Medication Fact Book SleepDisorder Pages222-229.pdf

Sleep Disorder Medications GENERAL PRESCRIBING TIPS There are seven medications plus one medication class in this chapter—armodafinil (Nuvigil), modafinil (Provigil), pitolisant (Wakix), sodium oxybate (Xyrem) plus its mixed-salts close cousin Xywav, solriamfetol (Sunosi), tasimelteon (Hetlioz), an...

Sleep Disorder Medications GENERAL PRESCRIBING TIPS There are seven medications plus one medication class in this chapter—armodafinil (Nuvigil), modafinil (Provigil), pitolisant (Wakix), sodium oxybate (Xyrem) plus its mixed-salts close cousin Xywav, solriamfetol (Sunosi), tasimelteon (Hetlioz), and the dopamine agonists used for restless legs syndrome (RLS). In reality, very few of you will ever prescribe Xyrem, Xywav, or Hetlioz. Xyrem and Xywav are approved for narcolepsy with cataplexy, which is a rare illness treated by sleep specialists, and Hetlioz is used for another rare condition seen primarily in the blind: non-24- hour sleep-wake disorder. The two “vigil” drugs (Provigil and Nuvigil), on the other hand, are heavily prescribed by psychiatrists for all manner of situations, including shift-work sleep disorder, jet lag, and antidepressant-induced sleepiness. These meds, along with the stimulants, are also sometimes requested for off-label use as “cognitive enhancers” by overachievers. Sunosi is a newer agent and, like the “vigil” drugs, it’s a Schedule IV controlled drug approved to be used in excessive daytime sedation due to narcolepsy or apnea. Wakix is the newest on the scene, approved only for cataplexy and excessive sedation in narcolepsy, and its primary distinction is that it’s not a controlled substance. These “wake promoting” agents are often prescribed when patients complain of excessive fatigue. In these clinical scenarios, we recommend a thorough workup to determine potential alternative strategies (eg, labs to rule out hypothyroidism, anemia, and other conditions; a sleep study to rule out apnea or RLS; a review of medications or other substances potentially contributing to daytime sedation; and education on good sleep habits). There’s no clear guidance on which of the wake-promoting agents to prescribe. Nuvigil lasts a few hours longer than Provigil, which can be a blessing for those who want to stay awake longer or a curse for those who find it causes them insomnia. We have less experience with Sunosi and Wakix, which are newer and more expensive. Clear benefits have not yet been identified; trial and error is the way to go with these agents. We’ve added the dopamine agonists fact sheet to this chapter because psychiatrists may at times manage patients with RLS. Dopamine agonists (pramipexole, ropinirole, rotigotine) are considered first-line treatments for RLS. Carbidopa/levodopa is not FDA approved for this condition but is used for intermittent RLS since regular or routine use often leads to worsening of symptoms. Gabapentin enacarbil (Horizant) is a prodrug of gabapentin, which is approved for RLS. We’ve included this in our table, but you’ll find the gabapentin fact sheet in the Mood Stabilizers and Anticonvulsants chapter. Sleep Disorder Medications Carlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SEVENTH EDITION 219  Table 19: Sleep Disorder Medications Generic Name (Brand Name) Usual Dosage Range Relevant FDA Indication(s) Rx Status Available Strengths Year FDA Approved (starting–max) [G] denotes generic availability Armodafinil [G] Excessive sleepiness Schedule IV 50, 150, 200, 250 mg 150–250 mg/day (Nuvigil) (obstructive sleep apnea, 2007 narcolepsy, shift-work sleep disorder) Calcium, magnesium, potassium, Cataplexy and excessive Schedule III 0.5 g/mL 6–9 g/night and sodium oxybates daytime sedation (narcolepsy) (Xywav) Idiopathic hypersomnia 2020 Carbidopa/levodopa [G] Not FDA approved but used for Rx 10/100, 25/100, 25/250 mg 12.5/50–75/300 mg/day (Sinemet) restless legs syndrome ODT: 10/100, 25/100, 25/250 mg 1975 (for Parkinson’s) ER: 25/100, 50/200 mg Gabapentin enacarbil Restless legs syndrome Rx 300, 600 mg 600 mg/day (Horizant) 2011 Modafinil [G] Excessive sleepiness Schedule IV 100, 200 mg 100–400 mg/day (Provigil) (obstructive sleep apnea, 1998 narcolepsy, shift-work sleep disorder) Pitolisant Cataplexy and excessive Rx 4.45, 17.8 mg 17.8–35.6 mg/day (Wakix) sleepiness (narcolepsy) 2019 Pramipexole [G] Restless legs syndrome Rx 0.125, 0.25, 0.5, 0.75, 1, 1.5 mg 0.125–0.5 mg/day (Mirapex, Mirapex ER) ER: 0.375, 0.75, 1.5, 2.25, 3, 3.75, 2007 (for RLS) 4.5 mg Ropinirole [G] Restless legs syndrome Rx 0.25, 0.5, 1, 2, 3, 4, 5 mg 0.25–4 mg/day (Requip, Requip XL) ER: 2, 4, 6, 8, 12 mg 2005 (for RLS) Rotigotine transdermal patch Restless legs syndrome Rx Patch: 1, 2, 3, 4, 6, 8 mg 1–3 mg/day (Neupro) 2012 Sodium oxybate [G] Cataplexy and excessive Schedule III Oral solution: 0.5 g/mL 6–9 g/night (divided (Xyrem) daytime sedation (narcolepsy) doses) 2002 Sodium oxybate ER Cataplexy and excessive Schedule III Oral suspension: 4.5, 6, 7.5, 9 g 6–9 g QHS (Lumryz) daytime sedation (narcolepsy) 2023 Solriamfetol Excessive sleepiness Schedule IV 75, 150 mg 37.5–150 mg/day (Sunosi) (obstructive sleep apnea, 2019 narcolepsy) Tasimelteon [G] Non-24-hour sleep-wake Rx 20 mg 20 mg/night (Hetlioz) disorder Liquid: 4 mg/mL 2014 220 Carlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SEVENTH EDITION ARMODAFINIL (Nuvigil) Fact Sheet [G] Bottom Line: Armodafinil is an effective wake-promoting agent with some potential for abuse and for drug interactions. It lasts a bit longer than modafinil. FDA Indications: Excessive sleepiness associated with obstructive sleep apnea, narcolepsy, or shift-work sleep disorder. Off-Label Uses: ADHD; fatigue; treatment-resistant depression. Dosage Forms: Tablets (G): 50 mg, 150 mg, 200 mg, 250 mg. Dosage Guidance: ⦁ Obstructive sleep apnea or narcolepsy: 150–250 mg QAM. ⦁ Shift-work sleep disorder: 150 mg QD, one hour before start of work shift. Monitoring: No routine monitoring recommended unless clinical picture warrants. Cost: $ Side Effects: ⦁ Most common: Headache, nausea, dizziness, insomnia, anxiety, irritability. ⦁ Serious but rare: Serious rash, including Stevens-Johnson syndrome, multi-organ hypersensitivity reaction, angioedema, and anaphylaxis reported rarely. Rare cases of mania, psychosis, and agitation reported. ⦁ Pregnancy/breastfeeding: Risk for major malformations, not recommended in pregnancy; not enough data in breastfeeding to recommend. Mechanism, Pharmacokinetics, and Drug Interactions: ⦁ Dopamine reuptake inhibitor. ⦁ Metabolized primarily by non-CYP450 liver pathways, but also to some degree by CYP3A4; t ½: 15 hours. ⦁ Duration of action about eight hours. ⦁ Potentially induces CYP1A2 and 3A4 and inhibits 2C19. Avoid concomitant use with steroidal contraceptives (hormone levels may be decreased due to 3A4 induction) and with CYP2C19 substrates (eg, omeprazole, phenytoin, diazepam); levels of these medications may be increased. Clinical Pearls: ⦁ Armodafinil is, as the name implies, the r-modafinil enantiomer (modafinil is a 1:1 mixture of both r- and s-enantiomers). ⦁ Schedule IV controlled substance due to abuse potential, mostly for euphoric and stimulant-like effects. ⦁ Increased heart rate and blood pressure may occur, particularly in patients who don’t suffer from excessive sedation or fatigue and when used at higher doses. Fun Fact: Sleep Disorder Medications In 2010, the FDA declined to approve use of Nuvigil to treat jet lag. Carlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SEVENTH EDITION 221 DOPAMINE AGONISTS (Mirapex, Neupro, Requip, Sinemet) Fact Sheet [G] Bottom Line: Dopamine agonists are effective first-line agents for restless legs syndrome (RLS), though rates of problematic impulsive or compulsive behaviors can be high. Reserve carbidopa/levodopa for intermittent use. FDA Indications: Parkinson’s disease; RLS (except Sinemet, only approved for Parkinson’s). Off-Label Uses: Treatment-resistant depression; cluster headache. Dosage Forms: ⦁ Carbidopa/levodopa tablets (Sinemet, Sinemet CR, [G]): IR: 10/100 mg, 25/100 mg, 25/250 mg; ER: 25/100 mg, 50/200 mg; ODT: 10/100 mg, 25/100 mg, 25/250 mg. ⦁ Pramipexole tablets (Mirapex, Mirapex ER, [G]): IR: 0.125 mg, 0.25 mg, 0.5 mg, 0.75 mg, 1 mg, 1.5 mg; ER: 0.375 mg, 0.75 mg, 1.5 mg, 2.25 mg, 3 mg, 3.75 mg, 4.5 mg. ⦁ Ropinirole tablets (Requip, Requip XL, [G]): IR: 0.25 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg; ER: 2 mg, 4 mg, 6 mg, 8 mg, 12 mg. ⦁ Rotigotine transdermal patches (Neupro): 1 mg, 2 mg, 3 mg, 4 mg, 6 mg, 8 mg. Dosage Guidance: ⦁ Carbidopa/levodopa: Start ½ of 25/100 mg tablet QHS PRN, then increase by ½ tablet every three days as necessary to max three 25/100 mg tablets. ⦁ Pramipexole: Start 0.125 mg taken one to three hours before HS, then double dose Q4–7 days; max 0.5 mg/day. ⦁ Ropinirole: Start 0.25 mg taken one to three hours before HS, then increase to 0.5 mg after two to three days, 1 mg after seven days, then increase by 0.5 mg weekly until 3 mg/day, then increase by 1 mg/day to maximum 4 mg/day if necessary. ⦁ Rotigotine transdermal patch: Start 1 mg/24 hours applied QD, can increase by 1 mg/24 hours at weekly intervals to maximum 3 mg/24 hours. Monitoring: No routine monitoring recommended unless clinical picture warrants. Cost: $; pramipexole ER: $$; rotigotine: $$$$$ Side Effects: ⦁ Most common: Nausea, headache, dizziness, anxiety, insomnia. Newer data suggest nearly half of patients will develop compulsive behaviors (eg, gambling, shopping, eating, sexual activity). ⦁ Serious but rare: Hallucinations, agitation (less common than when treating Parkinson’s). ⦁ Pregnancy/breastfeeding: Not enough data to recommend. Mechanism, Pharmacokinetics, and Drug Interactions: ⦁ Dopamine agonist. ⦁ Metabolized primarily by: CYP450 (carbidopa/levodopa, rotigotine), renal elimination (pramipexole), CYP1A2 (ropinirole); t ½: 0.75–1.5 hours (carbidopa/levodopa), 8 hours (pramipexole), 6 hours (ropinirole), 5–7 hours (rotigotine). Clinical Pearls: ⦁ Avoid rotigotine in patients with sulfite allergies because it contains sodium metabisulfite, which may induce anaphylaxis or respiratory symptoms in sensitive patients. Those with history of asthma have an increased risk of sulfite sensitivity. ⦁ Lower doses are used for RLS compared to Parkinson’s (eg, pramipexole max daily dose is 0.5 mg for RLS vs 4.5 mg for Parkinson’s). ⦁ Onset of action: Pramipexole takes effect upon first dose. Ropinirole takes four to 10 days. Rotigotine has onset with first dose but may require up to one week for full effect. ⦁ Caution patients about compulsive behaviors (gambling, shopping, eating). These occur commonly and can be devastating. Lower dose if such behaviors develop or discontinue if severe. ⦁ Pramipexole showed modest efficacy for treatment-resistant depression in a controlled study. Open-label studies suggest it may work in patients who have not responded to electroconvulsive therapy. Start with 0.125–0.25 mg QHS and increase to target dose of 0.75–2 mg QHS. Fun Fact: Some Parkinson’s patients have experienced an increased sex drive when taking these medications, sparking off-label use of these agents for managing low libido. Mirasex, anyone? 222 Carlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SEVENTH EDITION MODAFINIL (Provigil) Fact Sheet [G] Bottom Line: While modafinil can be helpful for many causes of excessive sleepiness, realize that many people end up using it off- label for lifestyle enhancement, such as working, studying, and partying. FDA Indications: Excessive sleepiness associated with obstructive sleep apnea, narcolepsy, or shift-work sleep disorder. Off-Label Uses: ADHD; fatigue; treatment-resistant depression. Dosage Forms: Tablets (G): 100 mg, 200 mg. Dosage Guidance: ⦁ Obstructive sleep apnea or narcolepsy: 100–400 mg QAM (usually 200 mg QAM). ⦁ Shift-work sleep disorder: 100–400 mg QD (usually 200 mg QAM), one hour before start of work shift. ⦁ ADHD (off-label): 100–400 mg QAM. ⦁ Treatment-resistant depression, bipolar or unipolar (off-label): 100–400 mg QAM added to antidepressant. Monitoring: No routine monitoring recommended unless clinical picture warrants. Cost: $ Side Effects: ⦁ Most common: Increased heart rate and blood pressure, headache, nausea, jitteriness, rhinitis, diarrhea, back pain, and insomnia. ⦁ Serious but rare: Serious rash, including Stevens-Johnson syndrome, multi-organ hypersensitivity reaction, angioedema, and anaphylaxis reported rarely. Rare cases of mania, psychosis, and agitation reported. ⦁ Pregnancy/breastfeeding: Risk for major malformations, not recommended in pregnancy; not enough data in breastfeeding to recommend. Mechanism, Pharmacokinetics, and Drug Interactions: ⦁ Dopamine reuptake inhibitor. ⦁ Metabolized primarily by non-CYP450 liver pathways, but also to some degree by CYP3A4; t ½: 15 hours. ⦁ Duration of action about six hours. ⦁ Potentially induces CYP1A2 and 3A4 and inhibits 2C19. Avoid concomitant use with steroidal contraceptives (hormone levels may be decreased due to 3A4 induction) and with CYP2C9/19 substrates (eg, omeprazole, phenytoin, diazepam); levels of these medications may be increased. Clinical Pearls: ⦁ Schedule IV controlled substance. ⦁ Increased heart rate and blood pressure may occur, particularly in patients who don’t suffer from excessive sedation or fatigue and at higher doses. Sleep Disorder Medications Fun Fact: An ADHD indication was rejected by the FDA because of modafinil’s possible association with Stevens-Johnson syndrome. Carlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SEVENTH EDITION 223 OXYBATES (Lumryz, Xyrem, Xywav) Fact Sheet [G] Bottom Line: The oxybates are often used by sleep specialists as first-line agents for narcolepsy with cataplexy. It’s unlikely that many psychiatrists will prescribe them, given the side effect profile and potential for misuse. Pitolisant, which is easier to use and is not a controlled substance, may be a better option for most patients with both cataplexy and excessive daytime sedation (EDS) associated with narcolepsy. FDA Indications: Cataplexy and EDS in narcolepsy (ages 7 and up); idiopathic hypersomnia (Xywav). Off-Label Uses: Fibromyalgia; chronic pain; neuropathic pain. Dosage Forms: ⦁ Sodium oxybate oral solution (Xyrem, [G]): 0.5 g/mL. ⦁ ER sodium oxybate oral suspension (Lumryz): 4.5 g, 7.5 g, 9 g. ⦁ Calcium, magnesium, potassium, and sodium oxybate oral solution (Xywav): 0.5 g/mL. Dosage Guidance: ⦁ IR: Start 4.5 g nightly, given in two equal, divided doses (because of extremely short half-life): 2.25 g at bedtime and 2.25 g taken 2.5 to four hours later. Titrate to effect in increments of 1.5 g/night at weekly intervals (0.75 g at bedtime and 0.75 g taken 2.5 to four hours later). Usual dose 6–9 g per night. Max 9 g/night. ⦁ ER: Start 4.5 g nightly, given QHS. Titrate to effect in increments of 1.5 g/night at weekly intervals; usual dose 6–9 g QHS. Max 9 g/night. Monitoring: No routine monitoring recommended unless clinical picture warrants. Cost: $$$$$ Side Effects: ⦁ Most common: Nausea, dizziness, vomiting, somnolence, enuresis, tremor, parasomnias (sleepwalking). ⦁ Serious but rare: Respiratory depression, depression and suicidality, impaired motor and cognitive function. ⦁ Pregnancy/breastfeeding: Not enough data to recommend. Mechanism, Pharmacokinetics, and Drug Interactions: ⦁ CNS depressant. ⦁ Metabolized primarily by conversion to carbon dioxide and then eliminated by expiration; t ½: 0.5–1 hour. ⦁ Avoid concomitant use with alcohol, sedative hypnotics, and other CNS depressants. Valproic acid increases oxybate levels by 25%; adjust valproic acid dose by at least 20%. Clinical Pearls: ⦁ Sodium oxybate is the sodium salt of gamma hydroxybutyrate (GHB), a Schedule I controlled substance (“date rape” drug). ⦁ Sodium oxybate is a Schedule III controlled substance and is available only through a restricted distribution program called the Xyrem REMS Program using a centralized pharmacy. Prescribers and patients must enroll in the program (www.xyremrems.com or 1-866-XYREM88). ⦁ Patients must wait at least two hours after eating before taking a dose. Both doses should be prepared (dilute in provided vials with water) before bedtime. Dose must be taken while in bed, and patients are to lie down after dosing. ⦁ Most patients find the taste of Xyrem to be awful. ⦁ Xyrem alone was just as effective as modafinil alone for excessive daytime sedation, but the combination was significantly better than either medication used alone in one narcolepsy study. ⦁ Xywav is the newer “mixed salts” version (patent extender for Xyrem’s manufacturer Jazz?) and delivers 92% less sodium than Xyrem. ⦁ The FDA granted a new indication for using Xywav to treat idiopathic hypersomnia, a rare and debilitating neurologic sleep disorder characterized by EDS, prolonged but non-restorative nighttime sleep, and severe sleep inertia (prolonged difficulty waking). ⦁ Newest to market is the once-nightly version of Xyrem, called Lumryz, which offers the huge benefit of not needing to set an alarm for middle-of-the-night dosing. Fun Fact: Xyrem, an orphan drug, is expensive, between $108,000 and $160,000 per year depending on the nightly dose. Jazz Pharmaceuticals is looking to expand its use by testing it in obstructive sleep apnea, Parkinson’s, chronic fatigue, schizophrenia, binge eating, and cluster headache. 224 Carlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SEVENTH EDITION PITOLISANT (Wakix) Fact Sheet Bottom Line: Pitolisant is the only non-DEA-scheduled treatment option approved for patients with narcolepsy, but limited experience and data, plus a higher price tag, make it a second-line option after the “vigil” drugs. However, for patients with both cataplexy and excessive daytime sleepiness (EDS), it may be a better option than Xyrem, Lumryz, or Xywav. FDA Indications: Cataplexy or excessive sleepiness associated with narcolepsy. Off-Label Uses: ADHD; fatigue; treatment-resistant depression. Dosage Forms: Tablets: 4.45 mg, 17.8 mg. Dosage Guidance: Start 8.9 mg QAM for week one. If tolerated, may increase to 17.8 mg QAM for week two. If needed, in week three or beyond, may increase to maximum dose of 35.6 mg QAM. Use lower doses in hepatic or renal impairment. Monitoring: No routine monitoring recommended unless clinical picture warrants. Cost: $$$$$ Side Effects: ⦁ Most common: Insomnia, nausea, anxiety. ⦁ Serious but rare: QT interval prolongation (4.2 msec at therapeutic doses; 16 msec at doses greater than maximum recommended). ⦁ Pregnancy/breastfeeding: Not enough data to recommend. Mechanism, Pharmacokinetics, and Drug Interactions: ⦁ Antagonist/inverse agonist of the histamine-3 (H3) receptor. ⦁ Metabolized primarily by CYP2D6 and, to a lesser extent, CYP3A4; t ½: 20 hours. ⦁ Strong CYP2D6 inhibitors or in poor metabolizers: Maximum recommended dosage is 17.8 mg once daily. Strong CYP3A4 inducers may reduce pitolisant levels by 50%; adjust dose. Avoid H1 antihistaminergic agents, which may decrease effectiveness of pitolisant. Clinical Pearls: ⦁ Not a controlled substance. ⦁ The H3 receptor is mainly found in the brain, where it regulates wakefulness, appetite, and memory. Pitolisant blocks the H3 receptor, which has downstream effects of increased dopamine and acetylcholine in the prefrontal cortex. ⦁ A head-to-head “non-inferiority” study with modafinil found pitolisant had nearly similar efficacy but was better tolerated. ⦁ A study in kids ages 6 and up showed good results for narcolepsy-related cataplexy and EDS. While the FDA has not yet given its blessing for use in kids, it already has that approval in Europe. Sleep Disorder Medications Fun Fact: Pitolisant is also being studied for efficacy in ADHD, dementia, obesity, and cognitive symptoms of schizophrenia. Carlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SEVENTH EDITION 225 SOLRIAMFETOL (Sunosi) Fact Sheet Bottom Line: Solriamfetol is a wakefulness promoter with a different mechanism of action from modafinil and armodafinil. Patients may ask you about it given all the TV ads, but time will tell how it compares with these more established (and cheaper) agents. FDA Indications: Excessive daytime sedation (EDS) associated with narcolepsy or obstructive sleep apnea (OSA). Off-Label Uses: ADHD; fatigue; treatment-resistant depression. Dosage Forms: Tablets: 75 mg, 150 mg (scored). Dosage Guidance: Start 37.5 mg QAM for sleep apnea or 75 mg QAM for narcolepsy. Increase dose at intervals of at least three days. Max dose 150 mg/day. Monitoring: No routine monitoring recommended unless clinical picture warrants. Cost: $$$$$ Side Effects: ⦁ Most common: Headache, nausea, decreased appetite, and anxiety. ⦁ Serious but rare: Increased blood pressure and pulse; psychosis or mania may occur. ⦁ Pregnancy/breastfeeding: Not enough data to recommend. Mechanism, Pharmacokinetics, and Drug Interactions: ⦁ Dopamine and norepinephrine reuptake inhibitor (DNRI). ⦁ Not metabolized, renally eliminated; t ½: 7 hours. ⦁ Avoid MAOIs. Clinical Pearls: ⦁ This new wake-promoting drug was approved based on four studies of more than 900 adults with narcolepsy or OSA. For example, in a 12-week randomized double-blind controlled trial of 239 adults with narcolepsy, 150 mg/day of Sunosi (but not 75 mg/day) showed statistically significant improvement on tests of wakefulness. ⦁ In a similar study of 476 adults with OSA, patients receiving 37.5 mg/day, 75 mg/day, and 150 mg/day of Sunosi showed statistically significant improvement over placebo at week 12. ⦁ Maintenance of efficacy of up to 50 weeks was shown in two open-label extension studies of patients with EDS associated with either narcolepsy or OSA. ⦁ Given that Sunosi is a DNRI (like bupropion), there has been interest in studying the drug for depression, though clinical trials have not yet been conducted. ⦁ Sunosi has demonstrated abuse potential, particularly at doses higher than recommended for EDS, and has been classified as a controlled substance (Schedule IV). Fun Fact: Sunosi is manufactured by Jazz Pharmaceuticals, the company that sold $1.4 billion of Xyrem (sodium oxybate) in 2018. Now that the FDA has approved generic versions of Xyrem, Jazz will likely be looking at Sunosi as their biggest profit-maker. 226 Carlat Publishing | MEDICATION FACT BOOK FOR PSYCHIATRIC PRACTICE, SEVENTH EDITION