INSOMNIA MEDICATIONS








Eszopiclone (Lunesta®)

Dosage forms

Tablet
  • 1 mg
  • 2 mg
  • 3 mg

Dosing

Insomnia
  • Starting: 1 mg at bedtime
  • Maintenance: 1 - 3 mg at bedtime
  • Elderly patients: do not exceed 2 mg
  • When taken with CYP3A4 strong inhibitors, do not exceed 2 mg
  • High-fat meals slow absorption and may decrease effect
With strong CYP3A4 inhibitors
Kidney disease
  • No dose adjustment is necessary
Liver disease
  • Mild-moderate (Child-Pugh A/B) - no dose adjustment necessary
  • Severe (Child-Pugh C) - do not exceed 2 mg

Generic / Price

- YES/$

Other

  • Eszopiclone is a CIV controlled substance
  • Abuse and dependence may occur in susceptible patients

Pharmacokinetics

  • Peak concentration: 1 hour
  • Half-life: 6 hours

Mechanism of action

  • Exact mechanism is not known
  • Eszopiclone interacts with GABA-receptor complexes at binding domains located close to or allosterically coupled to benzodiazepine receptors

FDA-approved indications

  • Insomnia - In controlled outpatient and sleep laboratory studies, eszopiclone administered at bedtime decreased sleep latency and improved sleep maintenance
  • The clinical trials performed in support of efficacy were up to 6 months in duration

Side effects



Side effect Eszopiclone Placebo
Unpleasant taste 17% (2 mg dose)
34% (3 mg dose)		 3%
Headache 21% 13%
Somnolence 10% 3%
Dry mouth 5% 3%
Nervousness 5% 3%
Respiratory infection 5% 3%
Depression 4% 0%
Painful menses 3% 0%
Gynecomastia 3% 0%
Anxiety 3% 0%
Vomiting 3% 1%
Rash 3% 1%

Drug interactions

  • CYP3A4 inducers and inhibitors - eszopiclone is a CYP3A4 sensitive substrate. CYP3A4 inhibitors and inducers may affect eszopiclone levels. The dose of eszopiclone should not exceed 2 mg when taken with CYP3A4 strong inhibitors.
  • CNS active drugs - medications that have central nervous system activity may interact with eszopiclone. Use caution.

Contraindications / Precautions

  • Angioedema - rare cases of angioedema have occurred with eszopiclone
  • Compromised respiratory function - use caution
  • Abnormal thinking and behavioral changes - a wide range of psychiatric side effects have been reported by patients taking eszopiclone. These effects are generally rare.
  • Withdrawal side effects - anxiety, abnormal dreams, nausea, and upset stomach may occur in patients who stop eszopiclone abruptly. Withdrawal side effects are rare (< 2% of patients).
  • Decreased mental alertness - eszopiclone should not be taken before activities that require mental alertness (ex. driving)
  • Worsening depression - worsening of depression may occur in some patients
  • Liver disease
    • Mild-moderate (Child-Pugh A/B) - no dose adjustment necessary
    • Severe (Child-Pugh C) - do not exceed 2 mg
  • Kidney disease - no dose adjustment is necessary

Zaleplon (Sonata®)

Dosage forms

Capsule
  • 5 mg
  • 10 mg

Dosing

Insomnia
  • Starting: 10 mg at bedtime
  • Maintenance: 10 - 20 mg at bedtime
  • Max: 20 mg at bedtime
  • Elderly patients: starting dose should be 5 mg. Do not exceed 10 mg.
  • Low weight individuals may want to start with 5 mg
  • A high-fat meal may slow absorption and decrease effect. Do not take immediately after a high-fat meal.
Kidney disease
  • Mild-moderate (CrCl > 30 ml/min) - no dose adjustment is necessary
  • Severe (CrCl < 30 ml/min) - has not been studied
Liver disease
  • Mild-moderate (Child-Pugh A/B) - use 5 mg dose
  • Severe (Child-Pugh C) - DO NOT USE
With cimetidine
  • Initial zaleplon dose should be 5 mg when given with cimetidine

Generic / Price

- YES/$

Other

  • Zaleplon is a CIV controlled substance
  • Abuse and dependence may occur in susceptible patients

Pharmacokinetics

  • Peak concentration: 1 hour
  • Half-life: 1 hour

Mechanism of action

  • Zaleplon interacts with the gamma-aminobutyric acid-benzodiazepine (GABA-BZ) receptor complex
  • Subunit modulation of the GABA-BZ receptor chloride channel macromolecular complex is hypothesized to be responsible for some of the pharmacological properties of benzodiazepines, which include sedative, anxiolytic, muscle relaxant, and anticonvulsant effects in animal models

FDA-approved indications

  • Insomnia - zaleplon is indicated for the short-term treatment of insomnia
  • Zaleplon has been shown to decrease the time to sleep onset for up to 30 days in controlled clinical studies
  • It has not been shown to increase total sleep time or decrease the number of awakenings

Side effects



Side effect Zaleplon Placebo
Abdominal pain 6% 3%
Somnolence 5% 4%
Eye pain 4% 2%
Paresthesia 3% 1%
Painful menses 3% 2%
Amnesia 2% 1%
Tremor 2% 1%

Drug interactions

  • Cimetidine - zaleplon is a substrate of aldehyde oxidase and CYP3A4. Cimetidine inhibits both enzymes and increases zaleplon exposure. Initial zaleplon dose should be 5 mg when given with cimetidine.
  • Promethazine - promethazine may decrease zaleplon levels
  • Aldehyde oxidase inhibitors - aldehyde oxidase is the primary enzyme that metabolizes zaleplon. Aldehyde oxidase and its inducers/inhibitors/substrates have not been studied extensively.
  • CYP3A4 strong inhibitors and inducers - zaleplon is a minor CYP3A4 substrate. CYP3A4 strong inhibitors and inducers may affect zaleplon levels. Use caution.
  • CNS active drugs - medications that have central nervous system activity may interact with zaleplon. Use caution.

Contraindications / Precautions

  • Severe liver disease - DO NOT USE
  • Compromised respiratory function - use caution
  • Angioedema - rare cases of angioedema have occurred with zaleplon
  • Abnormal thinking and behavioral changes - a wide range of psychiatric side effects have been reported by patients taking zaleplon. These effects are generally rare.
  • Decreased mental alertness - zaleplon should not be taken before activities that require mental alertness (ex. driving)
  • Worsening depression - worsening of depression may occur in some patients
  • Liver disease
    • Mild-moderate (Child-Pugh A/B) - use 5 mg dose
    • Severe (Child-Pugh C) - DO NOT USE
  • Kidney disease
    • Mild-moderate (CrCl > 30 ml/min) - no dose adjustment is necessary
    • Severe (CrCl < 30 ml/min) - has not been studied

Zolpidem | Ambien® | Ambien CR® | Edluar® | Intermezzo® | Zolpimist®

Dosage forms

Tablet (Ambien®)
  • 5 mg
  • 10 mg
Tablet, extended-release (Ambien CR®)
  • 6.25 mg
  • 12.5 mg
Sublingual tablet (Edluar®)
  • 5 mg
  • 10 mg
Sublingual tablet (Intermezzo®)
  • 1.75 mg
  • 3.5 mg
Oral spray (Zolpimist®)
  • 5 mg per spray

Dosing - insomnia

Ambien®
  • Starting (women): 5 mg at bedtime
  • Starting (men): 5 - 10 mg at bedtime
  • Max dose: 10 mg at bedtime
  • Elderly and Child-Pugh A/B: 5 mg at bedtime
  • Only take when at least 7 – 8 hours are remaining before planned awakening
  • Food decreases absorption and may decrease effect
Ambien CR®
  • Starting (women): 6.25 mg at bedtime
  • Starting (men): 6.25 - 12.5 mg at bedtime
  • Max dose: 12.5 mg at bedtime
  • Elderly and Child-Pugh A/B: 6.25 mg at bedtime
  • Only take when at least 7 – 8 hours are remaining before planned awakening
  • Do not crush, cut, or chew tablet
  • Food decreases absorption and may decrease effect
Edluar® sublingual tablet
  • Starting (women): 5 mg at bedtime
  • Starting (men): 5 - 10 mg at bedtime
  • Max dose: 10 mg at bedtime
  • Elderly and Child-Pugh A/B: 5 mg at bedtime
  • Place under tongue and allow to dissolve. Do not swallow tablet or take with water.
  • Only take when at least 7 – 8 hours are remaining before planned awakening
  • Food decreases absorption and may decrease effect
Zolpimist® oral spray
  • Starting (women): 5 mg at bedtime
  • Starting (men): 5 - 10 mg at bedtime
  • Max dose: 10 mg at bedtime
  • Elderly and Child-Pugh A/B: 5 mg at bedtime
  • Spray directly into mouth over tongue
  • Only take when at least 7 – 8 hours are remaining before planned awakening
  • Food decreases absorption and may decrease effect
Intermezzo® sublingual tablet
  • Dose (women): 1.75 mg
  • Dose (men): 3.5 mg
  • Dose (elderly and liver disease): 1.75 mg
  • Place under tongue and allow to dissolve. Do not swallow tablet or take with water.
  • Only take in bed if having difficulty falling back to sleep. Only take if at least 4 hours of bedtime remain before planned awakening.
  • Do not take more than once a night
  • Food decreases absorption and may decrease effect

Generic / Price

  • Ambien® - YES/$
  • Ambien CR® - YES/$
  • Edluar® - NO/$$$$
  • Intermezzo® - YES/$$$
  • Zolpimist® - NO/$$$$

Other

All
  • Zolpidem is a CIV controlled substance
  • Abuse and dependence may occur in susceptible patients

Pharmacokinetics

Ambien
  • Peak concentration: 1.6 hours
  • Half-life: 2.6 hours

Mechanism of action

  • Zolpidem interacts with a GABA-BZ receptor complex and shares some of the pharmacological properties of the benzodiazepines
  • In contrast to the benzodiazepines, which non-selectively bind to and activate all BZ receptor subtypes, zolpidem in vitro binds the BZ1 receptor preferentially with a high affinity ratio of the α1/α5 subunits
  • This selective binding of zolpidem on the BZ1 receptor is not absolute, but it may explain the relative absence of myorelaxant and anticonvulsant effects in animal studies as well as the preservation of deep sleep (stages 3 and 4) in human studies of zolpidem tartrate at hypnotic doses

FDA-approved indications

Ambien®
  • Insomnia - Ambien® is indicated for the short-term treatment of insomnia characterized by difficulties with sleep initiation
  • Ambien® has been shown to decrease sleep latency for up to 35 days in controlled clinical studies
Ambien CR®
  • Insomnia - Ambien CR® is indicated for the short-term treatment of insomnia characterized by difficulties with sleep onset and/or sleep maintenance
  • The clinical trials performed in support of efficacy were up to 24 weeks (using patient-reported assessment in adult patients only) in duration
Edluar®
  • Insomnia - Edluar® is indicated for the short-term treatment of insomnia characterized by difficulties with sleep initiation
  • The clinical trials performed with Edluar® in support of efficacy were 4-5 weeks in duration
Intermezzo®
  • Insomnia - Intermezzo® is indicated for use as needed for the treatment of insomnia when a middle-of-the-night awakening is followed by difficulty returning to sleep
  • Limitations of Use: Intermezzo® is not indicated for the treatment of middle-of-the-night insomnia when the patient has fewer than 4 hours of bedtime remaining before the planned time of waking
Zolpimist®
  • Insomnia - Zolpimist® is indicated for the short-term treatment of insomnia characterized by difficulties with sleep initiation
  • Zolpimist® has been shown to decrease sleep latency for up to 35 days in controlled clinical studies

Side effects



Side effect Ambien tablet Placebo
Drowsiness 8% 5%
Dizziness 5% 1%
Allergy 4% 1%
Sinusitis 4% 2%
Drugged feeling 3% 0%
Pharyngitis 3% 1%
Lethargy 3% 1%
Dry mouth 3% 1%
Palpitations 2% 0%

Drug interactions

  • CNS depressants - zolpidem may potentiate the effects of CNS depressants including alcohol. Use caution when combining and reduce dosages when necessary.
  • Opiate medications - the combination of opiate medications with zolpidem may increase the risk of respiratory depression. Use caution when combining and reduce dosages when necessary.
  • CYP3A4 strong inhibitors - zolpidem is a CYP3A4 sensitive substrate, and strong CYP3A4 inhibitors may increase zolpidem exposure. Consider lowering zolpidem doses when combining with strong CYP3A4 inhibitors.
  • CYP3A4 strong inducers - zolpidem is a CYP3A4 sensitive substrate, and strong CYP3A4 inducers may decrease zolpidem exposure.
  • Rifampin - DO NOT COMBINE. Rifampin is a strong CYP3A4 inducer.
  • St. John's wort - DO NOT COMBINE. St. John's wort is a strong CYP3A4 inducer.
  • Ciprofloxacin - ciprofloxacin may inhibit zolpidem metabolism and increase zolpidem blood levels. Concurrent use is not recommended.
  • Imipramine - zolpidem may decrease imipramine levels
  • Sertraline - sertraline may increase zolpidem levels
  • Fluoxetine - fluoxetine may increase the zolpidem half-life
  • Fluvoxamine - fluvoxamine may inhibit zolpidem metabolism and increase zolpidem blood levels

Contraindications / Precautions

  • Amnesia/complex sleep behaviors - cases of amnesia and not remembering complex behaviors such as driving and making phone calls have been reported with hypnotics like zolpidem. Discontinue zolpidem if patients report such events.
  • Respiratory depression - respiratory depression may occur in patients with impaired respiratory function (e.g. sleep apnea, myasthenia gravis). Concomitant opiates and other sedatives may increase the risk. Use caution in susceptible patients.
  • Angioedema - rare cases of angioedema have occurred with zolpidem
  • Abnormal thinking and behavioral changes - a wide range of psychiatric effects have been reported by patients taking zolpidem, including decreased inhibition (e.g., aggressiveness and extroversion that seemed out of character), bizarre behavior, agitation, and depersonalization. In controlled trials, < 1% of adults taking 10 mg reported hallucinations. In a trial involving pediatric patients, 7% of zolpidem-treated patients reported hallucinations compared to 0% of placebo-treated patients. It is unknown if zolpidem is causally related to these psychiatric effects, but if they occur, stopping zolpidem should be considered.
  • Next-day impairment - next-day psychomotor impairment may occur in the following circumstances: if zolpidem is taken with less than 7 - 8 hours of sleep remaining; if higher than normal doses are taken; if co-administered with other CNS depressants; if co-administered with other drugs that increase the blood levels of zolpidem (CYP3A4 inhibitors)
  • Withdrawal side effects - fatigue, nausea, flushing, lightheadedness, uncontrolled crying, emesis, stomach cramps, panic attack, nervousness, and abdominal discomfort have been reported in patients who stop zolpidem abruptly. Withdrawal side effects are rare (≤ 1% of patients).
  • Decreased mental alertness - zolpidem should not be taken before activities that require mental alertness (ex. driving)
  • Worsening depression - worsening of depression may occur in some patients
  • Hepatic encephalopathy - zolpidem may precipitate hepatic encephalopathy in patients with significant liver disease. Do not use in severe liver disease.
  • Kidney disease - no dose adjustment is necessary
  • Liver disease
    • Mild to moderate (Child-Pugh A/B) - recommended dose is 5 mg once daily (6.25 mg for Ambien CR)
    • Severe (Child-Pugh C) - DO NOT USE

Lemborexant (Dayvigo®)

Dosage forms

Tablet
  • 5 mg
  • 10 mg

Dosing

Insomnia
  • Starting: 5 mg at bedtime
  • Maintenance: 5 - 10 mg at bedtime
  • Maximum dose: 10 mg at bedtime
  • Take immediately before going to bed with at least 7 hours remaining before the planned time of awakening
  • Time to sleep onset may be delayed if taken with or soon after a meal. Food delays absorption.
  • Dayvigo® is a CIV controlled substance
With CYP3A4 modulators
  • Strong or moderate CYP3A4 inhibitors
    • DO NOT COMBINE. Lemborexant exposure is increased.
  • Weak CYP3A4 inhibitors
    • Maximum dose is 5 mg no more than once a night
  • Moderate or strong CYP3A4 inducers
    • DO NOT COMBINE. Lemborexant exposure is decreased.
See CYP3A4 inhibitors and inducers for more
Kidney disease
  • No dose adjustment is necessary in mild, moderate, or severe renal impairment. Exposure is increased in patients with severe renal impairment and somnolence may be increased.
Liver disease
  • Mild (Child-Pugh A) - no dose adjustment necessary. Exposure is increased and patients may experience increased somnolence.
  • Moderate (Child-Pugh B) - dose should not exceed 5 mg per night
  • Severe (Child-Pugh C) - has not been studied; not recommended

Efficacy

Generic / Price

- NO/$$$$

Pharmacokinetics

  • Peak concentration: 1 - 3 hours
  • Half-life: 17 - 19 hours

Mechanism of action

  • The mechanism of action of lemborexant in the treatment of insomnia is presumed to be through antagonism of orexin receptors. The orexin neuropeptide signaling system plays a role in wakefulness. Blocking the binding of wake-promoting neuropeptides orexin A and orexin B to receptors OX1R and OX2R is thought to suppress wake drive.

FDA-approved indications

  • Insomnia - characterized by difficulties with sleep onset and/or sleep maintenance

Side effects



Side effect Placebo
(N=528)		 Dayvigo 5 mg
(N=580)		 Dayvigo 10 mg
(N=582)
Somnolence or fatigue 1.3% 6.9% 9.6%
Headache 3.4% 5.9% 4.5%
Nightmare or abnormal dreams 0.9% 0.9% 2.2%
Sleep paralysis 0% 1.3% 1.6%
Hypnagogic hallucinations 0% 0.1% 0.7%

Drug interactions

  • Alcohol - DO NOT COMBINE. Lemborexant exposure is increased.
  • CYP3A4 strong or moderate inhibitors - DO NOT COMBINE. Lemborexant is a CYP3A4 sensitive substrate.
  • CYP3A4 weak inhibitors - lemborexant exposure is increased. Maximum recommended dose is 5 mg.
  • CYP3A4 strong or moderate inducers - DO NOT COMBINE. Lemborexant exposure is reduced.
  • CYP2B6 substrates - lemborexant is a CYP2B6 weak inducer. When given with CYP2B6 substrates, lemborexant may decrease exposure to the substrate. Monitor therapy and adjust dosing if necessary.
  • CNS depressants - taking lemborexant with other CNS depressants may potentiate the effect of both drugs. Use caution.

Contraindications / Precautions

  • Narcolepsy - DO NOT USE
  • Impairment of daytime wakefulness - lemborexant can impair daytime wakefulness even when used as prescribed. CNS depressant effects may persist in some patients for up to several days after discontinuing. Elderly patients are at greater risk.
  • Decreased mental alertness - lemborexant should not be taken before activities that require mental alertness (e.g. driving)
  • Cataplexy/sleep paralysis - weakness or inability to move during the transition from sleep to wakefulness has been reported in some patients. Cases of mild cataplexy, described as periods of leg weakness lasting from seconds to a few minutes at night or during the day, have also been reported.
  • Hypnagogic/Hypnopompic Hallucinations - hallucinations, including vivid and disturbing perceptions, just prior to falling asleep and upon awakening have been reported
  • Amnesia - cases of amnesia and not remembering complex behaviors such as driving have been reported with hypnotics like lemborexant. Discontinue lemborexant if patients report such events.
  • Compromised respiratory function (OSA and COPD) - in short-term studies, lemborexant had no significant effect on the AHI in patients with mild-to-severe OSA. Likewise, it had no detrimental effect on oxygenation in patients with moderate-to-severe COPD. The long-term effects of lemborexant in these conditions have not been studied, and caution is recommended.
  • Obstructive sleep apnea (OSA) - in a study of patients with mild OSA, lemborexant did not affect the apnea-hypopnea index or oxygen saturation. Lemborexant has not been studied in patients with moderate to severe OSA.
  • Worsening depression - worsening of depression and suicidal ideation has been reported in some patients. Use caution in susceptible patients.
  • Liver disease
    • Mild (Child-Pugh A) - no dose adjustment necessary. Exposure is increased and patients may experience increased somnolence.
    • Moderate (Child-Pugh B) - dose should not exceed 5 mg per night
    • Severe (Child-Pugh C) - has not been studied; not recommended
  • Kidney disease - no dose adjustment is necessary in mild, moderate, or severe renal impairment. Exposure is increased in patients with severe renal impairment and somnolence may be increased.

Daridorexant (Quviviq®)

Dosage forms

Tablet
  • 25 mg
  • 50 mg

Dosing

Insomnia
  • Dosing: 25 - 50 mg within 30 minutes of going to bed
  • Maximum dose: 50 mg/day
  • Take with at least 7 hours remaining before the planned time of awakening
  • Time to sleep onset may be delayed if taken with or soon after a meal. Food delays absorption.
With CYP3A4 modulators
  • Strong CYP3A4 inhibitors
    • DO NOT COMBINE. Daridorexant exposure is increased.
  • Moderate CYP3A4 inhibitors
    • Recommended dose is 25 mg no more than once per night
  • Moderate or strong CYP3A4 inducers
    • DO NOT COMBINE. Daridorexant exposure is decreased.
See CYP3A4 inhibitors and inducers for more
Liver disease
  • Child-Pugh B: maximum recommended dose is 25 mg no more than once per night
  • Child-Pugh C: DO NOT USE
Kidney disease
  • Mild to severe renal impairment did not have a clinically significant effect on the pharmacokinetics of daridorexant

Efficacy

Generic / Price

- NO/$$$$

Other

  • Quviviq® is a CIV controlled substance

Pharmacokinetics

  • Peak concentration: 1 - 2 hours
  • Half-life: 8 hours

Mechanism of action

  • The mechanism of action of daridorexant in the treatment of insomnia is presumed to be through antagonism of orexin receptors. The orexin neuropeptide signaling system plays a role in wakefulness. Blocking the binding of wake-promoting neuropeptides orexin A and orexin B to receptors OX1R and OX2R is thought to suppress wake drive.

FDA-approved indications

  • Insomnia - adult patients with insomnia, characterized by difficulties with sleep onset and/or sleep maintenance

Side effects



Side effect Quviviq 25 mg
(N=310)		 Quviviq 50 mg
(N=308)		 Placebo
(N=309)
Headache 6% 7% 5%
Somnolence or fatigue 6% 5% 4%
Dizziness 2% 3% 2%
Nausea 0% 3% 2%

Drug interactions

  • Alcohol - DO NOT COMBINE. Concomitant alcohol may increase CNS depression and impair psychomotor performance.
  • CNS depressants - taking daridorexant with other CNS depressants may potentiate the effects of both drugs. Use caution when combining.
  • CYP3A4 strong inhibitors - DO NOT COMBINE. Daridorexant exposure is increased.
  • CYP3A4 moderate inhibitors - daridorexant exposure is increased. Maximum recommended dose is 25 mg no more than once a night.
  • CYP3A4 strong or moderate inducers - DO NOT COMBINE. Daridorexant exposure is reduced.

Contraindications / Precautions

  • Narcolepsy - DO NOT USE
  • Impairment of daytime wakefulness - daridorexant can impair daytime wakefulness even when used as prescribed. CNS depressant effects may persist in some patients for up to several days after discontinuing. Elderly patients are at greater risk.
  • Decreased mental alertness - daridorexant should not be taken before activities that require mental alertness (e.g. driving)
  • Worsening depression - worsening of depression and suicidal ideation has been reported in some patients. Use caution in susceptible patients.
  • Cataplexy/sleep paralysis - weakness or inability to move during the transition from sleep to wakefulness has been reported in some patients. Cases of mild cataplexy, described as periods of leg weakness lasting from seconds to a few minutes at night or during the day, have also been reported.
  • Hypnagogic/Hypnopompic Hallucinations - hallucinations, including vivid and disturbing perceptions, just prior to falling asleep and upon awakening have been reported
  • Amnesia - cases of amnesia and not remembering complex behaviors such as driving have been reported with hypnotics like daridorexant. Discontinue daridorexant if patients report such events.
  • Compromised respiratory function - daridorexant has not been studied in patients with compromised respiratory function, including moderate OSA requiring CPAP or severe OSA. Use caution in these patients.
  • Liver disease
    • Child-Pugh B: maximum recommended dose is 25 mg no more than once per night
    • Child-Pugh C: DO NOT USE
  • Kidney disease - mild to severe renal impairment did not have a clinically significant effect on the pharmacokinetics of daridorexant

Suvorexant (Belsomra®)

Dosage forms

Tablet
  • 5 mg
  • 10 mg
  • 15 mg
  • 20 mg

Dosing

Insomnia
  • Starting: 10 mg at bedtime
  • Maintenance: 10 - 20 mg at bedtime
  • Maximum dose: 20 mg at bedtime
  • Take within 30 minutes of going to bed
  • Exposure is increased in obese patients and women. Use caution in obese women
With CYP3A4 modulators
  • Strong CYP3A4 inhibitors
    • DO NOT COMBINE. Suvorexant exposure is increased.
  • Moderate CYP3A4 inhibitors
    • Recommended dose is 5 mg taken no more than once per night (the dose generally should not exceed 10 mg)
See CYP3A4 inhibitors and inducers for more
Kidney disease
  • No dose adjustment is necessary
Liver disease
  • Mild-moderate (Child-Pugh A/B): no dose adjustment necessary
  • Severe (Child-Pugh C): has not been studied; not recommended

Efficacy

Insomnia Amyloid-beta levels

Generic / Price

- NO/$$$$

Other

  • Belsomra® is a CIV controlled substance
  • Time to effect may be delayed if taken with or soon after a meal
  • Only take with at least 7 hours remaining before the planned time of awakening

Pharmacokinetics

  • Peak concentration: 2 hours
  • Half-life: 12 hours

Mechanism of action

  • The mechanism by which suvorexant exerts its therapeutic effect in insomnia is presumed to be through antagonism of orexin receptors. The orexin neuropeptide signaling system is a central promoter of wakefulness. Blocking the binding of wake-promoting neuropeptides orexin A and orexin B to receptors OX1R and OX2R is thought to suppress wake drive.

FDA-approved indications

  • Insomnia - characterized by difficulties with sleep onset and/or sleep maintenance

Side effects



Side effect Suvorexant Placebo
Headache 7% 6%
Somnolence 7% 3%
Dizziness 3% 2%
Abnormal dreams 2% 1%

Drug interactions

  • CYP3A4 strong inhibitors - DO NOT COMBINE. Suvorexant is a CYP3A4 sensitive substrate and exposure is increased.
  • CYP3A4 moderate inhibitors - starting dose should be 5 mg when taken with CYP3A4 moderate inhibitors. Do not exceed 10 mg a day.
  • CYP3A4 strong inducers - suvorexant is a CYP3A4 sensitive substrate and exposure may be decreased
  • P-glycoprotein substrates - in vitro studies show that suvorexant is a p-glycoprotein inhibitor. Suvorexant may affect levels of p-glycoprotein substrates.
  • Digoxin - may increase digoxin levels
  • CNS active drugs - medications that have central nervous system activity may interact with suvorexant. Use caution.

Contraindications / Precautions

  • Narcolepsy - DO NOT USE
  • Obese patients - exposure to suvorexant is increased compared to non-obese
  • Women - exposure to suvorexant is increased compared to men
  • Impairment of daytime wakefulness - suvorexant can impair daytime wakefulness even when used as prescribed. Elderly patients are at greater risk.
  • Decreased mental alertness - suvorexant should not be taken before activities that require mental alertness (ex. driving)
  • Cataplexy/sleep paralysis - weakness or inability to move during the transition from sleep to wakefulness has been reported in some patients. Cases of mild cataplexy, described as periods of leg weakness lasting from seconds to a few minutes at night or during the day, have also been reported.
  • Abnormal thinking and behavioral changes - a wide range of psychiatric side effects have been reported by patients taking suvorexant. These effects are generally rare.
  • Amnesia - cases of amnesia and not remembering complex behaviors such as driving have been reported with hypnotics like suvorexant. Discontinue suvorexant if patients report such events.
  • Worsening depression - worsening of depression may occur in some patients
  • Compromised respiratory function - has not been studied; use caution
  • Severe sleep apnea - has not been studied; use caution
  • Liver disease
    • Mild-moderate (Child-Pugh A/B) - no dose adjustment necessary
    • Severe (Child-Pugh C) - has not been studied; not recommended
  • Kidney disease - no dose adjustment is necessary

Ramelteon (Rozerem®)

Dosage forms

Tablet
  • 8 mg tablet

Dosing

Insomnia
  • Dosing: 8 mg within 30 minutes of going to bed
  • Max: 8 mg a day
  • A high-fat meal may slow absorption and decrease effect. Do not take immediately after a high-fat meal.
Kidney disease
  • No dose adjustment is necessary
Liver disease
  • Mild-moderate (Child-Pugh A/B) - use caution
  • Severe (Child-Pugh C) - DO NOT USE

Generic / Price

- YES/$

Pharmacokinetics

  • Peak concentration: 45 minutes
  • Half-life (ramelteon): 1 - 2.6 hours
  • Half-life (major metabolite): 2 - 5 hours

Mechanism of action

  • Ramelteon is a melatonin receptor agonist with both high affinity for melatonin MT1 and MT2 receptors and selectivity over the MT3 receptor
  • The activity of ramelteon at the MT1 and MT2 receptors is believed to contribute to its sleep-promoting properties, as these receptors, acted upon by endogenous melatonin, are thought to be involved in the maintenance of the circadian rhythm underlying the normal sleep-wake cycle

FDA-approved indications

  • Insomnia - ramelteon is indicated for the treatment of insomnia characterized by difficulty with sleep onset
  • The clinical trials performed in support of efficacy were up to 6 months in duration

Side effects



Side effect Ramelteon Placebo
Dizziness 4% 3%
Somnolence 3% 2%
Fatigue 3% 2%
Nausea 3% 2%
Insomnia exacerbated 3% 2%

Drug interactions

  • Fluvoxamine - DO NOT COMBINE
  • CYP1A2 inducers and inhibitors - ramelteon is a CYP1A2 sensitive substrate. CYP1A2 inhibitors and inducers may affect ramelteon levels. Use caution.
  • CYP3A4 strong inhibitors - ramelteon is a minor CYP3A4 substrate. CYP3A4 strong inhibitors may affect ramelteon levels. Use caution.
  • CYP2C9 strong inhibitors - ramelteon is a minor CYP2C9 substrate. CYP2C9 strong inhibitors may affect ramelteon levels. Use caution.
  • CNS active drugs - medications that have central nervous system activity may interact with ramelteon. Use caution.

Contraindications / Precautions

  • Severe liver disease - DO NOT USE
  • Severe sleep apnea - not recommended
  • Compromised respiratory function - use caution
  • Increased prolactin levels - ramelteon can raise prolactin levels. In one study, ramelteon 16 mg a day raised prolactin levels in women by an average of 4.9 mcg/L.
  • Decreased testosterone levels - ramelteon can lower testosterone levels. This effect is not well-defined.
  • Angioedema - rare cases of angioedema have occurred with ramelteon
  • Abnormal thinking and behavioral changes - a wide range of psychiatric side effects have been reported by patients taking ramelteon. These effects are generally rare.
  • Decreased mental alertness - ramelteon should not be taken before activities that require mental alertness (ex. driving)
  • Worsening depression - worsening of depression may occur in some patients
  • Liver disease
    • Mild-moderate (Child-Pugh A/B) - use caution
    • Severe (Child-Pugh C) - DO NOT USE
  • Kidney disease - no dose adjustment is necessary




Pricing legend
  • $ = 0 - $50
  • $$ = $51 - $100
  • $$$ = $101 - $150
  • $$$$ = > $151
  • Pricing based on one month of therapy at standard dosing in an adult
  • Pricing based on information from GoodRX.com®
  • Pricing may vary by region and availability