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  • CLASSES

    Sedatives, Other

    DEA CLASS

    Rx, schedule IV

    DESCRIPTION

    Orexin receptor antagonist.
    Used for the treatment of insomnia in adults.
    Novel mechanism of action which alters the signaling of neurotransmitters called orexins that regulate the sleep-wake cycle.

    COMMON BRAND NAMES

    Belsomra

    HOW SUPPLIED

    Belsomra Oral Tab: 5mg, 10mg, 15mg, 20mg

    DOSAGE & INDICATIONS

    For the treatment of insomnia characterized by difficulties with sleep onset or sleep maintenance.
    Oral dosage
    Adults

    10 mg PO taken once per night within 30 minutes of going to bed, and with at least 7 hours remaining before the planned time of awakening. If needed, the dose may be increased to the maximum dose of 20 mg once per night; however, it should be noted that the risk of next-day impairment is increased with use of the higher dose. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.

    Geriatric Adults

    10 mg PO taken once per night within 30 minutes of going to bed, and with at least 7 hours remaining before the planned time of awakening. If needed, the dose may be increased to the maximum dose of 20 mg once per night; however, it should be noted that the risk of next-day impairment is increased with use of the higher dose. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. The federal Omnibus Budget Reconciliation Act (OBRA) regulates the use of sedative and hypnotics in long-term care facility (LTCF) residents. Specific dosage thresholds for suvorexant are not available; use in accordance with approved product labeling. If the sleep agent is used routinely and is beyond the manufacturer's recommendations for duration of use, the facility should attempt a quarterly taper unless clinically contraindicated as defined in the OBRA guidelines.

    MAXIMUM DOSAGE

    Adults

    20 mg/day PO.

    Geriatric

    20 mg/day PO.

    Adolescents

    Safety and efficacy have not been established.

    Children

    Safety and efficacy have not been established.

    Infants

    Not indicated.

    Neonates

    Not indicated.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Suvorexant is not recommended in patients with severe hepatic impairment. No dosage adjustment is required in patients with mild to moderate hepatic impairment.

    Renal Impairment

    No dosage adjustments are required in patients with renal impairment.

    ADMINISTRATION

    Oral Administration

    Administer 30 minutes prior to bedtime.
    The time to effect of suvorexant may be delayed if taken with or soon after a meal. For the fastest effect, take on an empty stomach.

    STORAGE

    Belsomra:
    - Protect from light
    - Protect from moisture
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    - Store in original package until time of use

    CONTRAINDICATIONS / PRECAUTIONS

    Narcolepsy

    Suvorexant is contraindicated for use in patients with narcolepsy. Sleep paralysis (an inability to move or speak for up to several minutes during sleep-wake transitions), hypnagogic/hypnopompic hallucinations (vivid and disturbing perceptions by the patient), and cataplexy-like symptoms (periods of leg weakness lasting from seconds to a few minutes) can occur during use of suvorexant. The mechanism by which suvorexant exerts its therapeutic effect (i.e., antagonism of orexin receptors) may account for its ability to produce signs of narcolepsy/cataplexy.

    Driving or operating machinery, ethanol ingestion, ethanol intoxication, mental status changes

    Products prescribed for insomnia due to difficulty with sleep initiation should only be administered immediately prior to retiring. Patients should be instructed to avoid driving or operating machinery or performing other tasks requiring mental alertness after taking their dosage. In one study of healthy adults, driving ability was impaired in some subjects receiving the 20 mg dose of suvorexant. Therefore, patients receiving the 20 mg dose should be advised against next-day driving or other activities requiring full alertness, even if the patient feels fully awake. Because individual sensitivity to sleep medications may vary, patients receiving the 10 mg dose should be cautioned about the potential for impairment during activities requiring full mental alertness. The risk for next-morning impairment is higher if suvorexant is taken with less than a full night of sleep remaining, if a higher than the recommended dose is taken, or if suvorexant is co-administered with other CNS depressants or drugs that increase the blood levels of suvorexant. Patients should be advised against next-day driving or other activities requiring full alertness when the drug is taken under any of these conditions. CNS depressant effects may persist in some patients for several days after discontinuing suvorexant. Sedative-hypnotic medications have the potential to cause sleep-related behaviors such as sleep-driving, a state of driving after ingestion of a sedative-hypnotic while not fully awake and having no memory of the event. Other sleep-related behaviors may include making phone calls or eating while asleep. The exact incidences among various sedative products are unknown; however patients should be informed of the risks prior to receiving any medication from this class. Additive effects may occur with alcohol or other CNS-depressant medications. Patients should avoid ethanol ingestion and should not drink alcoholic beverages and should avoid ingestion of other alcohol-containing products while taking suvorexant. Patients should also avoid acute or chronic ethanol intoxication while taking this medication. Lower dosages of suvorexant should be considered in patients taking other CNS-depressant therapies concurrently. Mental status changes (e.g., amnesia, anxiety, hallucinations) have been reported to occur with the use of sedatives-hypnotics, including the emergence of bizarre behaviors. While they are infrequent, any emergence of changes in thinking or behavior should be evaluated. Sleep disturbances may indicate an underlying physical or psychiatric problem. The failure of insomnia to remit after 7—10 days of suvorexant treatment may indicate the presence of a primary medical or psychiatric illness; therefore, evaluation for a potential co-morbid diagnosis is recommended at that time.

    Chronic obstructive pulmonary disease (COPD), pulmonary disease, respiratory depression, sleep apnea

    Sedative-hypnotics have the potential to cause respiratory depression or oxygen desaturation, particularly in patients with pre-existing pulmonary disease. Suvorexant has not been formally evaluated in patients with severe obstructive sleep apnea (OSA) or severe chronic obstructive pulmonary disease (COPD). Evaluation of suvorexant in patients with mild to moderate OSA or COPD resulted in a wide variation of effects, suggesting that clinically meaningful effects on respiratory function are possible in some individuals. Therefore, the benefits of treatment should be weighed against the potential for adverse respiratory effects prior to using suvorexant in patients with pulmonary disease.

    Depression, suicidal ideation

    Suvorexant, like all CNS depressants, should be used cautiously in patients with symptoms of depression. These patients may have suicidal ideation tendencies and may be more likely to intentionally overdose on medications. In addition, worsening of depression may occur during suvorexant administration. Suicidal thoughts and actions, including completed suicides, have been reported in association with the use of sedative/hypnotics. Suvorexant should be prescribed in the smallest quantity consistent with good patient management to reduce the risk of overdose.

    Hepatic disease

    Suvorexant is not recommended in patients with severe hepatic disease since the drug has not been studied in this patient population. No dosage adjustment is required in patients with mild to moderate hepatic impairment.

    Alcoholism, substance abuse

    Suvorexant should be used in patients with a history of substance abuse only if the benefit justifies the potential risk of psychological dependence, misuse, and/or abuse. If treatment with suvorexant is deemed necessary in such patients, careful monitoring is recommended. Abuse of suvorexant is associated with an increased risk of somnolence, daytime drowsiness, impaired reaction time, and impaired driving skills. Conditions that may increase the risk for abuse include prolonged use, a history of drug abuse or alcoholism, and those who use suvorexant in combination with alcohol or other abused drugs. In an abuse liability study of recreational polydrug users, suvorexant produced similar subjective measures of abuse liability (e.g., drug liking) as zolpidem. Prolonged use of suvorexant did not demonstrate evidence of physical dependence. There were no reported withdrawal symptoms after discontinuation of suvorexant.

    Geriatric

    There were no clinically meaningful differences in safety and efficacy between geriatric adults and younger adults during clinical trials of suvorexant. However, dose selection should generally be cautious in the geriatric population since these patients may be more likely to experience confusion and oversedation from sedative hypnotics. According to the Beers Criteria, sedative hypnotics are considered potentially inappropriate medications (PIMs) in geriatric patients with delirium or at high risk of delirium and should be avoided because new-onset or worsening delirium may occur. The federal Omnibus Budget Reconciliation Act (OBRA) regulates medication use in residents of long-term care facilities (LTCFs). According to the OBRA guidelines, factors potentially causing insomnia should be evaluated before initiating a sedative (e.g., sleep environment, inadequate physical activity, provision of care disruptions, caffeine or medications, pain and discomfort, or other underlying conditions that cause insomnia). Most cases of insomnia are associated with other underlying conditions. It is expected that non-pharmacologic interventions and maximized treatment of underlying conditions (if applicable) are implemented to address the causative factor(s). Initiation of sleep induction or maintenance medication should be preceded or accompanied by other interventions to attempt sleep improvement. All sleep medications should be used in accordance with approved product labeling. The use of sedating medications for individuals with diagnosed sleep apnea requires careful assessment, documented clinical rationale, and close monitoring. Exceptions to the OBRA provisions include: single dose sedative use for a dental or medical procedure or short-term sedative use during initiation of treatment for depression, pain, or other comorbid condition until symptoms improve or the underlying causative factor can be identified and/or effectively treated. OBRA provides dosing guidance for most sedatives; however, specific guidance for suvorexant is not available. When a drug is being used to induce sleep or treat a sleep disorder, the facility should attempt periodic tapering of the medication or provide documentation of medical necessity in accordance with OBRA guidelines.

    Labor, obstetric delivery, pregnancy

    Suvorexant is classified as FDA risk category C. There are no adequate or well-controlled studies in pregnant women. Administration of doses exceeding the maximum recommended human dose during animal studies resulted in reduced body weight in the offspring. There are case reports of withdrawal symptoms, severe neonatal respiratory depression, and possible neonatal flaccidity in neonates born to mothers taking other sedative hypnotics. Therefore, suvorexant should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Suvorexant has no established use during labor or obstetric delivery.

    Breast-feeding

    According to the manufacturer, it is not known if suvorexant is excreted into human milk, and caution should be used when the drug is administered to a nursing woman. In rat studies, suvorexant and its metabolite were excreted into maternal milk at levels higher than in the maternal plasma. Because the effects of suvorexant exposure during breast-feeding have not been evaluated, it may be preferable to use an alternate sedative such as zolpidem. Although the effects of zolpidem exposure on the breast-feeding infant have not been formally evaluated, the American Academy of Pediatrics has considered zolpidem usually compatible with lactation based on the available data. If use of a sedative becomes necessary during breast-feeding, lactating women should avoid breast-feeding their infants at times of peak drug concentrations, and observe the infant for any indications of adverse events, like sedation, increased crying, poor feeding, or irritability. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    Children, infants

    The safety and efficacy of suvorexant in children has not been established. There is no known indication for this drug in infants.

    ADVERSE REACTIONS

    Severe

    muscle paralysis / Delayed / Incidence not known
    suicidal ideation / Delayed / Incidence not known

    Moderate

    memory impairment / Delayed / Incidence not known
    myasthenia / Delayed / Incidence not known
    hallucinations / Early / Incidence not known
    cataplexy / Delayed / Incidence not known
    amnesia / Delayed / Incidence not known
    depression / Delayed / Incidence not known
    sleep-related behaviors / Early / Incidence not known
    psychological dependence / Delayed / Incidence not known

    Mild

    drowsiness / Early / 7.0-7.0
    headache / Early / 7.0-7.0
    dizziness / Early / 3.0-3.0
    abnormal dreams / Early / 2.0-2.0
    xerostomia / Early / 2.0-2.0
    diarrhea / Early / 2.0-2.0
    infection / Delayed / 0-2.0
    cough / Delayed / 2.0-2.0
    anxiety / Delayed / Incidence not known

    DRUG INTERACTIONS

    Acetaminophen; Aspirin, ASA; Caffeine: (Minor) Caffeine is a central nervous system (CNS) stimulant. Patients taking medications for sleep, such as suvorexant, eszopiclone, zaleplon, or zolpidem should avoid caffeine-containing medications, dietary supplements, foods, and beverages close to bedtime. Patients should be encouraged to avoid excessive total daily caffeine intake, as part of proper sleep hygiene, since caffeine intake can interfere with proper sleep.
    Acetaminophen; Butalbital: (Major) Suvorexant is primarily metabolized by CYP3A, and decreased systemic exposure of suvorexant may occur during concurrent use with strong CYP3A inducers such as primidone or barbiturates. Patients should be monitored for a reduction in efficacy if either of these combinations is necessary. In addition, patients should be monitored for additive sedative effects.
    Acetaminophen; Butalbital; Caffeine: (Major) Suvorexant is primarily metabolized by CYP3A, and decreased systemic exposure of suvorexant may occur during concurrent use with strong CYP3A inducers such as primidone or barbiturates. Patients should be monitored for a reduction in efficacy if either of these combinations is necessary. In addition, patients should be monitored for additive sedative effects. (Minor) Caffeine is a central nervous system (CNS) stimulant. Patients taking medications for sleep, such as suvorexant, eszopiclone, zaleplon, or zolpidem should avoid caffeine-containing medications, dietary supplements, foods, and beverages close to bedtime. Patients should be encouraged to avoid excessive total daily caffeine intake, as part of proper sleep hygiene, since caffeine intake can interfere with proper sleep.
    Acetaminophen; Butalbital; Caffeine; Codeine: (Major) Suvorexant is primarily metabolized by CYP3A, and decreased systemic exposure of suvorexant may occur during concurrent use with strong CYP3A inducers such as primidone or barbiturates. Patients should be monitored for a reduction in efficacy if either of these combinations is necessary. In addition, patients should be monitored for additive sedative effects. (Minor) Caffeine is a central nervous system (CNS) stimulant. Patients taking medications for sleep, such as suvorexant, eszopiclone, zaleplon, or zolpidem should avoid caffeine-containing medications, dietary supplements, foods, and beverages close to bedtime. Patients should be encouraged to avoid excessive total daily caffeine intake, as part of proper sleep hygiene, since caffeine intake can interfere with proper sleep.
    Acetaminophen; Caffeine; Dihydrocodeine: (Minor) Caffeine is a central nervous system (CNS) stimulant. Patients taking medications for sleep, such as suvorexant, eszopiclone, zaleplon, or zolpidem should avoid caffeine-containing medications, dietary supplements, foods, and beverages close to bedtime. Patients should be encouraged to avoid excessive total daily caffeine intake, as part of proper sleep hygiene, since caffeine intake can interfere with proper sleep.
    Acetaminophen; Caffeine; Magnesium Salicylate; Phenyltoloxamine: (Minor) Caffeine is a central nervous system (CNS) stimulant. Patients taking medications for sleep, such as suvorexant, eszopiclone, zaleplon, or zolpidem should avoid caffeine-containing medications, dietary supplements, foods, and beverages close to bedtime. Patients should be encouraged to avoid excessive total daily caffeine intake, as part of proper sleep hygiene, since caffeine intake can interfere with proper sleep.
    Acetaminophen; Caffeine; Phenyltoloxamine; Salicylamide: (Minor) Caffeine is a central nervous system (CNS) stimulant. Patients taking medications for sleep, such as suvorexant, eszopiclone, zaleplon, or zolpidem should avoid caffeine-containing medications, dietary supplements, foods, and beverages close to bedtime. Patients should be encouraged to avoid excessive total daily caffeine intake, as part of proper sleep hygiene, since caffeine intake can interfere with proper sleep.
    Acetaminophen; Pentazocine: (Moderate) CNS depressant drugs may have cumulative effects when administered concurrently and they should be used cautiously with suvorexant. A reduction in dose of the CNS depressant may be needed. These agents include mixed opiate agonists/antagonists.
    Acetaminophen; Tramadol: (Moderate) CNS depressant drugs may have cumulative effects when administered concurrently and they should be used cautiously with suvorexant. A reduction in dose of the CNS depressant may be needed in some cases.
    Afatinib: (Major) If the concomitant use of suvorexant and afatinib is necessary, consider reducing the afatinib dose by 10 mg per day if the original dose is not tolerated; resume the previous dose of afatinib as tolerated after discontinuation of suvorexant. Afatinib is a P-glycoprotein (P-gp) substrate and inhibitor in vitro, and suvorexant is a P-gp inhibitor; coadministration may increase plasma concentrations of afatinib. Administration of another P-gp inhibitor, ritonavir (200 mg twice daily for 3 days), 1 hour before afatinib (single dose) increased the afatinib AUC and Cmax by 48% and 39%, respectively; there was no change in the afatinib AUC when ritonavir was administered at the same time as afatinib or 6 hours later. In healthy subjects, the relative bioavailability for AUC and Cmax of afatinib was 119% and 104%, respectively, when coadministered with ritonavir, and 111% and 105% when ritonavir was administered 6 hours after afatinib. The manufacturer of afatinib recommends permanent discontinuation of therapy for severe or intolerant adverse drug reactions at a dose of 20 mg per day, but does not address a minimum dose otherwise.
    Alprazolam: (Moderate) CNS depressant drugs may have cumulative effects when administered concurrently and they should be used cautiously with suvorexant. A reduction in dose of the CNS depressant may be needed in some cases. These agents include the benzodiazepines.
    Amitriptyline; Chlordiazepoxide: (Moderate) CNS depressant drugs may have cumulative effects when administered concurrently and they should be used cautiously with suvorexant. A reduction in dose of the CNS depressant may be needed in some cases. These agents include the benzodiazepines.
    Amobarbital: (Major) Suvorexant is primarily metabolized by CYP3A, and decreased systemic exposure of suvorexant may occur during concurrent use with strong CYP3A inducers such as primidone or barbiturates. Patients should be monitored for a reduction in efficacy if either of these combinations is necessary. In addition, patients should be monitored for additive sedative effects.
    Amoxicillin; Clarithromycin; Lansoprazole: (Major) Suvorexant is primarily metabolized by CYP3A, and the manufacturer recommends against concurrent use of suvorexant with strong CYP3A inhibitors such as clarithromycin. Strong inhibitors of CYP3A significantly increase suvorexant exposure (AUC).
    Amoxicillin; Clarithromycin; Omeprazole: (Major) Suvorexant is primarily metabolized by CYP3A, and the manufacturer recommends against concurrent use of suvorexant with strong CYP3A inhibitors such as clarithromycin. Strong inhibitors of CYP3A significantly increase suvorexant exposure (AUC).
    Amprenavir: (Major) Suvorexant is primarily metabolized by CYP3A, and the manufacturer recommends a dose reduction to 5 mg of suvorexant during concurrent use with moderate CYP3A inhibitors such as amprenavir or fosamprenavir and a maximum recommended dose of 10 mg/day.
    Anxiolytics; Sedatives; and Hypnotics: (Moderate) CNS depressant drugs may have cumulative effects when administered concurrently and they should be used cautiously with suvorexant. A reduction in dose of the CNS depressant may be needed in some cases. Use cautiously with any anxiolytics; use with other sedatives and hypnotics should generally be avoided due to duplication of treatments.
    Aprepitant, Fosaprepitant: (Major) Use caution if suvorexant and aprepitant, fosaprepitant are used concurrently and monitor for an increase in suvorexant-related adverse effects for several days after administration of a multi-day aprepitant regimen. The manufacturer of suvorexant recommends a dose reduction to 5 mg of suvorexant during concurrent use with moderate CYP3A inhibitors, and a maximum recommended dose of 10 mg/day. Suvorexant is a CYP3A4 substrate. Aprepitant, when administered as a 3-day oral regimen (125 mg/80 mg/80 mg), is a moderate CYP3A4 inhibitor and inducer and may increase plasma concentrations of suvorexant. For example, a 5-day oral aprepitant regimen increased the AUC of another CYP3A4 substrate, midazolam (single dose), by 2.3-fold on day 1 and by 3.3-fold on day 5. After a 3-day oral aprepitant regimen, the AUC of midazolam (given on days 1, 4, 8, and 15) increased by 25% on day 4, and then decreased by 19% and 4% on days 8 and 15, respectively. As a single 125 mg or 40 mg oral dose, the inhibitory effect of aprepitant on CYP3A4 is weak, with the AUC of midazolam increased by 1.5-fold and 1.2-fold, respectively. After administration, fosaprepitant is rapidly converted to aprepitant and shares many of the same drug interactions. However, as a single 150 mg intravenous dose, fosaprepitant only weakly inhibits CYP3A4 for a duration of 2 days; there is no evidence of CYP3A4 induction. Fosaprepitant 150 mg IV as a single dose increased the AUC of midazolam (given on days 1 and 4) by approximately 1.8-fold on day 1; there was no effect on day 4. Less than a 2-fold increase in the midazolam AUC is not considered clinically important.
    Aripiprazole: (Moderate) Due to the primary CNS effects of aripiprazole, caution should be used when aripiprazole is given in combination with other centrally-acting medications including benzodiazepines and other anxiolytics, sedatives, and hypnotics.
    Aspirin, ASA; Butalbital; Caffeine: (Major) Suvorexant is primarily metabolized by CYP3A, and decreased systemic exposure of suvorexant may occur during concurrent use with strong CYP3A inducers such as primidone or barbiturates. Patients should be monitored for a reduction in efficacy if either of these combinations is necessary. In addition, patients should be monitored for additive sedative effects. (Minor) Caffeine is a central nervous system (CNS) stimulant. Patients taking medications for sleep, such as suvorexant, eszopiclone, zaleplon, or zolpidem should avoid caffeine-containing medications, dietary supplements, foods, and beverages close to bedtime. Patients should be encouraged to avoid excessive total daily caffeine intake, as part of proper sleep hygiene, since caffeine intake can interfere with proper sleep.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Major) Suvorexant is primarily metabolized by CYP3A, and decreased systemic exposure of suvorexant may occur during concurrent use with strong CYP3A inducers such as primidone or barbiturates. Patients should be monitored for a reduction in efficacy if either of these combinations is necessary. In addition, patients should be monitored for additive sedative effects. (Minor) Caffeine is a central nervous system (CNS) stimulant. Patients taking medications for sleep, such as suvorexant, eszopiclone, zaleplon, or zolpidem should avoid caffeine-containing medications, dietary supplements, foods, and beverages close to bedtime. Patients should be encouraged to avoid excessive total daily caffeine intake, as part of proper sleep hygiene, since caffeine intake can interfere with proper sleep.
    Aspirin, ASA; Caffeine; Dihydrocodeine: (Minor) Caffeine is a central nervous system (CNS) stimulant. Patients taking medications for sleep, such as suvorexant, eszopiclone, zaleplon, or zolpidem should avoid caffeine-containing medications, dietary supplements, foods, and beverages close to bedtime. Patients should be encouraged to avoid excessive total daily caffeine intake, as part of proper sleep hygiene, since caffeine intake can interfere with proper sleep.
    Atazanavir: (Major) Suvorexant is primarily metabolized by CYP3A, and the manufacturer recommends a dose reduction to 5 mg of suvorexant during concurrent use with moderate CYP3A inhibitors such as atazanavir and a maximum recommended dose of 10 mg/day.
    Atazanavir; Cobicistat: (Major) Suvorexant is primarily metabolized by CYP3A, and the manufacturer recommends a dose reduction to 5 mg of suvorexant during concurrent use with moderate CYP3A inhibitors such as atazanavir and a maximum recommended dose of 10 mg/day.
    Atropine; Hyoscyamine; Phenobarbital; Scopolamine: (Major) Suvorexant is primarily metabolized by CYP3A, and decreased systemic exposure of suvorexant may occur during concurrent use with strong CYP3A inducers such as primidone or barbiturates. Patients should be monitored for a reduction in efficacy if either of these combinations is necessary. In addition, patients should be monitored for additive sedative effects.
    Barbiturates: (Major) Suvorexant is primarily metabolized by CYP3A, and decreased systemic exposure of suvorexant may occur during concurrent use with strong CYP3A inducers such as primidone or barbiturates. Patients should be monitored for a reduction in efficacy if either of these combinations is necessary. In addition, patients should be monitored for additive sedative effects.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: (Major) Suvorexant is primarily metabolized by CYP3A, and decreased systemic exposure of suvorexant may occur during concurrent use with strong CYP3A inducers such as primidone or barbiturates. Patients should be monitored for a reduction in efficacy if either of these combinations is necessary. In addition, patients should be monitored for additive sedative effects.
    Benzodiazepines: (Moderate) CNS depressant drugs may have cumulative effects when administered concurrently and they should be used cautiously with suvorexant. A reduction in dose of the CNS depressant may be needed in some cases. These agents include the benzodiazepines.
    Boceprevir: (Major) Suvorexant is primarily metabolized by CYP3A, and the manufacturer recommends against concurrent use of suvorexant with strong CYP3A inhibitors such as telaprevir and boceprevir. Strong inhibitors of CYP3A significantly increase suvorexant exposure (AUC).
    Brigatinib: (Moderate) Monitor for decreased efficacy of suvorexant if coadministration with brigatinib is necessary. Suvorexant is a CYP3A substrate and brigatinib induces CYP3A in vitro; plasma concentrations of suvorexant may decrease.
    Buprenorphine: (Moderate) If concurrent use of suvorexant and buprenorphine is necessary, consider a dose reduction of one or both drugs because of the potential for additive pharmacological effects. Sedation, coma, or respiratory depression may occur during co-administration of buprenorphine and other CNS depressants. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Evaluate the patient's use of alcohol or illicit drugs. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
    Buprenorphine; Naloxone: (Moderate) If concurrent use of suvorexant and buprenorphine is necessary, consider a dose reduction of one or both drugs because of the potential for additive pharmacological effects. Sedation, coma, or respiratory depression may occur during co-administration of buprenorphine and other CNS depressants. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Evaluate the patient's use of alcohol or illicit drugs. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
    Butabarbital: (Major) Suvorexant is primarily metabolized by CYP3A, and decreased systemic exposure of suvorexant may occur during concurrent use with strong CYP3A inducers such as primidone or barbiturates. Patients should be monitored for a reduction in efficacy if either of these combinations is necessary. In addition, patients should be monitored for additive sedative effects.
    Caffeine: (Minor) Caffeine is a central nervous system (CNS) stimulant. Patients taking medications for sleep, such as suvorexant, eszopiclone, zaleplon, or zolpidem should avoid caffeine-containing medications, dietary supplements, foods, and beverages close to bedtime. Patients should be encouraged to avoid excessive total daily caffeine intake, as part of proper sleep hygiene, since caffeine intake can interfere with proper sleep.
    Caffeine; Ergotamine: (Minor) Caffeine is a central nervous system (CNS) stimulant. Patients taking medications for sleep, such as suvorexant, eszopiclone, zaleplon, or zolpidem should avoid caffeine-containing medications, dietary supplements, foods, and beverages close to bedtime. Patients should be encouraged to avoid excessive total daily caffeine intake, as part of proper sleep hygiene, since caffeine intake can interfere with proper sleep.
    Carbamazepine: (Major) Suvorexant is primarily metabolized by CYP3A, and decreased systemic exposure of suvorexant may occur during concurrent use with strong CYP3A inducers such as carbamazepine or eslicarbazepine. Patients should be monitored for a reduction in efficacy if either of these combinations is necessary.
    Carbidopa; Levodopa; Entacapone: (Moderate) CNS depressant drugs may have cumulative effects when administered concurrently and they should be used cautiously with suvorexant. A reduction in dose of the CNS depressant may be needed in some cases.
    Cariprazine: (Moderate) Due to the CNS effects of cariprazine, caution should be used when cariprazine is given in combination with other centrally-acting medications including benzodiazepines and other anxiolytics, sedatives, and hypnotics like suvorexant.
    Ceritinib: (Moderate) Monitor for suvorexant-related adverse reactions if coadministration with ceritinib is possible; a dose adjustment may be necessary. Patients should not drive or engage in other activities requiring full alertness within 8 hours of taking suvorexant. Ceritinib is a CYP3A4 inhibitor and suvorexant is primarily metabolized by CYP3A4. Coadministration with a strong CYP3A4 inhibitor increased suvorexant exposure 3-fold, while concomitant use of a moderate CYP3A4 inhibitor increased exposure 1.36-fold to 2.05-fold. The manufacturer of suvorexant recommends avoiding coadministration with strong CYP3A4 inhibitors and dosing at 5 mg (maximum, 10 mg) for patients taking moderate CYP3A4 inhibitors. The degree of CYP3A4 inhibition by ceritinib is unknown.
    Chloral Hydrate: (Moderate) CNS depressant drugs may have cumulative effects when administered concurrently and they should be used cautiously with suvorexant. A reduction in dose of the CNS depressant may be needed in some cases. Use cautiously with any anxiolytics; use with other sedatives and hypnotics should generally be avoided due to duplication of treatments.
    Chloramphenicol: (Major) Suvorexant is primarily metabolized by CYP3A, and the manufacturer recommends against concurrent use of suvorexant with strong CYP3A inhibitors. Chloramphenicol is a strong CYP3A4 inhibitor, and suvorexant plasma concentrations may increase during concurrent use of these drugs.
    Chlordiazepoxide: (Moderate) CNS depressant drugs may have cumulative effects when administered concurrently and they should be used cautiously with suvorexant. A reduction in dose of the CNS depressant may be needed in some cases. These agents include the benzodiazepines.
    Chlordiazepoxide; Clidinium: (Moderate) CNS depressant drugs may have cumulative effects when administered concurrently and they should be used cautiously with suvorexant. A reduction in dose of the CNS depressant may be needed in some cases. These agents include the benzodiazepines.
    Ciprofloxacin: (Major) Suvorexant is primarily metabolized by CYP3A, and the manufacturer recommends a dose reduction to 5 mg of suvorexant during concurrent use with moderate CYP3A inhibitors such as ciprofloxacin and a maximum recommended dose of 10 mg/day.
    Clarithromycin: (Major) Suvorexant is primarily metabolized by CYP3A, and the manufacturer recommends against concurrent use of suvorexant with strong CYP3A inhibitors such as clarithromycin. Strong inhibitors of CYP3A significantly increase suvorexant exposure (AUC).
    Clonazepam: (Moderate) CNS depressant drugs may have cumulative effects when administered concurrently and they should be used cautiously with suvorexant. A reduction in dose of the CNS depressant may be needed in some cases. These agents include the benzodiazepines.
    Clorazepate: (Moderate) CNS depressant drugs may have cumulative effects when administered concurrently and they should be used cautiously with suvorexant. A reduction in dose of the CNS depressant may be needed in some cases. These agents include the benzodiazepines.
    Cobimetinib: (Minor) If concurrent use of cobimetinib and suvorexant is necessary, use caution and monitor for a possible increase in cobimetinib-related adverse effects. Cobimetinib is a P-glycoprotein (P-gp) substrate, and suvorexant is a P-gp inhibitor; coadministration may result in increased cobimetinib exposure. However, coadministration of cobimetinib with another P-gp inhibitor, vemurafenib (960 mg twice daily), did not result in clinically relevant pharmacokinetic drug interactions.
    Conivaptan: (Major) Suvorexant is primarily metabolized by CYP3A, and the manufacturer recommends against concurrent use of suvorexant with strong CYP3A inhibitors such as conivaptan. Strong inhibitors of CYP3A significantly increase suvorexant exposure (AUC).
    Crizotinib: (Major) When coadministered with crizotinib, the recommended suvorexant dose if 5 mg; if necessary for efficacy the suvorexant dose may be increased to 10 mg. Suvorexant is a CYP3A4 substrate and crizotinib is a moderate CYP3A4 inhibitor. Coadministration with another moderate CYP3A4 inhibitor increased suvorexant exposure by 1.36-fold to 2.05-fold.
    Cyclobenzaprine: (Moderate) Cyclobenzaprine may cause additive CNS depression if used concomitantly with other CNS depressants, such as anxiolytics, sedatives, and hypnotics. Combination therapy can cause additive effects of sedation and dizziness, which can impair the patient's ability to undertake tasks requiring mental alertness. Dosage adjustments of either or both medications may be necessary.
    Dabigatran: (Moderate) Increased serum concentrations of dabigatran are possible when dabigatran, a P-glycoprotein (P-gp) substrate, is coadministered with suvorexant, a P-gp inhibitor. Patients should be monitored for increased adverse effects of dabigatran. When dabigatran is administered for treatment or reduction in risk of recurrence of deep venous thrombosis (DVT) or pulmonary embolism (PE) or prophylaxis of DVT or PE following hip replacement surgery, avoid coadministration with P-gp inhibitors like suvorexant in patients with CrCl less than 50 mL/minute. When dabigatran is used in patients with non-valvular atrial fibrillation and severe renal impairment (CrCl less than 30 mL/minute), avoid coadministration with suvorexant, as serum concentrations of dabigatran are expected to be higher than when administered to patients with normal renal function. P-gp inhibition and renal impairment are the major independent factors that result in increased exposure to dabigatran.
    Dalfopristin; Quinupristin: (Major) Suvorexant is primarily metabolized by CYP3A, and the manufacturer recommends against concurrent use of suvorexant with strong CYP3A inhibitors. Dalfopristin; quinupristin is a strong CYP3A4 inhibitor, and suvorexant plasma concentrations may increase during concurrent use of the drugs.
    Darunavir: (Major) Suvorexant is primarily metabolized by CYP3A, and the manufacturer recommends against concurrent use of suvorexant with strong CYP3A inhibitors such as darunavir, ritonavir, saquinavir, nelfinavir, tipranavir, and indinavir. Strong inhibitors of CYP3A significantly increase suvorexant exposure (AUC).
    Darunavir; Cobicistat: (Major) Suvorexant is primarily metabolized by CYP3A, and the manufacturer recommends against concurrent use of suvorexant with strong CYP3A inhibitors such as darunavir, ritonavir, saquinavir, nelfinavir, tipranavir, and indinavir. Strong inhibitors of CYP3A significantly increase suvorexant exposure (AUC).
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Major) Coadministration of suvorexant and dasabuvir; ombitasvir; paritaprevir; ritonavir should be avoided. The manufacturer of suvorexant, a CYP3A substrate, recommends against concurrent use with strong CYP3A inhibitors, such as ritonavir, as significantly increased suvorexant exposure (AUC) occurs. Additionally, suvorexant inhibits P-glycoprotein (P-gp) and could increase the concentrations of P-gp substrates such as each component of dasabuvir; ombitasvir; paritaprevir; ritonavir. (Major) Coadministration of suvorexant and dasabuvir; ombitasvir; paritaprevir; ritonavir should be avoided. The manufacturer of suvorexant, a CYP3A substrate, recommends against concurrent use with strong CYP3A inhibitors, such as ritonavir, as significantly increased suvorexant exposure (AUC) occurs. Additionally, suvorexant inhibits P-glycoprotein (P-gp) and could increase the concentrations of P-gp substrates such as each component of dasabuvir; ombitasvir; paritaprevir; ritonavir. (Major) Suvorexant is primarily metabolized by CYP3A, and the manufacturer recommends against concurrent use of suvorexant with strong CYP3A inhibitors such as ritonavir. Strong inhibitors of CYP3A significantly increase suvorexant exposure (AUC).
    Delavirdine: (Major) Suvorexant is primarily metabolized by CYP3A, and the manufacturer recommends against concurrent use of suvorexant with strong CYP3A inhibitors. Delavirdine is a strong CYP3A4 inhibitor, and suvorexant plasma concentrations may increase during concurrent use of these drugs.
    Deutetrabenazine: (Moderate) Advise patients that concurrent use of deutetrabenazine and drugs that can cause CNS depression, such as suvorexant, may have additive effects and worsen drowsiness or sedation.
    Diazepam: (Moderate) CNS depressant drugs may have cumulative effects when administered concurrently and they should be used cautiously with suvorexant. A reduction in dose of the CNS depressant may be needed in some cases. These agents include the benzodiazepines.
    Digoxin: (Major) Digoxin concentrations should be monitored during use with suvorexant. In one evaluation, concomitant administration of digoxin and suvorexant slightly increased digoxin levels presumably due to inhibition of intestinal P-glycoprotein (P-gp) by suvorexant.
    Diltiazem: (Major) Suvorexant is primarily metabolized by CYP3A, and the manufacturer recommends a dose reduction to 5 mg of suvorexant during concurrent use with moderate CYP3A inhibitors such as diltiazem or verapamil and a maximum recommended dose of 10 mg/day.
    Dronabinol, THC: (Moderate) CNS depressant drugs may have cumulative effects when administered concurrently and they should be used cautiously with suvorexant. A reduction in dose of the CNS depressant may be needed in some cases.
    Dronedarone: (Major) Suvorexant is primarily metabolized by CYP3A, and the manufacturer recommends a dose reduction to 5 mg of suvorexant during concurrent use with moderate CYP3A inhibitors and a maximum recommended dose of 10 mg/day. Dronedarone is a moderate CYP3A4 inhibitor, and increased plasma concentrations of suvorexant are possible during concurrent use of these drugs.
    Droperidol: (Moderate) CNS depressant drugs may have cumulative effects when administered concurrently and they should be used cautiously with suvorexant. A reduction in dose of the CNS depressant may be needed in some cases.
    Efavirenz: (Major) Suvorexant is primarily metabolized by CYP3A, and decreased systemic exposure of suvorexant may occur during concurrent use with strong CYP3A inducers such as efavirenz. Patients should be monitored for a reduction in efficacy if this combination is necessary.
    Efavirenz; Emtricitabine; Tenofovir: (Major) Suvorexant is primarily metabolized by CYP3A, and decreased systemic exposure of suvorexant may occur during concurrent use with strong CYP3A inducers such as efavirenz. Patients should be monitored for a reduction in efficacy if this combination is necessary.
    Elbasvir; Grazoprevir: (Moderate) Administering suvorexant with elbasvir; grazoprevir may result in elevated suvorexant plasma concentrations. Suvorexant is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
    Entacapone: (Moderate) CNS depressant drugs may have cumulative effects when administered concurrently and they should be used cautiously with suvorexant. A reduction in dose of the CNS depressant may be needed in some cases.
    Enzalutamide: (Moderate) Monitor for decreased efficacy of suvorexant if coadministration with enzalutamide is necessary. Suvorexant is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A inducer decreased suvorexant exposure by 77% to 88%.
    Erythromycin: (Major) Suvorexant is primarily metabolized by CYP3A, and the manufacturer recommends a dose reduction to 5 mg of suvorexant during concurrent use with moderate CYP3A inhibitors such as erythromycin and a maximum recommended dose of 10 mg/day.
    Erythromycin; Sulfisoxazole: (Major) Suvorexant is primarily metabolized by CYP3A, and the manufacturer recommends a dose reduction to 5 mg of suvorexant during concurrent use with moderate CYP3A inhibitors such as erythromycin and a maximum recommended dose of 10 mg/day.
    Eslicarbazepine: (Major) Suvorexant is primarily metabolized by CYP3A, and decreased systemic exposure of suvorexant may occur during concurrent use with strong CYP3A inducers such as eslicarbazepine. Patients should be monitored for a reduction in efficacy if either of these combinations is necessary.
    Estazolam: (Moderate) CNS depressant drugs may have cumulative effects when administered concurrently and they should be used cautiously with suvorexant. A reduction in dose of the CNS depressant may be needed in some cases. These agents include the benzodiazepines.
    Eszopiclone: (Moderate) CNS depressant drugs may have cumulative effects when administered concurrently and they should be used cautiously with suvorexant. A reduction in dose of the CNS depressant may be needed in some cases. Use cautiously with any anxiolytics; use with other sedatives and hypnotics should generally be avoided due to duplication of treatments.
    Ethanol: (Major) Alcohol is associated with CNS depression. The combined use of alcohol and CNS depressants can lead to additive CNS depression, which could be dangerous in tasks requiring mental alertness and fatal in overdose. Alcohol taken with other CNS depressants can lead to additive respiratory depression, hypotension, profound sedation, or coma. Consider the patient's use of alcohol or illicit drugs when prescribing CNS depressant medications. In many cases, the patient should receive a lower dose of the CNS depressant initially if the patient is not likely to be compliant with avoiding alcohol.
    Etoposide, VP-16: (Major) Monitor for an increased incidence of etoposide-related adverse effects if used concomitantly with suvorexant. Suvorexant is an inhibitor of P-glycoprotein (P-gp) and etoposide, VP-16 is a P-gp substrate. Coadministration may increase etoposide concentrations.
    Etravirine: (Major) Suvorexant is primarily metabolized by CYP3A, and decreased systemic exposure of suvorexant may occur during concurrent use with strong CYP3A inducers such as etravirine. Patients should be monitored for a reduction in efficacy if this combination is necessary.
    Fluconazole: (Major) Suvorexant is primarily metabolized by CYP3A, and the manufacturer recommends a dose reduction to 5 mg of suvorexant during concurrent use with moderate CYP3A inhibitors such as fluconazole and maximum recommended dose of 10 mg/day.
    Flurazepam: (Moderate) CNS depressant drugs may have cumulative effects when administered concurrently and they should be used cautiously with suvorexant. A reduction in dose of the CNS depressant may be needed in some cases. These agents include the benzodiazepines.
    Fosamprenavir: (Major) Suvorexant is primarily metabolized by CYP3A, and the manufacturer recommends a dose reduction to 5 mg of suvorexant during concurrent use with moderate CYP3A inhibitors such as amprenavir or fosamprenavir and a maximum recommended dose of 10 mg/day.
    Fosphenytoin: (Major) Suvorexant is primarily metabolized by CYP3A, and decreased systemic exposure of suvorexant may occur during concurrent use with strong CYP3A inducers such as phenytoin or fosphenytoin. Patients should be monitored for a reduction in efficacy if this combination is necessary.
    General anesthetics: (Moderate) CNS depressant drugs may have cumulative effects when administered concurrently and they should be used cautiously with suvorexant. A reduction in dose of the CNS depressant may be needed in some cases. These agents include the general anesthetics.
    Grapefruit juice: (Major) Suvorexant is primarily metabolized by CYP3A, and the manufacturer recommends a dose reduction to 5 mg of suvorexant during concurrent use with moderate CYP3A inhibitors. A dose reduction should be considered in patients who regularly consume grapefruit juice, a moderate CYP3A inhibitor with the potential to increase suvorexant exposure.
    Idelalisib: (Major) Suvorexant is primarily metabolized by CYP3A, and the manufacturer recommends against concurrent use of suvorexant with strong CYP3A inhibitors. Idelalisib is a strong CYP3A4 inhibitor, and suvorexant plasma concentrations may increase during concurrent use of these drugs.
    Imatinib: (Major) Suvorexant is primarily metabolized by CYP3A, and the manufacturer recommends a dose reduction to 5 mg of suvorexant during concurrent use with moderate CYP3A inhibitors such as imatinib, STI-571 and a maximum recommended dose of 10 mg/day.
    Indinavir: (Major) Suvorexant is primarily metabolized by CYP3A, and the manufacturer recommends against concurrent use of suvorexant with strong CYP3A inhibitors such as indinavir. Strong inhibitors of CYP3A significantly increase suvorexant exposure (AUC).
    Isavuconazonium: (Major) Suvorexant is primarily metabolized by CYP3A4, and the manufacturer recommends a dose reduction to 5 mg of suvorexant during concurrent use with moderate CYP3A4 inhibitors and a maximum recommended dose of 10 mg/day. Isavuconazole, the active moiety of isavuconazonium, is a moderate inhibitor of CYP3A4, and increased plasma concentrations of suvorexant are possible during concurrent use of these drugs.
    Isoniazid, INH: (Major) Suvorexant is primarily metabolized by CYP3A, and the manufacturer recommends against concurrent use of suvorexant with strong CYP3A inhibitors. Isoniazid, INH is a strong CYP3A4 inhibitor, and suvorexant plasma concentrations may increase during concurrent use of the drugs.
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Suvorexant is primarily metabolized by CYP3A, and a substantial decrease in systemic exposure of suvorexant occurs during concurrent use with strong CYP3A inducers such as rifampin. Patients should be monitored for a reduction in efficacy if this combination is necessary. (Major) Suvorexant is primarily metabolized by CYP3A, and the manufacturer recommends against concurrent use of suvorexant with strong CYP3A inhibitors. Isoniazid, INH is a strong CYP3A4 inhibitor, and suvorexant plasma concentrations may increase during concurrent use of the drugs.
    Isoniazid, INH; Rifampin: (Major) Suvorexant is primarily metabolized by CYP3A, and a substantial decrease in systemic exposure of suvorexant occurs during concurrent use with strong CYP3A inducers such as rifampin. Patients should be monitored for a reduction in efficacy if this combination is necessary. (Major) Suvorexant is primarily metabolized by CYP3A, and the manufacturer recommends against concurrent use of suvorexant with strong CYP3A inhibitors. Isoniazid, INH is a strong CYP3A4 inhibitor, and suvorexant plasma concentrations may increase during concurrent use of the drugs.
    Itraconazole: (Major) Suvorexant is primarily metabolized by CYP3A, and the manufacturer recommends against concurrent use of suvorexant with strong CYP3A inhibitors such as itraconazole. Strong inhibitors of CYP3A significantly increase suvorexant exposure (AUC).
    Kava Kava, Piper methysticum: (Major) Any substance that acts on the CNS may interact with certain herbal products including kava kava, Piper methysticum. These interactions are probably pharmacodynamic in nature, or result from additive mechanisms of action. The possibility of pharmacodynamic interactions at normal prescription dosages of suvorexant signals the need for patients to avoid concomitant administration of dietary supplements promoted for sleep and relaxation.
    Ketoconazole: (Major) Suvorexant is primarily metabolized by CYP3A, and the manufacturer recommends against concurrent use of suvorexant with strong CYP3A inhibitors such as ketoconazole. Strong inhibitors of CYP3A significantly increase suvorexant exposure (AUC).
    Lapatinib: (Major) Suvorexant is primarily metabolized by CYP3A, and the manufacturer recommends a dose reduction to 5 mg of suvorexant during concurrent use with moderate CYP3A inhibitors and a maximum recommended dose of 10 mg/day. Lapatinib is a moderate CYP3A4 inhibitor, and increased plasma concentrations of suvorexant are possible during concurrent use of these drugs.
    Loperamide: (Moderate) The plasma concentration of loperamide, a P-glycoprotein (P-gp) substrate, may be increased when administered concurrently with suvorexant, a P-gp inhibitor. If these drugs are used together, monitor for loperamide-associated adverse reactions, such as CNS effects and cardiac toxicities (i.e., syncope, ventricular tachycardia, QT prolongation, torsade de pointes, cardiac arrest).
    Loperamide; Simethicone: (Moderate) The plasma concentration of loperamide, a P-glycoprotein (P-gp) substrate, may be increased when administered concurrently with suvorexant, a P-gp inhibitor. If these drugs are used together, monitor for loperamide-associated adverse reactions, such as CNS effects and cardiac toxicities (i.e., syncope, ventricular tachycardia, QT prolongation, torsade de pointes, cardiac arrest).
    Lopinavir; Ritonavir: (Major) Suvorexant is primarily metabolized by CYP3A, and the manufacturer recommends against concurrent use of suvorexant with strong CYP3A inhibitors such as ritonavir. Strong inhibitors of CYP3A significantly increase suvorexant exposure (AUC).
    Lorazepam: (Moderate) CNS depressant drugs may have cumulative effects when administered concurrently and they should be used cautiously with suvorexant. A reduction in dose of the CNS depressant may be needed in some cases. These agents include the benzodiazepines.
    Lumacaftor; Ivacaftor: (Moderate) Lumacaftor; ivacaftor may reduce the efficacy of suvorexant by substantially decreasing its systemic exposure; if used together, monitor patients for appropriate clinical response. Suvorexant is a primary substrate of CYP3A, and lumacaftor is a strong CYP3A inducer.
    Lurasidone: (Moderate) Drugs that can cause CNS depression, if used concomitantly with atypical antipsychotics, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, and dizziness.
    Maraviroc: (Moderate) Use caution and closely monitor for increased adverse effects with the coadministration of maraviroc and suvorexant as increased maraviroc concentrations may occur. Maraviroc is a substrate of P-glycoprotein (P-gp); suvorexant is an inhibitor of P-gp. The effects of P-gp on the concentrations of maraviroc are unknown, although an increase in concentrations and thus, toxicity, are possible.
    Melatonin: (Major) Pharmacodynamic interactions often occur when sedative agents are used together. Until more data are available, avoid combining melatonin with other hypnotics, including suvorexant. In a clinical trial, there was clear evidence for a transitory pharmacodynamic interaction between melatonin and another hypnotic agent one hour following co-dosing. Concomitant administration resulted in increased impairment of attention, memory and co-ordination compared to the hypnotic agent alone. Use of more than one agent for hypnotic purposes may increase the risk for over-sedation, CNS effects, or sleep-related behaviors. Be alert for unusual changes in moods or behaviors. Patients reporting unusual sleep-related behaviors likely should discontinue melatonin use.
    Mephobarbital: (Major) Suvorexant is primarily metabolized by CYP3A, and decreased systemic exposure of suvorexant may occur during concurrent use with strong CYP3A inducers such as primidone or barbiturates. Patients should be monitored for a reduction in efficacy if either of these combinations is necessary. In addition, patients should be monitored for additive sedative effects.
    Meprobamate: (Moderate) CNS depressant drugs may have cumulative effects when administered concurrently and they should be used cautiously with suvorexant. A reduction in dose of the CNS depressant may be needed in some cases. Use cautiously with any anxiolytics; use with other sedatives and hypnotics should generally be avoided due to duplication of treatments.
    Methohexital: (Major) Suvorexant is primarily metabolized by CYP3A, and decreased systemic exposure of suvorexant may occur during concurrent use with strong CYP3A inducers such as primidone or barbiturates. Patients should be monitored for a reduction in efficacy if either of these combinations is necessary. In addition, patients should be monitored for additive sedative effects.
    Metyrapone: (Major) Suvorexant is primarily metabolized by CYP3A, and decreased systemic exposure of suvorexant may occur during concurrent use with strong CYP3A inducers such as metyrapone. Patients should be monitored for a reduction in efficacy if this combination is necessary.
    Midazolam: (Moderate) CNS depressant drugs may have cumulative effects when administered concurrently and they should be used cautiously with suvorexant. A reduction in dose of the CNS depressant may be needed in some cases. These agents include the benzodiazepines.
    Mifepristone, RU-486: (Major) Suvorexant is primarily metabolized by CYP3A, and the manufacturer recommends a dose reduction to 5 mg of suvorexant during concurrent use with moderate CYP3A inhibitors and a maximum recommended dose of 10 mg/day. Mifepristone, RU-486 is a moderate CYP3A4 inhibitor, and increased plasma concentrations of suvorexant are possible during concurrent use of these drugs.
    Mirtazapine: (Moderate) CNS depressant drugs may have cumulative effects when administered concurrently and they should be used cautiously with suvorexant. A reduction in dose of the CNS depressant may be needed in some cases.
    Mitotane: (Moderate) Use caution if mitotane and suvorexant are used concomitantly, and monitor for decreased efficacy of suvorexant and a possible change in dosage requirements (maximum, 20 mg). Mitotane is a strong CYP3A4 inducer and suvorexant is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of suvorexant.
    Modafinil: (Major) Suvorexant is primarily metabolized by CYP3A, and decreased systemic exposure of suvorexant may occur during concurrent use with strong CYP3A inducers such as modafinil. Patients should be monitored for a reduction in efficacy if this combination is necessary.
    Nabilone: (Moderate) CNS depressant drugs may have cumulative effects when administered concurrently and they should be used cautiously with suvorexant. A reduction in dose of the CNS depressant may be needed in some cases.
    Nalbuphine: (Moderate) CNS depressant drugs may have cumulative effects when administered concurrently and they should be used cautiously with suvorexant. A reduction in dose of the CNS depressant may be needed. These agents include mixed opiate agonists/antagonists.
    Nefazodone: (Major) Suvorexant is primarily metabolized by CYP3A, and the manufacturer recommends against concurrent use of suvorexant with strong CYP3A inhibitors such as nefazodone. Strong inhibitors of CYP3A significantly increase suvorexant exposure (AUC).
    Nelfinavir: (Major) Suvorexant is primarily metabolized by CYP3A, and the manufacturer recommends against concurrent use of suvorexant with strong CYP3A inhibitors such as darunavir, ritonavir, saquinavir, nelfinavir, tipranavir, and indinavir. Strong inhibitors of CYP3A significantly increase suvorexant exposure (AUC).
    Nevirapine: (Major) Suvorexant is primarily metabolized by CYP3A, and decreased systemic exposure of suvorexant may occur during concurrent use with strong CYP3A inducers such as nevirapine. Patients should be monitored for a reduction in efficacy if this combination is necessary.
    Ombitasvir; Paritaprevir; Ritonavir: (Major) Coadministration of suvorexant and dasabuvir; ombitasvir; paritaprevir; ritonavir should be avoided. The manufacturer of suvorexant, a CYP3A substrate, recommends against concurrent use with strong CYP3A inhibitors, such as ritonavir, as significantly increased suvorexant exposure (AUC) occurs. Additionally, suvorexant inhibits P-glycoprotein (P-gp) and could increase the concentrations of P-gp substrates such as each component of dasabuvir; ombitasvir; paritaprevir; ritonavir. (Major) Suvorexant is primarily metabolized by CYP3A, and the manufacturer recommends against concurrent use of suvorexant with strong CYP3A inhibitors such as ritonavir. Strong inhibitors of CYP3A significantly increase suvorexant exposure (AUC).
    Opiate Agonists: (Moderate) CNS depressant drugs may have cumulative effects when administered concurrently and they should be used cautiously with suvorexant. A reduction in dose of the CNS depressant may be needed in some cases.
    Oxazepam: (Moderate) CNS depressant drugs may have cumulative effects when administered concurrently and they should be used cautiously with suvorexant. A reduction in dose of the CNS depressant may be needed in some cases. These agents include the benzodiazepines.
    Oxcarbazepine: (Major) Suvorexant is primarily metabolized by CYP3A, and decreased systemic exposure of suvorexant may occur during concurrent use with CYP3A inducers such as oxcarbazepine. Patients should be monitored for a reduction in efficacy if this combination is necessary.
    Pantoprazole: (Major) Suvorexant is primarily metabolized by CYP3A, and the manufacturer recommends a dose reduction to 5 mg of suvorexant during concurrent use with moderate CYP3A inhibitors and a maximum recommended dose of 10 mg/day. Pantoprazole is a moderate CYP3A4 inhibitor, and increased plasma concentrations of suvorexant are possible during concurrent use of these drugs.
    Pentazocine: (Moderate) CNS depressant drugs may have cumulative effects when administered concurrently and they should be used cautiously with suvorexant. A reduction in dose of the CNS depressant may be needed. These agents include mixed opiate agonists/antagonists.
    Pentazocine; Naloxone: (Moderate) CNS depressant drugs may have cumulative effects when administered concurrently and they should be used cautiously with suvorexant. A reduction in dose of the CNS depressant may be needed. These agents include mixed opiate agonists/antagonists.
    Pentobarbital: (Major) Suvorexant is primarily metabolized by CYP3A, and decreased systemic exposure of suvorexant may occur during concurrent use with strong CYP3A inducers such as primidone or barbiturates. Patients should be monitored for a reduction in efficacy if either of these combinations is necessary. In addition, patients should be monitored for additive sedative effects.
    Phenobarbital: (Major) Suvorexant is primarily metabolized by CYP3A, and decreased systemic exposure of suvorexant may occur during concurrent use with strong CYP3A inducers such as primidone or barbiturates. Patients should be monitored for a reduction in efficacy if either of these combinations is necessary. In addition, patients should be monitored for additive sedative effects.
    Phenytoin: (Major) Suvorexant is primarily metabolized by CYP3A, and decreased systemic exposure of suvorexant may occur during concurrent use with strong CYP3A inducers such as phenytoin. Patients should be monitored for a reduction in efficacy if this combination is necessary.
    Posaconazole: (Major) Suvorexant is primarily metabolized by CYP3A, and the manufacturer recommends against concurrent use of suvorexant with strong CYP3A inhibitors such as posaconazole. Strong inhibitors of CYP3A significantly increase suvorexant exposure (AUC).
    Pramipexole: (Moderate) CNS depressant drugs may have cumulative effects when administered concurrently and they should be used cautiously with suvorexant. A reduction in dose of the CNS depressant may be needed in some cases.
    Pregabalin: (Moderate) CNS depressant drugs may have cumulative effects when administered concurrently and they should be used cautiously with suvorexant. A reduction in dose of the CNS depressant may be needed in some cases.
    Primidone: (Major) Suvorexant is primarily metabolized by CYP3A, and decreased systemic exposure of suvorexant may occur during concurrent use with strong CYP3A inducers such as primidone or barbiturates. Patients should be monitored for a reduction in efficacy if either of these combinations is necessary. In addition, patients should be monitored for additive sedative effects.
    Quazepam: (Moderate) CNS depressant drugs may have cumulative effects when administered concurrently and they should be used cautiously with suvorexant. A reduction in dose of the CNS depressant may be needed in some cases. These agents include the benzodiazepines.
    Ramelteon: (Moderate) CNS depressant drugs may have cumulative effects when administered concurrently and they should be used cautiously with suvorexant. These agents include any other sedatives and hypnotics. Ramelteon and suvorexant would be considered duplicate treatments and use together should generally be avoided.
    Ribociclib: (Major) If coadministration of ribociclib, a moderate CYP3A4 inhibitor, with suvorexant, a CYP3A4 substrate, is necessary, the recommended dose of suvorexant is 5 mg (maximum, 10 mg). The systemic exposure of suvorexant may be increased during concurrent use resulting in an increase in treatment-related adverse reactions.
    Ribociclib; Letrozole: (Major) If coadministration of ribociclib, a moderate CYP3A4 inhibitor, with suvorexant, a CYP3A4 substrate, is necessary, the recommended dose of suvorexant is 5 mg (maximum, 10 mg). The systemic exposure of suvorexant may be increased during concurrent use resulting in an increase in treatment-related adverse reactions.
    Rifampin: (Major) Suvorexant is primarily metabolized by CYP3A, and a substantial decrease in systemic exposure of suvorexant occurs during concurrent use with strong CYP3A inducers such as rifampin. Patients should be monitored for a reduction in efficacy if this combination is necessary.
    Ritonavir: (Major) Suvorexant is primarily metabolized by CYP3A, and the manufacturer recommends against concurrent use of suvorexant with strong CYP3A inhibitors such as ritonavir. Strong inhibitors of CYP3A significantly increase suvorexant exposure (AUC).
    Ropinirole: (Moderate) CNS depressant drugs may have cumulative effects when administered concurrently and they should be used cautiously with suvorexant. A reduction in dose of the CNS depressant may be needed in some cases.
    Safinamide: (Moderate) Dopaminergic medications, including safinamide, may cause a sudden onset of somnolence which sometimes has resulted in motor vehicle accidents. Patients may not perceive warning signs, such as excessive drowsiness, or they may report feeling alert immediately prior to the event. Because of possible additive effects, advise patients about the potential for increased somnolence during concurrent use of safinamide with other sedating medications, such as suvorexant.
    Saquinavir: (Major) Suvorexant is primarily metabolized by CYP3A, and the manufacturer recommends against concurrent use of suvorexant with strong CYP3A inhibitors such as saquinavir. Strong inhibitors of CYP3A significantly increase suvorexant exposure (AUC).
    Secobarbital: (Major) Suvorexant is primarily metabolized by CYP3A, and decreased systemic exposure of suvorexant may occur during concurrent use with strong CYP3A inducers such as primidone or barbiturates. Patients should be monitored for a reduction in efficacy if either of these combinations is necessary. In addition, patients should be monitored for additive sedative effects.
    Sedating H1-blockers: (Moderate) CNS depressant drugs may have cumulative effects when administered concurrently and they should be used cautiously with suvorexant. A reduction in dose of the CNS depressant may be needed in some cases.
    Sofosbuvir; Velpatasvir: (Moderate) Use caution when administering velpatasvir with suvorexant. Taking these drugs together may increase the plasma concentrations of velpatasvir, potentially resulting in adverse events. Velpatasvir is a substrate of the drug transporter P-glycoprotein (P-gp); suvorexant is an inhibitor of P-gp.
    Sofosbuvir; Velpatasvir; Voxilaprevir: (Moderate) Use caution when administering velpatasvir with suvorexant. Taking these drugs together may increase the plasma concentrations of velpatasvir, potentially resulting in adverse events. Velpatasvir is a substrate of the drug transporter P-glycoprotein (P-gp); suvorexant is an inhibitor of P-gp.
    St. John's Wort, Hypericum perforatum: (Major) Suvorexant is primarily metabolized by CYP3A, and decreased systemic exposure of suvorexant may occur during concurrent use with strong CYP3A inducers such as St. John's Wort. Patients should be monitored for a reduction in efficacy if this combination is necessary.
    Streptogramins: (Major) Suvorexant is primarily metabolized by CYP3A, and the manufacturer recommends against concurrent use of suvorexant with strong CYP3A inhibitors. Dalfopristin; quinupristin is a strong CYP3A4 inhibitor, and suvorexant plasma concentrations may increase during concurrent use of the drugs.
    Tasimelteon: (Moderate) CNS depressant drugs may have cumulative effects when administered concurrently and they should be used cautiously with suvorexant. These agents include any other sedatives and hypnotics. Tasimelteon and suvorexant would be considered duplicate treatments and use together should generally be avoided.
    Telaprevir: (Major) Suvorexant is primarily metabolized by CYP3A, and the manufacturer recommends against concurrent use of suvorexant with strong CYP3A inhibitors such as telaprevir and boceprevir. Strong inhibitors of CYP3A significantly increase suvorexant exposure (AUC).
    Telithromycin: (Major) Suvorexant is primarily metabolized by CYP3A, and the manufacturer recommends against concurrent use of suvorexant with strong CYP3A inhibitors such as telithromycin. Strong inhibitors of CYP3A significantly increase suvorexant exposure (AUC).
    Telotristat Ethyl: (Moderate) Use caution if coadministration of telotristat ethyl and suvorexant is necessary, as the systemic exposure of suvorexant may be decreased resulting in reduced efficacy; exposure to telotristat ethyl may also be increased. If these drugs are used together, monitor patients for suboptimal efficacy of suvorexant as well as an increase in adverse reactions related to telotristat ethyl. Consider increasing the dose of suvorexant if necessary. Suvorexant is a CYP3A4 substrate. The mean Cmax and AUC of another sensitive CYP3A4 substrate was decreased by 25% and 48%, respectively, when coadministered with telotristat ethyl; the mechanism of this interaction appears to be that telotristat ethyl increases the glucuronidation of the CYP3A4 substrate. Additionally, the active metabolite of telotristat ethyl, telotristat, is a substrate of P-glycoprotein (P-gp) and suvorexant is a P-gp inhibitor. Exposure to telotristat ethyl may increase.
    Temazepam: (Moderate) CNS depressant drugs may have cumulative effects when administered concurrently and they should be used cautiously with suvorexant. A reduction in dose of the CNS depressant may be needed in some cases. These agents include the benzodiazepines.
    Temsirolimus: (Moderate) Use caution if coadministration of temsirolimus with suvorexant is necessary, and monitor for an increase in temsirolimus-related adverse reactions. Temsirolimus is a P-glycoprotein (P-gp) substrate in vitro and suvorexant is a P-gp inhibitor. Pharmacokinetic data are not available for concomitant use of temsirolimus with P-gp inhibitors, but temsirolimus (and active metabolite, sirolimus) exposure is likely to increase.
    Tenofovir Alafenamide: (Minor) Caution is advised when administering tenofovir alafenamide concurrently with suvorexant, as coadministration may result in elevated tenofovir alafenamide plasma concentrations. Inhibitors of the drug transporter P-glycoprotein (P-gp), such as suvorexant, may increase absorption of tenofovir alafenamide, a P-gp substrate. If these medications are administered together, monitor for tenofovir-associated adverse reactions. Of note, when tenofovir alafenamide is administered as part of a cobicistat-containing product, its availability is increased by cobicistat and a further increase of tenofovir alafenamide concentrations is not expected upon coadministration of an additional P-gp inhibitor.
    Thiopental: (Major) Suvorexant is primarily metabolized by CYP3A, and decreased systemic exposure of suvorexant may occur during concurrent use with strong CYP3A inducers such as primidone or barbiturates. Patients should be monitored for a reduction in efficacy if either of these combinations is necessary. In addition, patients should be monitored for additive sedative effects.
    Tipranavir: (Major) Suvorexant is primarily metabolized by CYP3A, and the manufacturer recommends against concurrent use of suvorexant with strong CYP3A inhibitors such as darunavir, ritonavir, saquinavir, nelfinavir, tipranavir, and indinavir. Strong inhibitors of CYP3A significantly increase suvorexant exposure (AUC).
    Tolcapone: (Moderate) CNS depressant drugs may have cumulative effects when administered concurrently and they should be used cautiously with suvorexant. A reduction in dose of the CNS depressant may be needed in some cases.
    Topotecan: (Major) Avoid the concomitant use of suvorexant, a P-glycoprotein (P-gp) inhibitor, with oral topotecan, a P-gp substrate; P-gp inhibitors have less of an effect on intravenous topotecan and these may be coadministered with caution. If coadministration of suvorexant and oral topotecan is necessary, carefully monitor for increased toxicity of topotecan, including severe myelosuppression and diarrhea. In a pharmacokinetic cohort study, coadministration of oral topotecan with a potent P-gp inhibitor (n = 8) increased the Cmax and AUC of topotecan by 2 to 3 fold (p = 0.008); coadministration with intravenous topotecan (n = 8) increased total topotecan exposure by 1.2-fold (p = 0.02) and topotecan lactone by 1.1-fold (not significant).
    Tramadol: (Moderate) CNS depressant drugs may have cumulative effects when administered concurrently and they should be used cautiously with suvorexant. A reduction in dose of the CNS depressant may be needed in some cases.
    Trandolapril; Verapamil: (Major) Suvorexant is primarily metabolized by CYP3A, and the manufacturer recommends a dose reduction to 5 mg of suvorexant during concurrent use with moderate CYP3A inhibitors such as diltiazem or verapamil and a maximum recommended dose of 10 mg/day.
    Trazodone: (Moderate) CNS depressant drugs may have cumulative effects when administered concurrently and they should be used cautiously with suvorexant. A reduction in dose of the CNS depressant may be needed in some cases.
    Triazolam: (Moderate) CNS depressant drugs may have cumulative effects when administered concurrently and they should be used cautiously with suvorexant. A reduction in dose of the CNS depressant may be needed in some cases. These agents include the benzodiazepines.
    Valerian, Valeriana officinalis: (Major) Any substance that acts on the CNS may interact with certain herbal products including valerian, Valeriana officinalis. These interactions are probably pharmacodynamic in nature, or result from additive mechanisms of action. The possibility of pharmacodynamic interactions at normal prescription dosages of suvorexant signals the need for patients to avoid concomitant administration of dietary supplements promoted for sleep and relaxation.
    Vemurafenib: (Major) Suvorexant is primarily metabolized by CYP3A, and decreased systemic exposure of suvorexant may occur during concurrent use with strong CYP3A inducers such as vemurafenib. Patients should be monitored for a reduction in efficacy if this combination is necessary.
    Venetoclax: (Major) Avoid the concomitant use of venetoclax and suvorexant; venetoclax is a substrate of P-glycoprotein (P-gp) and suvorexant is an inhibitor of P-gp. Consider alternative agents. If concomitant use of these drugs is required, reduce the venetoclax dosage by at least 50% (maximum dose of 200 mg/day). If suvorexant is discontinued, wait 2 to 3 days and then resume the recommended venetoclax dosage (or prior dosage if less). Monitor patients for signs and symptoms of venetoclax toxicity such as hematologic toxicity, GI toxicity, and tumor lysis syndrome. In a drug interaction study (n = 11), the venetoclax Cmax and AUC values were increased by 106% and 78%, respectively, when a P-gp inhibitor was co-administered in healthy subjects.
    Verapamil: (Major) Suvorexant is primarily metabolized by CYP3A, and the manufacturer recommends a dose reduction to 5 mg of suvorexant during concurrent use with moderate CYP3A inhibitors such as diltiazem or verapamil and a maximum recommended dose of 10 mg/day.
    Vinorelbine: (Moderate) Caution is warranted when suvorexant is administered with vinorelbine as there is a potential for elevated vinorelbine concentrations. Monitor patients for an earlier onset and/or an increased severity of adverse effects including neurotoxicity and myelosuppression. Vinorelbine is a substrate of P-glycoprotein (P-gp) and suvorexant is an inhibitor of P-gp.
    Voriconazole: (Major) Suvorexant is primarily metabolized by CYP3A, and the manufacturer recommends a dose reduction to 5 mg of suvorexant during concurrent use with moderate CYP3A inhibitors and a maximum recommended dose of 10 mg/day. Voriconazole is a moderate CYP3A4 inhibitor, and increased plasma concentrations of suvorexant are possible during concurrent use of these drugs.
    Zafirlukast: (Major) Suvorexant is primarily metabolized by CYP3A, and the manufacturer recommends a dose reduction to 5 mg of suvorexant during concurrent use with moderate CYP3A inhibitors and a maximum recommended dose of 10 mg/day. Zafirlukast is a moderate CYP3A4 inhibitor, and increased plasma concentrations of suvorexant are possible during concurrent use of these drugs.
    Zaleplon: (Moderate) CNS depressant drugs may have cumulative effects when administered concurrently and they should be used cautiously with suvorexant. A reduction in dose of the CNS depressant may be needed in some cases. Use cautiously with any anxiolytics; use with other sedatives and hypnotics should generally be avoided due to duplication of treatments.
    Zolpidem: (Moderate) CNS depressant drugs may have cumulative effects when administered concurrently and they should be used cautiously with suvorexant. A reduction in dose of the CNS depressant may be needed in some cases. Use cautiously with any anxiolytics; use with other sedatives and hypnotics should generally be avoided due to duplication of treatments.

    PREGNANCY AND LACTATION

    Pregnancy

    According to the manufacturer, it is not known if suvorexant is excreted into human milk, and caution should be used when the drug is administered to a nursing woman. In rat studies, suvorexant and its metabolite were excreted into maternal milk at levels higher than in the maternal plasma. Because the effects of suvorexant exposure during breast-feeding have not been evaluated, it may be preferable to use an alternate sedative such as zolpidem. Although the effects of zolpidem exposure on the breast-feeding infant have not been formally evaluated, the American Academy of Pediatrics has considered zolpidem usually compatible with lactation based on the available data. If use of a sedative becomes necessary during breast-feeding, lactating women should avoid breast-feeding their infants at times of peak drug concentrations, and observe the infant for any indications of adverse events, like sedation, increased crying, poor feeding, or irritability. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    MECHANISM OF ACTION

    The mechanism by which suvorexant exerts its therapeutic effect in treating insomnia is thought to occur through its antagonism of orexin receptors. Suvorexant blocks the binding of wake-promoting neuropeptides orexin A and orexin B to the OX1R and OX2R receptors, subsequently suppressing the wake drive.

    PHARMACOKINETICS

    Suvorexant is administered orally. The kinetics of suvorexant are similar in healthy subjects and patients with insomnia. The mean volume of distribution is about 49 liters. Suvorexant is highly protein bound (> 99%) to both serum albumin and alpha-1 acid glycoprotein. Suvorexant is primarily metabolized by CYP3A, with minor involvement of CYP2C19, to form the inactive metabolite hydroxy-suvorexant. The mean half-life of suvorexant is about 12 hours. Elimination occurs primarily through the feces (66%), and to a lesser extent in the urine (23%).
     
    Affected Cytochrome P450 enzymes and drug transporters: CYP3A, P-glycoprotein (P-gp)
    Suvorexant is primarily metabolized by CYP3A, and drugs which inhibit or induce CYP3A may have a significant effect on suvorexant exposure. Suvorexant presumably inhibits P-gp, and may alter the exposure to drugs which are dependent on intestinal P-gp transport (e.g., digoxin).

    Oral Route

    After oral administration, peak concentrations occur at a median Tmax of 2 hours (range: 30 minutes to 6 hours) under fasting conditions. The Tmax is delayed by about 1.5 hours when suvorexant is administered with a high-fat meal, but there are no meaningful changes in AUC or Cmax. For fastest sleep onset, suvorexant should not be administered with or soon after a meal. The mean absolute bioavailability of the 10 mg dose is 82%. Suvorexant exposure increases in a less than dose-proportional manner over a range of 10 to 80 mg because of decreased absorption at higher doses.