “They Mount Sinai Integrative Sleep Center, had an onset of AD that looked just “We should be both in New York, said that cogni- like people who had no sleep apnea.” thinking of doing tive impairment is now a recognized While this study was limited by clinical consequence of OSA and sleep apnea being self-reported – honest and rigorous that OSA treatment could be a target and by the lack of severity data for the prevention of cognitive im- – the newly reported study may be clinical trials pairment and Alzheimer’s disease in limited by the use of ICD codes and particular. the fact that OSA is often entered for sleep apnea “I absolutely bring it up with into patient’s chart before diagnosis with cognitive patients in their 60s and 70s. I’m is confirmed through a sleep study, honest – I say, there seems to be Dr. Varga said. outcomes.” more and more evidence for links “The field is mature enough that between apnea and Alzheimer’s we should be thinking of doing nificantly associated with lower odds in particular. I tell them we don’t honest and rigorous clinical trials of AD, but not with significantly know 100% whether PAP reverses for sleep apnea with cognitive out- lower odds of DNOS or MCI, she any of this, but it stands to reason comes being a main measure of said. OSA was confirmed by ICD-9 that it does,” said Dr. Varga, who interest,” he said. “The issue we’re diagnosis codes plus the presence of was asked to comment on the study struggling with in the field is that relevant polysomnography current and related research. such a trial would not be short.” procedural terminology code. An analysis published several There are several theories for the All told, the findings “suggest that years ago in Neurology from the link between OSA and cognitive im- PAP therapy for OSA may lower Alzheimer’s Disease Neuroimaging pairment, he said, including disrup- short-term risk for dementia in old- Initiative cohort found that patients tions in sleep architecture leading er persons,” Dr. Dunietz and her with self-reported sleep apnea had to increased production of amyloid coinvestigators said in their poster a younger age of MCI or AD onset and tau and/or decreased “clear- presentation. “If a causal pathway (about 10 years) and that patients ance” of extracellular amyloid, exists between OSA and dementia, who used continuous positive airway neuronal sensitivity to hypoxia, and treatment of OSA may offer new pressure had a delayed age of onset cardiovascular comorbidities. opportunities to improve cognitive (2015;84[19]:1964-71). “Those who Dr. Dunietz’s study was supported outcomes in older adults with OSA.” had a subjective diagnosis of sleep by the American Academy of Sleep Andrew W. Varga, MD, of the divi- apnea and who also reported using Medicine Foundation. She reported sion of pulmonary, critical care, and CPAP as treatment seemed to go in having no disclosures. Dr. Varga said sleep medicine at the Icahn School the opposite direction,” said Dr. Var- he has no relevant disclosures.

A Special Report • June 2021 23

20to23ASUPP21Sleep.indd 23 5/17/2021 3:51:15 PM Short sleep predicts incident dementia and all-cause mortality

BY HEIDI SPLETE Association between sleep disturbance and incident dementia FROM AGING 2.5 ore evidence has emerged Signicant at P < .05 level linking sleep deficiency, de- 2.0 mentia, and mortality. “Sleep disturbance and Minsufficiency have been shown to be 1.5 associated with both the development and progression of Alzheimer’s 1.0 disease and with all-cause mortality,” Hazard ratio wrote Rebecca S. Robbins, PhD, of 0.5 Brigham and Women’s Hospital, Boston, and colleagues. However, Reference Reference 0 MDedge News research on this topic has yielded <15 15-30 >30 7-8 ≤5 6-7 ≥9 conflicting results, and “few studies Sleep latency (minutes) Sleep duration (hours) have included a comprehensive set of sleep characteristics in a single ex- Note: Based on data for 2,812 Medicare bene ciaries included in the 2013 and amination of incident dementia and 2014 National Health and Aging Trends Study surveys. all-cause mortality.” Source: Aging. 2021 Feb 11;13(3):3254-68. doi: 10.18632/aging.202591 In a study published in Aging (2021 Feb 11;13[3]:3254-68. doi: Participants completed surveys ticipants was 76.9 years, 60% were 10.18632/aging.202591), the re- about sleep disturbance and duration women, and 72% were White. searchers identified 2,812 adults in 2013 (1,575 individuals) and in Overall, approximately 60% of the aged 65 years and older from the 2014 (1,237 individuals), and the re- participants reported never or rarely National Health and Aging Trends searchers examined the relationship having problems with alertness, ap- Study (NHATS), a nationally rep- between sleep disturbance and defi- proximately half said that they rarely resentative longitudinal study of ciency and incident dementia and all- or never napped, and more than half Medicare beneficiaries aged 65 years cause mortality over the next 5 years. said they fell asleep in 15 minutes or and older in the United States. The average age of the study par- less. Approximately 70% rated their sleep quality as good or very good, and more than 90% said they rarely or never snored. The researchers examined the relationships between sleep characteristics and the development of incident dementia over 5 years. In a fully adjusted Cox multivariate analysis, individuals who slept 5 hours or less per night had approximately twice the risk for incident dementia as those who slept longer (hazard ratio, 2.04); risk of dementia also was higher among those who took 30 minutes or longer to fall asleep (HR, 1.45). In addition, the risk of all-cause mortality was significantly higher among individuals who reported difficulty maintaining alertness some days or most days/every day (HR, 1.49 and HR, 1.65, respectively), routinely nap-

amenic181/Getty Images Continued on following page }

24 June 2021 • Sleep Medicine

24to28ASUPP21Sleep.indd 24 5/17/2021 4:00:22 PM Study links sleep meds and dementia risk in older adults with sleep problems

BY HEIDI SPLETE with those who did not use sleep leagues. However, data on this asso- FROM SLEEP MEDICINE medications, findings from a pro- ciation among adults in the United spective study of 6,373 individuals States are limited, they said. leep medications for older show. In a study published in Sleep patients who report sleep Adults aged 65 and older report Medicine, the researchers surveyed problems may not be the a higher burden of sleep problems 6,373 adults aged 65 years and older best treatment given growing than other age groups, but major who were enrolled in the nationally Sevidence of the link between these medical associations discourage the representative National Health and medications and the risk of incident use of sleep medications by older Aging Trends Study (NHATS). The dementia. adults because of growing evidence majority of the participants were Adults aged 65 years and older of a link between sleep medication non-Hispanic White (71%), 59% who used sleep medications 5-7 use and cognitive decline, wrote Re- were women, and 21% ranged in days a week demonstrated a 30% in- becca Robbins, MD, of Brigham and age from 70 to 74 years. creased risk of dementia, compared Women’s Hospital, Boston, and col- Continued on following page }

| Continued from previous page ping some days or most days/every day (HR, 1.38 Commentary by Dr. Benca and HR, 1.73, respectively), poor or very poor Across the life span, individuals reporting less than recommended sleep quality (HR, 1.75), and sleeping 5 hours or amounts of sleep are more likely to experience numerous adverse less each night (HR, 2.38). health outcomes, including psychiatric disorders, suicidal behaviors, The study findings were limited by several obesity, cardiovascular disease, cognitive complaints, accidents, and factors including a population representing mortality. In older adults, sleep problems including insomnia, reduced only one-quarter of the NHATS cohort, which total sleep, and prolonged sleep latency have been associated with prevented nationally representative estimates, increased mortality as well as dementia, particularly Alzheimer’s the availability of only 2 years of sleep data, disease (AD). and small sample size for certain response cate- The association of reduced sleep time and AD may be explained by gories, the researchers noted. the bidirectional relationship between sleep and AD pathology. In AD, However, “our study offers a contribution to amyloid-beta plaques and tau protein tangles accumulate in the brain, the literature on sleep among aging populations resulting in nerve cell dysfunction and loss. Normally, amyloid and tau in its assessment of incident dementia and all- proteins are cleared from the brain during sleep, particularly deep slow cause mortality and a range of sleep characteris- wave sleep. Disturbed sleep thus interferes with their clearance, and tics among older adults,” they said. In particular, conversely, as these substances build up in the brain they interfere with “short sleep duration was a strong predictor of sleep, setting up a vicious cycle. The association between poor sleep and both incident dementia and all-cause mortality, mortality is likely multifactorial, given the impact of sleep loss and sleep suggesting this may be a sleep characteristic disorders on many medical conditions. that is important – over and above the other Whereas prior studies have tended to look at the predictive value predictors – of adverse outcomes among older of sleep problems on either dementia or mortality, this large epidemi- adults,” and future areas for research include the ological sample of elderly subjects demonstrated that both dementia development of novel behavioral interventions and mortality were associated with self-reported sleep amounts of to improve sleep in this population. less than 5 hours within the same cohort. Interestingly, subjects who The study was supported in part by the Na- reported obtaining 6-7 hours of sleep had lower risks of subsequent tional Institute for Occupational Safety and dementia and mortality, and this sleep amount is consistent with the Health; the National Heart, Lung, and Blood recommendation for 6-8 hours of sleep in those aged over 65 years. Institute; the National Institute on Aging; and A critical question is how much reduced sleep duration is actu- the Brigham Research Institute Fund to Sustain ally contributing to the increased risks of dementia and death, or if Research Excellence. Lead author Dr. Robbins instead sleep difficulties are an early sign of neurodegenerative and disclosed fees from Denihan Hospitality, Rituals other physiological processes leading to health problems. Clearly, Cosmetics, Dagmejan, Asystem, and SleepCycle. well-controlled intervention studies are needed to determine wheth- Several coauthors disclosed relationships with er treating insomnia and other sleep disorders can improve health multiple pharmaceutical companies, and support outcomes in the elderly. from various philanthropic organizations.

A Special Report • June 2021 25

24to28ASUPP21Sleep.indd 25 5/17/2021 4:00:28 PM | Continued from previous page for the prescription, the researchers Dr. D’Ambrosio said she was not Participants responded to ques- noted. surprised by the study findings “as tions about routine sleep medica- “Also, sleep medication use leads elderly patients often have sleep tion use. Routine was defined as to worse performance on cognitive issues and sometimes a well-mean- “most nights” or “every night.” The testing, such as the ing health care pro- data were collected for an 8-year questionnaires used to vider gives them period from 2011 to 2018. The study screen for dementia in sleep medication to began in 2011, with a core interview this study, and there- help. We have known administered annually. fore could have result- that some of these Approximately 15% of the study ed in a false diagnosis sleep medications population reported routine use of dementia,” they such as benzodiaze- of sleep medications. Overall, rou- added. pines affect cognitive tine use of sleep medication was However, the results performance,” she significantly associated with risk were strengthened by said. of incident dementia (hazard ratio, the large, nationally Dr. D’Ambrosio said 1.30; P < .01) after controlling for representative study she avoids prescribing multiple variables including age, population and sup- Dr. D’Ambrosio sleep medications for sex, education level, and chronic port the need for quality older adults if possible. conditions. geriatric care, the researchers said. “A deep dive into sleep habits, envi- Dementia screening was con- “Our findings provide further sup- ronment, and other things that dis- ducted by participants rating their port and evidence that sleep med- rupt sleep often gets to the problem memory and then performing a ications are all too commonly rather than just masking it with a memory-related activity (imme- administered, yet associated with sleep medication,” she noted. Al- diate and delayed 10-word recall) greater risk for incident dementia, ternatives to improve sleep in older and other exercises to assess ex- and that the U.S. health care system adults include exercise, exposure ecutive function and orientation. is in need of creative solutions for to bright light during the day, and A separate eight-item informant addressing poor sleep among older good healthy sleep habits, all of screener was performed for pa- individuals,” they concluded. which contribute to improved sleep tient proxies. The researcher in the elderly, said Dr. D’Ambrosio. noted, “Sensitivity of the NHATS Implications and alternatives She also recommends screening old- probable dementia screening The study is important as the er adults for other issues that affect measure has been determined in number of aging Americans in- sleep, such as chronic pain. previous research to be 66%, and creases, said Carolyn M. D’Ambro- The current study highlighted the specificity is 87%, with respect to sio, MD, FCCP, of Brigham and association between sleep medica- a clinical dementia diagnosis.” Women’s Hospital and Harvard tion use and dementia, but it does The study findings were limited Medical School, Boston, in an in- not show causation, Dr. D’Ambro- by several factors including the use terview. “In the elderly, inability to sio said. “So much more needs to of self-reports, the lack of data on fall asleep or stay asleep are com- be done to determine whether the type or dose of sleep medication, mon issues that are brought to sleep medications are causing wors- and lack of data on the indication a health care provider,” she said. ening cognitive function long term,

Commentary by Dr. Sundar sleep medication use for 5-7 days a week being a risk factor Over the next few decades, it is expected that more than 10 for dementia in this large national health and aging trends million U.S. adults will be affected with dementia. Besides the study adds significantly to the existing literature linking sed- morbidity and mortality stemming directly from dementia to ative medication use and AD. A key finding is the significant the patient, there is also a significant burden on the health proportion of adults aged more than 65 years that reported care system from the costs of caring for these patients. Among routine use of sleep medications (15%), which represents the many factors that may cause Alzheimer’s disease (AD), the 4.6 million older U.S. adults. Despite adjusting for a variety role of sleep disturbance in leading to amyloid-beta and tau of demographic and comorbid disease–related risk factors, a protein accumulation – the basis of neurodegeneration be- significant hazard ratio of 1.3 was noted for incident dementia cause of neurofibrillary tangle formation – is becoming better in routine sleep medication users over an 8-year duration. recognized (Neuropsychopharmacology. 2020;45:104-20). The authors discuss a number of factors explaining this as- Among the multitude of sleep-related disturbances, sleep sociation, including sleep disruption in preclinical AD. While duration is a key factor in amyloid-beta and tau clearance. mechanistic aspects of this relationship need to be elucidated, While bidirectional relationships between amyloid-beta and practitioners need to be cautious with sleep medication use tau deposition and sleep have been shown, the finding of in an elderly population.

26 June 2021 • Sleep Medicine

24to28ASUPP21Sleep.indd 26 5/17/2021 4:00:35 PM or if the dementia is starting but not that sleep difficulties represent only yet diagnosed and the sleep medi- 12% of the indication for sleep med- cation is given but not the cause of ication prescriptions,” Dr. Farmer the dementia,” she noted. noted. “Future research could exam- ine the strength of the underlying Research gaps and motivation to use sleep medication treatment strategies even in light of suggested long-term Older adults experiencing sleep effects, and the effectiveness of oth- difficulties may try various medi- er measures to avoid or minimize cations including pharmacologics sleep difficulties,” she said. (for instance, benzodiazepines), “My experience is that the major- over-the-counter agents, such as ity of ambulatory patients recently diphenhydramine or doxylamine seen in sleep clinic want to avoid preparations, and/or herbal and long-term use of sleep medications nutritional supplements such as and will ask what other measures valerian or melatonin, said Mary Jo can be tried to consistently achieve S. Farmer, MD, FCCP, of the Uni- a good night’s sleep without med- versity of Massachusetts Medical ication use,” Dr. Farmer said. “If School–Baystate, Springfield, in an medications are used, patients interview. “However, sleep medica- would rather try melatonin than tions, particularly benzodiazepines, a benzodiazepine. Many patients are strongly discouraged by major who come to sleep clinic with sleep medical associations including the medications already prescribed and American Geriatrics Society in part are subsequently found to have because of the growing evidence sleep apnea and/or restless legs find that use of sleep medications is as- that they no longer need sleep med- sociated with cognitive impairment ication when these other medical and decline,” she said. conditions are appropriately diag- The current study results contrib- nosed and managed,” she explained. ute to previous work demonstrat- “Finally, many patients tell me they ing that both pharmacologic and feel less energetic upon awakening, nonpharmacologic almost feel hung over,

sleep medication, and express being less Images/The Image Bank/Getty Images Gravity although commonly sharp cognitively when administered, is associ- taking pharmacolog- promote sleep by eliminating noise ated with subsequent ic sleep medication, and bright lights, avoiding stimulant adverse outcomes in whether for short or medications and substances such older adults, Dr. Farm- long periods of time, as caffeine and nicotine before bed- er said. This associa- and therefore they time, avoiding excessive amounts tion sets the stage for want to avoid continu- of alcohol, avoiding diuretics before creative and different ing with sleep medica- bedtime, encouraging physical activ- solutions for address- tion use,” she said. ity during the day, spending time in ing poor sleep among Dr. Farmer’s strat- the sunlight as much as possible to older adults, such as Dr. Farmer egy for developing help regulate the sleep cycle, limit- behavioral treatments alternatives to sleep ing daytime naps, and establishing a including cognitive-behavioral ther- medications in older adults includes regular sleep schedule,” she said. apy, she noted. taking a careful history, including The study was supported by Na- Dr. Farmer said, “Areas for future a complete list of medical prob- tional Institutes of Health awards research include exploring the causal lems, review of medications, and K01HL150339, U54MD000538, link between prescription and/or a thorough sleep history including K07AG052685, R01AG056531, and over-the-counter sleep medication use usual time of sleep onset, awake R01AG056031. Lead author Dr. and incident dementia in a random- time, and the frequency of daytime Robbins had no financial conflicts to ized controlled trial,” she added. naps. “Tips for improving the qual- disclose. Dr. D’Ambrosio disclosed “Another interesting opportunity ity of nighttime sleep may include serving as a section editor for sleep for future research is to explore the adequately treating pain and other medicine for Dynamed and owning indications for sleep medications medical conditions such as heart- a patent on a circadian program- among older adults since it has been burn, sleep apnea, and restless legs, ming device. Dr. Farmer had no shown in the general population creating a soothing environment to disclosures.

A Special Report • June 2021 27

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