XYREM, Sodium Oxybate Form

Sodium oxybate (Xyrem®) and calcium, magnesium, potassium, and sodium oxybate (Xywav®) are central nervous system (CNS) depressants. FDA Approved Indication(s) Xyrem and Xywav are indicated for the treatment of patients 7 years of age and older with: • Cataplexy in narcolepsy • Excessive daytime sleepiness (EDS) in narcolepsy Xywav is also indicated for the treatment of idiopathic hypersomnia (IH) in adults. Policy/Criteria Provider must submit documentation (such as office chart notes, lab results or other clinical information) supporting that member has met all approval criteria. It is the policy of health plans affiliated with Centene Corporation® that Xyrem and Xywav are medically necessary when the following criteria are met:
I. Initial Approval Criteria
A. Narcolepsy with Cataplexy (must meet all):

1. Prescribed for the treatment of cataplexy in narcolepsy;
   2. Age ≥ 7 years;
   3. Prescribed by or in consultation with a neurologist or sleep medicine specialist;
   4. Documentation of one of the following (a or b): a. EDS associated with narcolepsy as confirmed by documented multiple sleep latency test (MSLT) and one of the following (i or ii): i. Mean sleep latency ≤ 8 minutes with evidence of two or more sleep-onset rapid eye movement periods (SOREMPs); ii. At least one SOREMP on MSLT and a SOREMP (less than 15 minutes) on the preceding overnight polysomnography (PSG); b. Lumbar puncture shows cerebrospinal fluid (CSF) hypocretin-1 level ≤ 110 pg/mL;

2. Failure of 2 of the following antidepressants, each used for ≥ 1 month, unless clinically significant adverse effects are experienced or all are contraindicated: venlafaxine, fluoxetine, atomoxetine, clomipramine, protriptyline; *If member’s age is ≥ 65 years, tricyclic antidepressants are not required for trial. Page 1 of 12

   CLINICAL POLICY Sodium Oxybate

3. Failure of a 1-month trial of Wakix® at up to maximally indicated doses, unless contraindicated or clinically significant side effects are experienced; *Prior authorization may be required for Wakix
4. If request is for Xywav and member has failed Wakix, failure of Xyrem at up to maximally indicated doses, unless contraindicated or clinically significant side effects are experienced;
5. Dose does not exceed both of the following (a and b): a. 9 grams per day; b. 18 mL per day. Approval duration:
   Medicaid/HIM – 12 months Commercial – 12 months or duration of request, whichever is less B. Narcolepsy with Excessive Daytime Sleepiness (must meet all):
6. Diagnosis of narcolepsy with EDS;
   2. Age ≥ 7 years;
   3. Prescribed by or in consultation with a neurologist or sleep medicine specialist;
   4. Documentation of both of the following (a and b): a. EDS associated with narcolepsy as confirmed by documented MSLT and one of the following (i or ii): i. Mean sleep latency ≤ 8 minutes with evidence of two or more SOREMPs; ii. At least one SOREMP on MSLT and a SOREMP (less than 15 minutes) on the preceding overnight PSG; b. Member has daily periods of irrepressible need to sleep or daytime lapses into sleep occurring for at least 3 months;
7. Failure of a 1-month trial of one of the following generic central nervous system stimulant-containing agent at up to maximally indicated doses, unless clinically significant adverse effects are experienced or all are contraindicated: amphetamine, dextroamphetamine, methylphenidate;
   *Prior authorization may be required for CNS stimulants
8. If member is ≥ 17 years of age, failure of a 1-month trial of armodafinil or modafinil at up to maximally indicated doses, unless clinically significant adverse effects are experienced or both are contraindicated;
   *Prior authorization may be required for armodafinil and modafinil
9. Failure of a 1-month trial of Sunosi™ at up to maximally indicated doses, unless contraindicated or clinically significant side effects are experienced; *Prior authorization may be required for Sunosi
10. If member has failed Sunosi, then failure of a 1-month trial of Wakix at up to maximally indicated doses, unless contraindicated or clinically significant side effects are experienced; *Prior authorization may be required for Wakix

11. If request is for Xywav and member has failed Sunosi and Wakix, then failure of Xyrem at up to maximally indicated doses, unless contraindicated or clinically significant side effects are experienced; Page 2 of 12

    CLINICAL POLICY Sodium Oxybate

12. If request is for concomitant therapy with other antinarcoleptic agents (e.g., Wakix, Sunosi) for members ≥ 18 years of age, failure of combination therapy with modafinil or armodafinil and Sunosi, unless clinically significant adverse effects are experienced or all are contraindicated;
13. Dose does not exceed both of the following (a and b): a. 9 grams per day; b. 18 mL per day. Approval duration:
    Medicaid/HIM – 12 months Commercial – 12 months or duration of request, whichever is less C. Idiopathic Hypersomnia (must meet all):
14. Diagnosis of IH;
    2. Request is for Xywav;
    3. Prescribed by or in consultation with a neurologist or sleep medicine specialist;
    4. Age ≥ 18 years;
    5. Exclusion of all of the following (a,b, and c): a. Narcolepsy of cataplexy; b. Narcolepsy of EDS;
       c. Insufficient sleep syndrome;
15. Documentation of all of the following (a, b, and c): a. MSLT documents either (i or ii): i. Fewer than two SOREMPs; ii. No SOREMPs if the REM sleep latency on the preceding PSG was ≤ 15 minutes;
    b. Presence of at least one of the following (i or ii): i. MSLT shows a mean sleep latency of ≤ 8 minutes; ii. Total 24-hour sleep time is ≥ 660 minutes on 24-hour PSG or by wrist actigraphy in association with a sleep log; c. Minimal scoring on at least one of the following (i or ii): i. Score ≥ 10 on Epworth Sleepiness Scale (ESS); ii. Score ≥ 22 on Idiopathic Hypersomnia Severity Scale (IHSS);
16. Failure of a 1-month trial of armodafinil or modafinil at up to maximally indicated doses, unless clinically significant adverse effects are experienced or both are contraindicated; *Prior authorization may be required for armodafinil and modafinil

17. Failure of a 1-month trial of one of the following generic central nervous system stimulant-containing agent at up to maximally indicated doses, unless clinically significant adverse effects are experienced or all are contraindicated: amphetamine, dextroamphetamine, methylphenidate;
    *Prior authorization may be required for CNS stimulants

    9. Dose does not exceed both of the following (a and b): a. Both i and ii: i. 6 grams per day for once nightly dosing; ii. 12 mL per day for once nightly dosing; Page 3 of 12

    CLINICAL POLICY Sodium Oxybate b. Both i and ii: i. 9 grams per day for twice nightly dosing; ii. 18 mL per day for twice nightly dosing. Approval duration:
    Medicaid/HIM – 12 months Commercial – 12 months or duration of request, whichever is less D. Other diagnoses/indications (must meet 1 or 2):

18. If this drug has recently (within the last 6 months) undergone a label change (e.g., newly approved indication, age expansion, new dosing regimen) that is not yet reflected in this policy, refer to one of the following policies (a or b): a. For drugs on the formulary (commercial, health insurance marketplace) or PDL (Medicaid), the no coverage criteria policy for the relevant line of business: CP.CPA.190 for commercial, HIM.PA.33 for health insurance marketplace, and CP.PMN.255 for Medicaid; or b. For drugs NOT on the formulary (commercial, health insurance marketplace) or PDL (Medicaid), the non-formulary policy for the relevant line of business: CP.CPA.190 for commercial, HIM.PA.103 for health insurance marketplace, and CP.PMN.16 for Medicaid; or
19. If the requested use (e.g., diagnosis, age, dosing regimen) is NOT specifically listed under section III (Diagnoses/Indications for which coverage is NOT authorized) AND criterion 1 above does not apply, refer to the off-label use policy for the relevant line of business: CP.CPA.09 for commercial, HIM.PA.154 for health insurance marketplace, and CP.PMN.53 for Medicaid.
    II. Continued Therapy A. All Indications in Section I (must meet all):
20. Member meets one of the following (a or b): a. Currently receiving medication via Centene benefit or member has previously met initial approval criteria; b. Member is currently receiving medication and is enrolled in a state and product with continuity of care regulations (refer to state specific addendums for CC.PHARM.03A and CC.PHARM.03B);
21. Member is responding positively to therapy as evidenced by, but not limited to, improvement in any of the following parameters: reduction in frequency of cataplexy attacks, reported daytime improvements in wakefulness;

22. If request is for a dose increase, new dose does not exceed both of the following (a and b): a. 9 grams per day; b. 18 mL per day.
    Approval duration:
    Medicaid/HIM – 12 months Commercial – 12 months or duration of request, whichever is less Page 4 of 12

    CLINICAL POLICY Sodium Oxybate B. Other diagnoses/indications (must meet 1 or 2):

23. If this drug has recently (within the last 6 months) undergone a label change (e.g., newly approved indication, age expansion, new dosing regimen) that is not yet reflected in this policy, refer to one of the following policies (a or b): a. For drugs on the formulary (commercial, health insurance marketplace) or PDL (Medicaid), the no coverage criteria policy for the relevant line of business: CP.CPA.190 for commercial, HIM.PA.33 for health insurance marketplace, and CP.PMN.255 for Medicaid; or b. For drugs NOT on the formulary (commercial, health insurance marketplace) or PDL (Medicaid), the non-formulary policy for the relevant line of business: CP.CPA.190 for commercial, HIM.PA.103 for health insurance marketplace, and CP.PMN.16 for Medicaid; or

24. If the requested use (e.g., diagnosis, age, dosing regimen) is NOT specifically listed under section III (Diagnoses/Indications for which coverage is NOT authorized) AND criterion 1 above does not apply, refer to the off-label use policy for the relevant line of business: CP.CPA.09 for commercial, HIM.PA.154 for health insurance marketplace, and CP.PMN.53 for Medicaid.
    III. Diagnoses/Indications for which coverage is NOT authorized:
    A. Non-FDA approved indications, which are not addressed in this policy, unless there is sufficient documentation of efficacy and safety according to the off label use policies – CP.CPA.09 for commercial, HIM.PA.154 for health insurance marketplace, and CP.PMN.53 for Medicaid or evidence of coverage documents.
    IV. Appendices/General Information Appendix A: Abbreviation/Acronym Key CNS: central nervous system EDS: excessive daytime sleepiness ESS: Epworth Sleepiness Scale FDA: Food and Drug Administration IHSS: Idiopathic Hypersomnia Severity Scale MSLT: multiple sleep latency test PSG: polysomnography SOREMP: sleep-onset rapid eye movement period Appendix B: Therapeutic Alternatives
    This table provides a listing of preferred alternative therapy recommended in the approval criteria. The drugs listed here may not be a formulary agent for all relevant lines of business and may require prior authorization.
    Drug Name Dosing Regimen Dose Limit/ Maximum Dose Cataplexy venlafaxine (Effexor®)† 75–150 mg PO BID, or 75–150 mg (extended release) PO QAM fluoxetine (Prozac®)† 20 to 80 mg PO QAM 375 mg/day
    (IR tablets);
    225 mg/day (extended release) 80 mg/day Page 5 of 12

    CLINICAL POLICY Sodium Oxybate Drug Name Dosing Regimen clomipramine (Anafranil®)† protriptyline (Vivactil®)† atomoxetine (Strattera®)† Excessive daytime sleepiness amphetamine (Evekeo®) amphetamine/ dextroamphetamine (Adderall®) dextroamphetamine ER (Dexedrine® Spansule®) dextroamphetamine IR (Zenzedi®, Procentra®) methylphenidate (Ritalin® LA or SR, Concerta®, Metadate® CD or ER, Methylin® ER, Daytrana®) armodafinil (Nuvigil®) modafinil (Provigil®) Sunosi™ (solriamfetol) Wakix® (pitolisant) 10 to 150 mg PO as a single dose every morning or in divided doses 5 to 60 mg PO as a single dose every morning or in divided doses 40–60 mg PO QD 5 to 60 mg/day PO in divided doses Dose Limit/ Maximum Dose 250 mg/day 60 mg/day 100 mg/day 60 mg/day Dosing varies; 10-60 mg PO divided 2 to 3 times daily 30-45 min before meals 60 mg/day 150 mg to 250 mg PO once a day 250 mg/day 400 mg/day 200 mg PO QD as a single dose in the morning Initiate at 75 mg PO once a day; dose may be doubled at intervals of at least 3 days Dose range is 17.8 to 35.6 mg PO once daily in the morning upon wakening. Titrate dosage as follows: • Week 1: Initiate with a dosage 150 mg/day 35.6 mg/day of 8.9 mg once daily • Week 2: Increase dosage to 17.8 mg once daily • Week 3: May increase to the maximum recommended dosage of 35.6 mg once daily Idiopathic hypersomnia modafinil (Provigil®)† armodafinil (Nuvigil®)† methylphenidate (Ritalin® LA or SR, Concerta®, Metadate® CD or ER, Methylin® ER, Daytrana®)† amphetamine (Evekeo®)† amphetamine/ 200 mg PO Q AM 400 mg/day 150 mg to 250 mg PO once a day 250 mg/day 60 mg/day Dosing varies; 10-60 mg PO divided 2 to 3 times daily 30-45 min before meals 5 to 60 mg/day PO in divided doses 60 mg/day Page 6 of 12

    CLINICAL POLICY Sodium Oxybate Drug Name Dosing Regimen Dose Limit/ Maximum Dose dextroamphetamine (Adderall®)† dextroamphetamine ER (Dexedrine® Spansule®)† dextroamphetamine IR (Zenzedi®, Procentra®)† Therapeutic alternatives are listed as Brand name® (generic) when the drug is available by brand name only and generic (Brand name®) when the drug is available by both brand and generic. *Non-indication specific (maximum dose for the drug) †Off-label indication Appendix C: Contraindications/Boxed Warnings • Contraindication(s):
    o In combination with sedative hypnotics or alcohol o Succinic semialdehyde dehydrogenase deficiency • Boxed warning(s):
    o Central nervous system depression: In clinical trials at recommended doses, obtundation and clinically significant respiratory depression occurred in adult patients treated with Xyrem or Xywav. o Abuse and misuse: Xyrem and Xywav are a sodium salt of gamma-hydroxybutyrate (GHB). Abuse or misuse of illicit GHB is associated with CNS adverse reactions, including seizure, respiratory depression, decreased consciousness, coma and death.
    Appendix D: General Information • PSG: o In IH, PSG may show a short sleep latency, increased total sleep time, increased sleep spindles, and variable changes in sleep efficiency and sleep stage distribution
    o Used in diagnostic criteria of IH  If no SOREMPs are present on MSLT, REM sleep latency on preceding PSG can be < 15 minutes for diagnosis
     Presence of total 24-hour sleep time > 660 minutes on 24-hour PSG or by wrist actigraphy in association with a sleep log • MSLT: o This test is a series of five daytime nap opportunies that allow objective characterization of the patient’s level of daytime sleepiness, physiological sleep tendency, as reflected by the mean sleep latency o In IH, mean sleep latency is shortened and less than 8 minutes and number of SOREMPs is less than two • IHSS: o Ranges from 0 to 50 and made up of 2 components: 5 questions about night and inertia, 9 questions about day and performances o Cutoff value of 22 out of 50 can discriminate patients with IH from patients without EDS o A cutoff value of 29 out of 50 can discriminate patients with IH from patients with narcolepsy type 1 Page 7 of 12

    CLINICAL POLICY Sodium Oxybate • ESS: o Score is based on scale of 0 to 24  0-5 Lower normal daytime sleepiness  6-10 Higher normal daytime sleepiness  11-12 Mild excessive daytime sleepiness  13-15 Moderate excessive daytime sleepiness  16-24 Severe excessive daytime sleepiness V. Dosage and Administration
    Indication Dosing Regimen Cataplexy in narcolepsy EDS in narcolepsy Adults: The recommended starting dose is 4.5 grams (g) per night administered orally in two equal, divided doses: 2.25 g at bedtime and 2.25 g taken 2.5 to 4 hours later. Increase the dose by 1.5 g per night at weekly intervals (additional 0.75 g at bedtime and 0.75 g taken 2.5 to 4 hours later) to the effective dose range of 6 g to 9 g per night orally Maximum Dose 9 g/night Pediatrics: Dosing is weight-based as follows: 20 to < 30 kg: ≤ 1 g at bedtime and ≤ 1 g taken 2.5 to 4 hours later. Increase the dose by 1 g per night at weekly intervals (additional 0.5 g at bedtime and 0.5 g taken 2.5 to 4 hours later) to a maximum dose of 6 g per night orally 30 to < 45 kg: ≤ 1.5 g at bedtime and ≤ 1.5 g taken 2.5 to 4 hours later. Increase the dose by 1 g per night at weekly intervals (additional 0.5 g at bedtime and 0.5 g taken 2.5 to 4 hours later) to a maximum dose of 7.5 g per night orally ≥ 45 kg: ≤ 2.25 g at bedtime and ≤ 2.25 g taken 2.5 to 4 hours later. Increase the dose by 1.5 g per night at weekly intervals (additional 0.75 g at bedtime and 0.75 g taken 2.5 to 4 hours later) to a maximum dose of 9 g per night orally Adults: Administered twice or once nightly regimen in adults. For twice nightly, initiate dose at 4.5 g or less per night PO, divided into two doses. Titrate to effect in increments of up to 1.5 g per night per week, up to 9 g total nightly dose. For once nightly, initiate dosage at 3 g or less per nightly PO, as one dose. Titrate to effect in increments of up to 1.5 g per night per week, up to 6 g total nightly dose.
    9 g/night IH VI. Product Availability
    Drug Name Xyrem (sodium oxybate) Xywav (calcium, magnesium, potassium, and sodium oxybate) Availability Oral solution: 0.5 g per mL in 180 mL bottle Oral solution: 0.5 g per mL in 180 mL bottle Page 8 of 12

    CLINICAL POLICY Sodium Oxybate VII.