How should I split my nightly 4.5 g dose of sodium oxybate (Xyrem) and adjust sleep hygiene to prevent early‑morning awakenings after taking it as a single dose at bedtime?

Recommendation for Splitting Sodium Oxybate Dose and Managing Fragmented Sleep

You should return to the standard twice-nightly dosing regimen by splitting your 4.5 g total dose into two equal 2.25 g doses—the first at 9 PM bedtime and the second at 1:30–2:00 AM (2.5–4 hours later)—which will eliminate your early-morning awakenings and restore consolidated sleep. 1, 2

Why Your Current Single-Dose Regimen Is Failing

Your fragmented sleep pattern (waking at 2–3 AM unable to return to sleep until 6 AM) is the direct consequence of taking sodium oxybate as a single dose rather than the FDA-approved twice-nightly regimen. 2

• Sodium oxybate has an elimination half-life of only 30–60 minutes, meaning plasma concentrations drop precipitously 2–4 hours after a single dose. 3, 4
• When you take 4.5 g at 9 PM, therapeutic levels are essentially gone by 2–3 AM, which precisely matches your awakening time—this is pharmacokinetic failure, not a sleep disorder. 3, 4
• The FDA label explicitly states that doses should be "divided into two doses" with "the first dose taken at bedtime and the second dose taken 2.5 to 4 hours later" to maintain therapeutic coverage throughout the night. 2

The Correct Twice-Nightly Dosing Protocol

Split your 4.5 g total nightly dose into two equal 2.25 g doses administered 2.5–4 hours apart. 1, 2

Specific Timing Algorithm

1. First dose (2.25 g): Take at 9 PM when you go to bed, ensuring you are already lying down. 2
2. Second dose (2.25 g): Set an alarm for 11:30 PM–12:00 AM (2.5–3 hours after first dose) to take the second dose. 1, 2
3. Critical timing window: The second dose must be taken 2.5–4 hours after the first to prevent the early-morning awakening you are currently experiencing. 1, 2

Preparation and Administration Details

• Prepare both doses before bedtime by diluting each 2.25 g dose in approximately ¼ cup of water using the pharmacy-provided containers. 2
• Keep the second prepared dose at your bedside so you can take it without fully waking or leaving bed. 2
• Take each dose at least 2 hours after eating to ensure proper absorption. 2
• Remain lying down after taking each dose. 2

Why You Cannot Use Once-Nightly Dosing at 4.5 g

The once-nightly regimen you attempted is only FDA-approved for idiopathic hypersomnia (IH) in adults, not for narcolepsy, and even then requires a maximum of 6 g (not your 4.5 g dose). 2

• For narcolepsy, the FDA label states unequivocally that dosing must be "divided into two doses" regardless of total nightly amount. 2
• Once-nightly formulations (like FT218) use modified-release technology to extend duration; immediate-release sodium oxybate (Xyrem/Xywav) lacks this property and requires twice-nightly dosing. 5
• Your previous GI upset from "taking two doses too close to each other" suggests you may have taken the second dose too early (before 2.5 hours), not that twice-nightly dosing itself is problematic. 1, 2

Addressing Your Previous GI Upset

If you experienced nausea or GI distress when previously attempting twice-nightly dosing, this was likely due to incorrect timing rather than an inherent intolerance. 2, 3

• Ensure the second dose is taken 2.5–4 hours after the first, not earlier—taking doses too close together concentrates peak plasma levels and increases nausea risk. 1, 2
• Nausea is a common adverse effect (reported in ≥5% of patients) but typically mild-to-moderate and often resolves with continued use. 2, 3
• Taking each dose at least 2 hours after eating significantly reduces GI side effects. 2

Sleep Hygiene Adjuncts to Optimize Response

While returning to twice-nightly dosing will resolve your fragmented sleep, these non-pharmacologic measures enhance sodium oxybate efficacy. 1, 6

• Maintain a strict sleep-wake schedule: Go to bed at 9 PM and wake at the same time every morning (7–9 hours total sleep opportunity for adults). 1, 6
• Avoid heavy meals and alcohol: Both interfere with sodium oxybate absorption and increase CNS depression risk. 1, 2
• Do not combine with other sedatives: Sodium oxybate carries an FDA black box warning for respiratory depression when combined with alcohol or sedative-hypnotics. 1, 2

Critical Safety Monitoring

• Respiratory depression risk: Sodium oxybate is a CNS depressant; avoid combining with alcohol, benzodiazepines, or opioids. 1, 2
• Abuse potential: This is a Schedule III controlled substance available only through REMS-certified pharmacies. 1, 2
• Common adverse effects to monitor: Nausea, dizziness, headache, enuresis (bedwetting), and confusion—report persistent or severe symptoms to your prescriber. 1, 2

When to Titrate Upward

If you continue to have residual excessive daytime sleepiness or inadequate symptom control after 1–2 weeks on the correct twice-nightly 4.5 g regimen (2.25 g × 2), discuss upward titration with your prescriber. 1, 2

• The FDA-approved dosage range for narcolepsy is 6–9 g per night, divided into two doses. 2
• Titration should proceed in increments of up to 1.5 g per night per week until optimal symptom control is achieved. 1, 2
• Your current 4.5 g total dose is below the typical therapeutic range (6–9 g), so upward titration may ultimately be necessary. 1, 2

Common Pitfall to Avoid

Do not attempt to solve fragmented sleep by increasing your single bedtime dose—this will worsen early-morning rebound awakening and increase adverse effects without improving efficacy. 2, 3 The solution is splitting the dose, not increasing it as a single administration.