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  • CLASSES

    Melatonin Receptor Agonists

    DEA CLASS

    Rx

    DESCRIPTION

    Melatonin receptor agonist
    Used for non-24-hour sleep-wake disorder in blind patients
    May take weeks or months for drug effect to occur due to variable circadian rhythms

    COMMON BRAND NAMES

    HETLIOZ

    HOW SUPPLIED

    HETLIOZ Oral Cap: 20mg

    DOSAGE & INDICATIONS

    For the treatment of non-24-hour sleep-wake disorder.
    Oral dosage
    Adults

    20 mg PO prior to bedtime at the same time every night; take without food. The therapeutic effect may not occur for weeks or months due to individual differences in circadian rhythms. The risk of adverse reactions may be increased in geriatric patients compared to younger patients because of an approximate 2-fold increase in exposure; however, the manufacturer does not recommend dosage adjustments based upon age.

    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

    Safety and efficacy have not been established.

    Neonates

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Tasimelteon is extensively metabolized; however, no dosage adjustments are necessary in patients with mild or moderate hepatic impairment. Tasimelteon has not been studied in those with severe hepatic impairment; therefore, the drug is not recommended in these patients.

    Renal Impairment

    Due to insignificant renal excretion of unchanged tasimelteon, dosage adjustments in patients with renal impairment are not necessary.

    ADMINISTRATION

    Oral Administration

    Administration with a high-fat meal affects absorption; tasimelteon should be administered without food.
    Administer prior to bedtime. Thereafter, activities should be limited to those necessary to get ready for bed.

    Oral Solid Formulations

    Oral Capsules:
    Do not chew or break capsules; swallow whole.

    STORAGE

    HETLIOZ:
    - Protect from light
    - Protect from moisture
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    Activities requiring coordination and concentration, alcoholism, driving or operating machinery, ethanol ingestion, ethanol intoxication

    Patients should avoid engaging in activities requiring coordination and concentration, including driving or operating machinery, after taking tasimelteon. Patients should confine their activities to those necessary to prepare for bed. A single dose study indicated a trend towards additive effects of tasimelteon and alcohol on some psychomotor tests. Those with a history of alcoholism may not be appropriate candidates for tasimelteon therapy. Patients should be cautioned about the potential adverse effects of ethanol ingestion and ethanol intoxication during treatment with tasimelteon.

    Hepatic disease

    Tasimelteon is extensively metabolized in the liver; however, dosage adjustments are not necessary in patients with mild to moderate hepatic impairment. Because tasimelteon has not been studied in patients with severe hepatic disease, use is not recommended in this patient population.

    Tobacco smoking

    Tasimelteon exposure is decreased by about 40% in smokers compared to non-smokers. Patients should be advised of the potential for reduced efficacy of the drug during tobacco smoking.

    Geriatric

    The risk of adverse reactions during treatment with tasimelteon may be increased in geriatric patients compared to younger adults due to an approximate 2-fold increase in exposure; however, the manufacturer does not recommend dosage adjustments based upon age. Further study in this patient population is needed. As with other melatonin receptor agonists, cognitive and behavioral changes are possible during treatment with tasimelteon. 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. Use all sleep medications by following the 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 OBRA include 1) single dose sedative use for a dental or medical procedure or 2) short-term sedative use during initiation of treatment for depression, pain, or other comorbid condition until symptoms improve or the underlying causative factor is identified or effectively treated. OBRA provides dosing guidance for most sedatives, including ramelteon. 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 per the OBRA guidelines.

    Pregnancy

    Tasimelteon should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Available postmarketing case reports with use of tasimelteon in pregnant women are not sufficient to evaluate drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. In pregnant rats, no embryofetal developmental toxicity was observed at exposures of up to 50 mg/kg/day (the no-effect dose), or approximately 25 times the human exposure at the maximum recommended human dose (MRHD) of 20 mg/day. Oral administration of tasimelteon at 50, 150, or 450 mg/kg/day to rats throughout organogenesis resulted in persistent reductions in body weight, delayed sexual maturation, and physical development, and neurobehavioral impairment in offspring at the highest dose tested which is approximately 220 times the MRHD based on body surface area. Reduced body weight in offspring was also observed at the mid-dose. It is not known what effect tasimelteon would have during labor or obstetric delivery.

    Breast-feeding

    There are no data on the presence of tasimelteon in human milk, the effects on the breastfed infant, or the effects on milk production. Caution is advisable when administering tasimelteon to a woman who is breast-feeding an infant. Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for tasimelteon and any potential adverse effects on the breastfed infant from tasimelteon or the underlying maternal condition. 

    Endocrine disease, hyperprolactinemia, infertility

    Tasimelteon should be used cautiously in any patient who has a history of endocrine disease. Melatonin and another melatonin agonist, ramelteon, have been associated with an effect on reproductive hormones in adults (e.g., decreased testosterone levels and increased prolactin levels; hyperprolactinemia). It is not known what effect chronic or even chronic intermittent use of melatonin agonists may have on reproduction, or if tasimelteon would adversely impact fertility. When male and female rats were given tasimelteon at oral doses of 5, 50, or 500 mg/kg/day prior to and throughout mating and continuing in females to gestation day 7, estrus cycle disruption and decreased fertility were observed at all but the lowest dose tested. The no-effect dose for effects on female reproduction (5 mg/kg/day) is approximately 2 times the maximum recommended human dose (MHRD) based on body surface area. Advise patients to consult their health care providers if they experience one of the following: irregular menses or galactorrhea in females, decreased libido in either gender, or problems with fertility (infertility). Assessment of prolactin concentrations and testosterone concentrations should be considered as clinically appropriate. It is clear that endogenous melatonin plays an important role in the regulation of endocrine functions in the body, particularly the regulation of other hormones, but the effect of tasimelteon is not known.

    Children, infants

    The safety and effectiveness of the use of tasimelteon in children and adolescents under the age of 18 years of age has not been established. While melatonin has been used as a dietary supplement for children with circadian-related sleep-wake disorders, the use of melatonin-receptor agonists in pediatrics has remained controversial and there is a lack of data to support safety and efficacy. In addition, melatonin and other melatonin analogs have been associated with an effect on reproductive hormones in adults, e.g., decreased testosterone levels and increased prolactin levels. It is not known what effect chronic or even chronic intermittent use of melatonin analogs may have on the reproductive axis in developing humans. There is no known indication for the use of these agents in infants.

    ADVERSE REACTIONS

    Moderate

    elevated hepatic enzymes / Delayed / 10.0-10.0

    Mild

    headache / Early / 17.0-17.0
    nightmares / Early / 0-10.0
    abnormal dreams / Early / 0-10.0
    infection / Delayed / 0-7.0
    drowsiness / Early / 10.0

    DRUG INTERACTIONS

    Acebutolol: (Major) The efficacy of tasimelteon in treating circadian rhythm disruptions may be reduced in patients receiving beta-blockers. Because the circadian rhythm of melatonin is regulated by the sympathetic nervous system, administration of beta-blockers may result in a clinically relevant blockade of melatonin secretion.
    Acetaminophen; Aspirin, ASA; Caffeine: (Minor) Caffeine is a central nervous system (CNS) stimulant. Patients taking melatonin or the melatonin analogs (ramelteon, tasimelteon) for sleep 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) Concurrent use of tasimelteon and strong inducers of CYP3A4, such as barbiturates or primidone, should be avoided. Because tasimelteon is partially metabolized via CYP3A4, a large decrease in exposure is possible with the potential for reduced efficacy. During administration of tasimelteon with another potent inducer of CYP3A4, tasimelteon exposure decreased by about 90%. Barbiturates also induce CYP1A2, a secondary metabolic pathway of tasimelteon.
    Acetaminophen; Butalbital; Caffeine: (Major) Concurrent use of tasimelteon and strong inducers of CYP3A4, such as barbiturates or primidone, should be avoided. Because tasimelteon is partially metabolized via CYP3A4, a large decrease in exposure is possible with the potential for reduced efficacy. During administration of tasimelteon with another potent inducer of CYP3A4, tasimelteon exposure decreased by about 90%. Barbiturates also induce CYP1A2, a secondary metabolic pathway of tasimelteon. (Minor) Caffeine is a central nervous system (CNS) stimulant. Patients taking melatonin or the melatonin analogs (ramelteon, tasimelteon) for sleep 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) Concurrent use of tasimelteon and strong inducers of CYP3A4, such as barbiturates or primidone, should be avoided. Because tasimelteon is partially metabolized via CYP3A4, a large decrease in exposure is possible with the potential for reduced efficacy. During administration of tasimelteon with another potent inducer of CYP3A4, tasimelteon exposure decreased by about 90%. Barbiturates also induce CYP1A2, a secondary metabolic pathway of tasimelteon. (Moderate) Concomitant use of opioid agonists with tasimelteon may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking tasimelteon. Limit the use of opioid pain medications with tasimelteon to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression. (Minor) Caffeine is a central nervous system (CNS) stimulant. Patients taking melatonin or the melatonin analogs (ramelteon, tasimelteon) for sleep 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: (Minor) Caffeine is a central nervous system (CNS) stimulant. Patients taking melatonin or the melatonin analogs (ramelteon, tasimelteon) for sleep 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: (Moderate) Concomitant use of opioid agonists with tasimelteon may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking tasimelteon. Limit the use of opioid pain medications with tasimelteon to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression. (Minor) Caffeine is a central nervous system (CNS) stimulant. Patients taking melatonin or the melatonin analogs (ramelteon, tasimelteon) for sleep 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: (Moderate) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect may occur when it is combined with other CNS depressants including anxiolytics, sedatives, and hypnotics, such as tasimelteon. (Minor) Caffeine is a central nervous system (CNS) stimulant. Patients taking melatonin or the melatonin analogs (ramelteon, tasimelteon) for sleep 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: (Moderate) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect may occur when it is combined with other CNS depressants including anxiolytics, sedatives, and hypnotics, such as tasimelteon. (Minor) Caffeine is a central nervous system (CNS) stimulant. Patients taking melatonin or the melatonin analogs (ramelteon, tasimelteon) for sleep 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; Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect may occur when it is combined with other CNS depressants including anxiolytics, sedatives, and hypnotics, such as tasimelteon.
    Acetaminophen; Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect may occur when it is combined with other CNS depressants including anxiolytics, sedatives, and hypnotics, such as tasimelteon.
    Acetaminophen; Chlorpheniramine; Phenylephrine; Phenyltoloxamine: (Moderate) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect may occur when it is combined with other CNS depressants including anxiolytics, sedatives, and hypnotics, such as tasimelteon.
    Acetaminophen; Codeine: (Moderate) Concomitant use of opioid agonists with tasimelteon may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking tasimelteon. Limit the use of opioid pain medications with tasimelteon to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Acetaminophen; Dextromethorphan; Doxylamine: (Moderate) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect may occur when it is combined with other CNS depressants including anxiolytics, sedatives, and hypnotics, such as tasimelteon.
    Acetaminophen; Dextromethorphan; Phenylephrine: (Moderate) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect may occur when it is combined with other CNS depressants including anxiolytics, sedatives, and hypnotics, such as tasimelteon.
    Acetaminophen; Diphenhydramine: (Moderate) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect may occur when it is combined with other CNS depressants including anxiolytics, sedatives, and hypnotics, such as tasimelteon.
    Acetaminophen; Hydrocodone: (Moderate) Concomitant use of opioid agonists with tasimelteon may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking tasimelteon. Limit the use of opioid pain medications with tasimelteon to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Acetaminophen; Oxycodone: (Moderate) Concomitant use of opioid agonists with tasimelteon may cause excessive sedation and somnolence. Limit the use of opioid pain medications with tasimelteon to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Acetaminophen; Tramadol: (Moderate) Concomitant use of opioid agonists with tasimelteon may cause excessive sedation and somnolence. Limit the use of opioid pain medications with tasimelteon to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Acrivastine; Pseudoephedrine: (Moderate) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect may occur when it is combined with other CNS depressants including anxiolytics, sedatives, and hypnotics, such as tasimelteon.
    Alfentanil: (Moderate) Concomitant use of opioid agonists with tasimelteon may cause excessive sedation and somnolence. Limit the use of opioid pain medications with tasimelteon to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Alprazolam: (Moderate) Concomitant administration of alprazolam with CNS-depressant drugs can potentiate the CNS effects of either agent.
    Amobarbital: (Major) Concurrent use of tasimelteon and strong inducers of CYP3A4, such as barbiturates or primidone, should be avoided. Because tasimelteon is partially metabolized via CYP3A4, a large decrease in exposure is possible with the potential for reduced efficacy. During administration of tasimelteon with another potent inducer of CYP3A4, tasimelteon exposure decreased by about 90%. Barbiturates also induce CYP1A2, a secondary metabolic pathway of tasimelteon.
    Amoxicillin; Clarithromycin; Lansoprazole: (Major) Concurrent use of tasimelteon and strong inhibitors of CYP3A4, such as clarithromycin, should be avoided if possible. Because tasimelteon is partially metabolized via CYP3A4, a large increase in exposure of tasimelteon with the potential for adverse reactions is possible if these drugs are coadministered. During administration of tasimelteon and another potent CYP3A4 inhibitor, tasimelteon exposure increased by about 50%.
    Amoxicillin; Clarithromycin; Omeprazole: (Major) Concurrent use of tasimelteon and strong inhibitors of CYP3A4, such as clarithromycin, should be avoided if possible. Because tasimelteon is partially metabolized via CYP3A4, a large increase in exposure of tasimelteon with the potential for adverse reactions is possible if these drugs are coadministered. During administration of tasimelteon and another potent CYP3A4 inhibitor, tasimelteon exposure increased by about 50%.
    Amprenavir: (Major) Concurrent use of tasimelteon and strong inhibitors of CYP3A4, such as amprenavir or fosamprenavir, should be avoided if possible. Because tasimelteon is partially metabolized via CYP3A4, a large increase in exposure of tasimelteon with the potential for adverse reactions is possible if these drugs are coadministered. During administration of tasimelteon and another potent CYP3A4 inhibitor, tasimelteon exposure increased by about 50%.
    Apalutamide: (Major) Avoid coadministration of tasimelteon with apalutamide due to the potential for a large decrease in tasimelteon exposure resulting in reduced efficacy. Tasimelteon is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased tasimelteon exposure by about 90%.
    Aprepitant, Fosaprepitant: (Moderate) Use caution if tasimelteon and aprepitant, fosaprepitant are used concurrently and monitor for an increase in tasimelteon-related adverse effects for several days after administration of a multi-day aprepitant regimen.Tasimelteon 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 tasimelteon. 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.
    Armodafinil: (Moderate) Caution is recommended during concurrent use of tasimelteon and modafinil or armodafinil. Because tasimelteon is metabolized via CYP3A4 and CYP1A2, inducers of these isoenzymes, such as modafinil and armodafinil, may reduce the efficacy of tasimelteon.
    Aspirin, ASA; Butalbital; Caffeine: (Major) Concurrent use of tasimelteon and strong inducers of CYP3A4, such as barbiturates or primidone, should be avoided. Because tasimelteon is partially metabolized via CYP3A4, a large decrease in exposure is possible with the potential for reduced efficacy. During administration of tasimelteon with another potent inducer of CYP3A4, tasimelteon exposure decreased by about 90%. Barbiturates also induce CYP1A2, a secondary metabolic pathway of tasimelteon. (Minor) Caffeine is a central nervous system (CNS) stimulant. Patients taking melatonin or the melatonin analogs (ramelteon, tasimelteon) for sleep 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) Concurrent use of tasimelteon and strong inducers of CYP3A4, such as barbiturates or primidone, should be avoided. Because tasimelteon is partially metabolized via CYP3A4, a large decrease in exposure is possible with the potential for reduced efficacy. During administration of tasimelteon with another potent inducer of CYP3A4, tasimelteon exposure decreased by about 90%. Barbiturates also induce CYP1A2, a secondary metabolic pathway of tasimelteon. (Moderate) Concomitant use of opioid agonists with tasimelteon may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking tasimelteon. Limit the use of opioid pain medications with tasimelteon to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression. (Minor) Caffeine is a central nervous system (CNS) stimulant. Patients taking melatonin or the melatonin analogs (ramelteon, tasimelteon) for sleep 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: (Moderate) Concomitant use of opioid agonists with tasimelteon may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking tasimelteon. Limit the use of opioid pain medications with tasimelteon to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression. (Minor) Caffeine is a central nervous system (CNS) stimulant. Patients taking melatonin or the melatonin analogs (ramelteon, tasimelteon) for sleep 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; Orphenadrine: (Minor) Caffeine is a central nervous system (CNS) stimulant. Patients taking melatonin or the melatonin analogs (ramelteon, tasimelteon) for sleep 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; Carisoprodol; Codeine: (Moderate) Concomitant use of opioid agonists with tasimelteon may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking tasimelteon. Limit the use of opioid pain medications with tasimelteon to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Aspirin, ASA; Oxycodone: (Moderate) Concomitant use of opioid agonists with tasimelteon may cause excessive sedation and somnolence. Limit the use of opioid pain medications with tasimelteon to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Atazanavir: (Moderate) Caution is recommended during concurrent use of tasimelteon and atazanavir. Because tasimelteon is partially metabolized via CYP3A4, use with CYP3A4 inhibitors, such as atazanavir, may increase exposure to tasimelteon with the potential for adverse reactions.
    Atazanavir; Cobicistat: (Moderate) Caution is recommended during concurrent use of tasimelteon and atazanavir. Because tasimelteon is partially metabolized via CYP3A4, use with CYP3A4 inhibitors, such as atazanavir, may increase exposure to tasimelteon with the potential for adverse reactions.
    Atenolol: (Major) The efficacy of tasimelteon in treating circadian rhythm disruptions may be reduced in patients receiving beta-blockers. Because the circadian rhythm of melatonin is regulated by the sympathetic nervous system, administration of beta-blockers may result in a clinically relevant blockade of melatonin secretion.
    Atenolol; Chlorthalidone: (Major) The efficacy of tasimelteon in treating circadian rhythm disruptions may be reduced in patients receiving beta-blockers. Because the circadian rhythm of melatonin is regulated by the sympathetic nervous system, administration of beta-blockers may result in a clinically relevant blockade of melatonin secretion.
    Atropine; Hyoscyamine; Phenobarbital; Scopolamine: (Major) Concurrent use of tasimelteon and strong inducers of CYP3A4, such as barbiturates or primidone, should be avoided. Because tasimelteon is partially metabolized via CYP3A4, a large decrease in exposure is possible with the potential for reduced efficacy. During administration of tasimelteon with another potent inducer of CYP3A4, tasimelteon exposure decreased by about 90%. Barbiturates also induce CYP1A2, a secondary metabolic pathway of tasimelteon.
    Barbiturates: (Major) Concurrent use of tasimelteon and strong inducers of CYP3A4, such as barbiturates or primidone, should be avoided. Because tasimelteon is partially metabolized via CYP3A4, a large decrease in exposure is possible with the potential for reduced efficacy. During administration of tasimelteon with another potent inducer of CYP3A4, tasimelteon exposure decreased by about 90%. Barbiturates also induce CYP1A2, a secondary metabolic pathway of tasimelteon.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: (Major) Concurrent use of tasimelteon and strong inducers of CYP3A4, such as barbiturates or primidone, should be avoided. Because tasimelteon is partially metabolized via CYP3A4, a large decrease in exposure is possible with the potential for reduced efficacy. During administration of tasimelteon with another potent inducer of CYP3A4, tasimelteon exposure decreased by about 90%. Barbiturates also induce CYP1A2, a secondary metabolic pathway of tasimelteon.
    Belladonna; Opium: (Moderate) Concomitant use of opioid agonists with tasimelteon may cause excessive sedation and somnolence. Limit the use of opioid pain medications with tasimelteon to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Bendroflumethiazide; Nadolol: (Major) The efficacy of tasimelteon in treating circadian rhythm disruptions may be reduced in patients receiving beta-blockers. Because the circadian rhythm of melatonin is regulated by the sympathetic nervous system, administration of beta-blockers may result in a clinically relevant blockade of melatonin secretion.
    Benzhydrocodone; Acetaminophen: (Moderate) Concomitant use of opioid agonists with tasimelteon may cause excessive sedation and somnolence. Limit the use of opioid pain medications with tasimelteon to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Beta-blockers: (Major) The efficacy of tasimelteon in treating circadian rhythm disruptions may be reduced in patients receiving beta-blockers. Because the circadian rhythm of melatonin is regulated by the sympathetic nervous system, administration of beta-blockers may result in a clinically relevant blockade of melatonin secretion.
    Betaxolol: (Major) The efficacy of tasimelteon in treating circadian rhythm disruptions may be reduced in patients receiving beta-blockers. Because the circadian rhythm of melatonin is regulated by the sympathetic nervous system, administration of beta-blockers may result in a clinically relevant blockade of melatonin secretion.
    Bexarotene: (Moderate) Caution is recommended during concurrent use of tasimelteon and bexarotene. Because tasimelteon is partially metabolized via CYP3A4, use with CYP3A4 inducers, such as bexarotene, may reduce the efficacy of tasimelteon.
    Bisoprolol: (Major) The efficacy of tasimelteon in treating circadian rhythm disruptions may be reduced in patients receiving beta-blockers. Because the circadian rhythm of melatonin is regulated by the sympathetic nervous system, administration of beta-blockers may result in a clinically relevant blockade of melatonin secretion.
    Bisoprolol; Hydrochlorothiazide, HCTZ: (Major) The efficacy of tasimelteon in treating circadian rhythm disruptions may be reduced in patients receiving beta-blockers. Because the circadian rhythm of melatonin is regulated by the sympathetic nervous system, administration of beta-blockers may result in a clinically relevant blockade of melatonin secretion.
    Boceprevir: (Major) Concurrent use of tasimelteon and strong inhibitors of CYP3A4, such as boceprevir, should be avoided if possible. Because tasimelteon is partially metabolized via CYP3A4, a large increase in exposure of tasimelteon with the potential for adverse reactions is possible if these drugs are coadministered. During administration of tasimelteon and another potent CYP3A4 inhibitor, tasimelteon exposure increased by about 50%.
    Bosentan: (Moderate) Caution is recommended during concurrent use of tasimelteon and bosentan. Because tasimelteon is partially metabolized via CYP3A4, use with CYP3A4 inducers, such as bosentan, may reduce the efficacy of tasimelteon.
    Brimonidine; Timolol: (Major) The efficacy of tasimelteon in treating circadian rhythm disruptions may be reduced in patients receiving beta-blockers. Because the circadian rhythm of melatonin is regulated by the sympathetic nervous system, administration of beta-blockers may result in a clinically relevant blockade of melatonin secretion.
    Brompheniramine: (Moderate) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect may occur when it is combined with other CNS depressants including anxiolytics, sedatives, and hypnotics, such as tasimelteon.
    Brompheniramine; Carbetapentane; Phenylephrine: (Moderate) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect may occur when it is combined with other CNS depressants including anxiolytics, sedatives, and hypnotics, such as tasimelteon.
    Brompheniramine; Dextromethorphan; Guaifenesin: (Moderate) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect may occur when it is combined with other CNS depressants including anxiolytics, sedatives, and hypnotics, such as tasimelteon.
    Brompheniramine; Guaifenesin; Hydrocodone: (Moderate) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect may occur when it is combined with other CNS depressants including anxiolytics, sedatives, and hypnotics, such as tasimelteon. (Moderate) Concomitant use of opioid agonists with tasimelteon may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking tasimelteon. Limit the use of opioid pain medications with tasimelteon to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Brompheniramine; Hydrocodone; Pseudoephedrine: (Moderate) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect may occur when it is combined with other CNS depressants including anxiolytics, sedatives, and hypnotics, such as tasimelteon. (Moderate) Concomitant use of opioid agonists with tasimelteon may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking tasimelteon. Limit the use of opioid pain medications with tasimelteon to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Brompheniramine; Pseudoephedrine: (Moderate) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect may occur when it is combined with other CNS depressants including anxiolytics, sedatives, and hypnotics, such as tasimelteon.
    Buprenorphine: (Moderate) If concurrent use of tasimelteon and buprenorphine is necessary, consider a dose reduction of one or both drugs because of the potential for additive pharmacological effects. Hypotension, profound sedation, coma, respiratory depression, or death 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 tasimelteon and buprenorphine is necessary, consider a dose reduction of one or both drugs because of the potential for additive pharmacological effects. Hypotension, profound sedation, coma, respiratory depression, or death 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) Concurrent use of tasimelteon and strong inducers of CYP3A4, such as barbiturates or primidone, should be avoided. Because tasimelteon is partially metabolized via CYP3A4, a large decrease in exposure is possible with the potential for reduced efficacy. During administration of tasimelteon with another potent inducer of CYP3A4, tasimelteon exposure decreased by about 90%. Barbiturates also induce CYP1A2, a secondary metabolic pathway of tasimelteon.
    Caffeine: (Minor) Caffeine is a central nervous system (CNS) stimulant. Patients taking melatonin or the melatonin analogs (ramelteon, tasimelteon) for sleep 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 melatonin or the melatonin analogs (ramelteon, tasimelteon) for sleep 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.
    Cannabidiol: (Moderate) Consider a dose adjustment of tasimelteon as clinically appropriate when administered with cannabidiol. Increased or decreased tasimelteon exposure is possible. Additive somnolence and sedation may occur. Tasimelteon is a sensitive CYP1A2 substrate. In vitro data predicts inhibition or induction of CYP1A2 by cannabidiol potentially resulting in clinically significant interactions.
    Carbamazepine: (Major) Concurrent use of tasimelteon and strong inducers of CYP3A4, such as carbamazepine, should be avoided. Because tasimelteon is partially metabolized via CYP3A4, a large decrease in exposure is possible with the potential for reduced efficacy. During administration of tasimelteon with another potent inducer of CYP3A4, tasimelteon exposure decreased by about 90%. Carbamazepine also induces CYP1A2, a secondary metabolic pathway of tasimelteon.
    Carbetapentane; Chlorpheniramine: (Moderate) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect may occur when it is combined with other CNS depressants including anxiolytics, sedatives, and hypnotics, such as tasimelteon.
    Carbetapentane; Chlorpheniramine; Phenylephrine: (Moderate) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect may occur when it is combined with other CNS depressants including anxiolytics, sedatives, and hypnotics, such as tasimelteon.
    Carbetapentane; Diphenhydramine; Phenylephrine: (Moderate) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect may occur when it is combined with other CNS depressants including anxiolytics, sedatives, and hypnotics, such as tasimelteon.
    Carbetapentane; Phenylephrine; Pyrilamine: (Moderate) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect may occur when it is combined with other CNS depressants including anxiolytics, sedatives, and hypnotics, such as tasimelteon.
    Carbetapentane; Pyrilamine: (Moderate) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect may occur when it is combined with other CNS depressants including anxiolytics, sedatives, and hypnotics, such as tasimelteon.
    Carbinoxamine: (Moderate) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect may occur when it is combined with other CNS depressants including anxiolytics, sedatives, and hypnotics, such as tasimelteon.
    Carbinoxamine; Dextromethorphan; Pseudoephedrine: (Moderate) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect may occur when it is combined with other CNS depressants including anxiolytics, sedatives, and hypnotics, such as tasimelteon.
    Carbinoxamine; Hydrocodone; Phenylephrine: (Moderate) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect may occur when it is combined with other CNS depressants including anxiolytics, sedatives, and hypnotics, such as tasimelteon. (Moderate) Concomitant use of opioid agonists with tasimelteon may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking tasimelteon. Limit the use of opioid pain medications with tasimelteon to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Carbinoxamine; Hydrocodone; Pseudoephedrine: (Moderate) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect may occur when it is combined with other CNS depressants including anxiolytics, sedatives, and hypnotics, such as tasimelteon. (Moderate) Concomitant use of opioid agonists with tasimelteon may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking tasimelteon. Limit the use of opioid pain medications with tasimelteon to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Carbinoxamine; Phenylephrine: (Moderate) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect may occur when it is combined with other CNS depressants including anxiolytics, sedatives, and hypnotics, such as tasimelteon.
    Carbinoxamine; Pseudoephedrine: (Moderate) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect may occur when it is combined with other CNS depressants including anxiolytics, sedatives, and hypnotics, such as tasimelteon.
    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 tasimelteon.
    Carteolol: (Major) The efficacy of tasimelteon in treating circadian rhythm disruptions may be reduced in patients receiving beta-blockers. Because the circadian rhythm of melatonin is regulated by the sympathetic nervous system, administration of beta-blockers may result in a clinically relevant blockade of melatonin secretion.
    Carvedilol: (Major) The efficacy of tasimelteon in treating circadian rhythm disruptions may be reduced in patients receiving beta-blockers. Because the circadian rhythm of melatonin is regulated by the sympathetic nervous system, administration of beta-blockers may result in a clinically relevant blockade of melatonin secretion.
    Cetirizine: (Moderate) Concurrent use of cetirizine/levocetirizine with tasimelteon should generally be avoided. Coadministration may increase the risk of CNS depressant-related side effects. If concurrent use is necessary, monitor for excessive sedation and somnolence.
    Cetirizine; Pseudoephedrine: (Moderate) Concurrent use of cetirizine/levocetirizine with tasimelteon should generally be avoided. Coadministration may increase the risk of CNS depressant-related side effects. If concurrent use is necessary, monitor for excessive sedation and somnolence.
    Chlophedianol; Dexbrompheniramine: (Moderate) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect may occur when it is combined with other CNS depressants including anxiolytics, sedatives, and hypnotics, such as tasimelteon.
    Chlophedianol; Dexchlorpheniramine; Pseudoephedrine: (Moderate) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect may occur when it is combined with other CNS depressants including anxiolytics, sedatives, and hypnotics, such as tasimelteon.
    Chloramphenicol: (Moderate) Caution is recommended during concurrent use of tasimelteon and chloramphenicol. Because tasimelteon is partially metabolized via CYP3A4, use with CYP3A4 inhibitors, such as chloramphenicol, may increase exposure to tasimelteon with the potential for adverse reactions.
    Chlorcyclizine: (Moderate) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect may occur when it is combined with other CNS depressants including anxiolytics, sedatives, and hypnotics, such as tasimelteon.
    Chlorpheniramine: (Moderate) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect may occur when it is combined with other CNS depressants including anxiolytics, sedatives, and hypnotics, such as tasimelteon.
    Chlorpheniramine; Codeine: (Moderate) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect may occur when it is combined with other CNS depressants including anxiolytics, sedatives, and hypnotics, such as tasimelteon. (Moderate) Concomitant use of opioid agonists with tasimelteon may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking tasimelteon. Limit the use of opioid pain medications with tasimelteon to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Chlorpheniramine; Dextromethorphan: (Moderate) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect may occur when it is combined with other CNS depressants including anxiolytics, sedatives, and hypnotics, such as tasimelteon.
    Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect may occur when it is combined with other CNS depressants including anxiolytics, sedatives, and hypnotics, such as tasimelteon.
    Chlorpheniramine; Dihydrocodeine; Phenylephrine: (Moderate) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect may occur when it is combined with other CNS depressants including anxiolytics, sedatives, and hypnotics, such as tasimelteon. (Moderate) Concomitant use of opioid agonists with tasimelteon may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking tasimelteon. Limit the use of opioid pain medications with tasimelteon to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Chlorpheniramine; Dihydrocodeine; Pseudoephedrine: (Moderate) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect may occur when it is combined with other CNS depressants including anxiolytics, sedatives, and hypnotics, such as tasimelteon. (Moderate) Concomitant use of opioid agonists with tasimelteon may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking tasimelteon. Limit the use of opioid pain medications with tasimelteon to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Chlorpheniramine; Guaifenesin; Hydrocodone; Pseudoephedrine: (Moderate) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect may occur when it is combined with other CNS depressants including anxiolytics, sedatives, and hypnotics, such as tasimelteon. (Moderate) Concomitant use of opioid agonists with tasimelteon may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking tasimelteon. Limit the use of opioid pain medications with tasimelteon to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Chlorpheniramine; Hydrocodone: (Moderate) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect may occur when it is combined with other CNS depressants including anxiolytics, sedatives, and hypnotics, such as tasimelteon. (Moderate) Concomitant use of opioid agonists with tasimelteon may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking tasimelteon. Limit the use of opioid pain medications with tasimelteon to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Chlorpheniramine; Hydrocodone; Phenylephrine: (Moderate) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect may occur when it is combined with other CNS depressants including anxiolytics, sedatives, and hypnotics, such as tasimelteon. (Moderate) Concomitant use of opioid agonists with tasimelteon may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking tasimelteon. Limit the use of opioid pain medications with tasimelteon to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Chlorpheniramine; Hydrocodone; Pseudoephedrine: (Moderate) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect may occur when it is combined with other CNS depressants including anxiolytics, sedatives, and hypnotics, such as tasimelteon. (Moderate) Concomitant use of opioid agonists with tasimelteon may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking tasimelteon. Limit the use of opioid pain medications with tasimelteon to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Chlorpheniramine; Phenylephrine: (Moderate) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect may occur when it is combined with other CNS depressants including anxiolytics, sedatives, and hypnotics, such as tasimelteon.
    Chlorpheniramine; Pseudoephedrine: (Moderate) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect may occur when it is combined with other CNS depressants including anxiolytics, sedatives, and hypnotics, such as tasimelteon.
    Cimetidine: (Moderate) Caution is recommended during concurrent use of tasimelteon and cimetidine. Because tasimelteon is metabolized via CYP3A4 and CYP1A2, use with CYP3A4 and CYP1A2 inhibitors, such as cimetidine, may increase exposure to tasimelteon and the potential for adverse reactions.
    Ciprofloxacin: (Moderate) Caution is recommended during concurrent use of tasimelteon and enoxacin or ciprofloxacin. Because tasimelteon is partially metabolized via CYP1A2, use with CYP1A2 inhibitors, such as enoxacin or ciprofloxacin, may increase exposure to tasimelteon and the potential for adverse reactions.
    Clarithromycin: (Major) Concurrent use of tasimelteon and strong inhibitors of CYP3A4, such as clarithromycin, should be avoided if possible. Because tasimelteon is partially metabolized via CYP3A4, a large increase in exposure of tasimelteon with the potential for adverse reactions is possible if these drugs are coadministered. During administration of tasimelteon and another potent CYP3A4 inhibitor, tasimelteon exposure increased by about 50%.
    Clemastine: (Moderate) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect may occur when it is combined with other CNS depressants including anxiolytics, sedatives, and hypnotics, such as tasimelteon.
    Codeine: (Moderate) Concomitant use of opioid agonists with tasimelteon may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking tasimelteon. Limit the use of opioid pain medications with tasimelteon to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Codeine; Guaifenesin: (Moderate) Concomitant use of opioid agonists with tasimelteon may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking tasimelteon. Limit the use of opioid pain medications with tasimelteon to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Codeine; Phenylephrine; Promethazine: (Moderate) Concomitant use of opioid agonists with tasimelteon may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking tasimelteon. Limit the use of opioid pain medications with tasimelteon to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Codeine; Promethazine: (Moderate) Concomitant use of opioid agonists with tasimelteon may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking tasimelteon. Limit the use of opioid pain medications with tasimelteon to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Conivaptan: (Major) Concurrent use of tasimelteon and strong inhibitors of CYP3A4, such as conivaptan, should be avoided if possible. Because tasimelteon is partially metabolized via CYP3A4, a large increase in exposure of tasimelteon with the potential for adverse reactions is possible if these drugs are coadministered. During administration of tasimelteon and another potent CYP3A4 inhibitor, tasimelteon exposure increased by about 50%.
    Cyclizine: (Moderate) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect may occur when it is combined with other CNS depressants including anxiolytics, sedatives, and hypnotics, such as tasimelteon.
    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.
    Cyproheptadine: (Moderate) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect may occur when it is combined with other CNS depressants including anxiolytics, sedatives, and hypnotics, such as tasimelteon.
    Dabrafenib: (Moderate) Caution is recommended during concurrent use of tasimelteon and dabrafenib. Because tasimelteon is partially metabolized via CYP3A4, use with CYP3A4 inducers, such as dabrafenib, may reduce the efficacy of tasimelteon.
    Danazol: (Moderate) Caution is recommended during concurrent use of tasimelteon and danazol. Because tasimelteon is partially metabolized via CYP3A4, use with CYP3A4 inhibitors, such as danazol, may increase exposure to tasimelteon with the potential for adverse reactions.
    Darunavir: (Moderate) Caution is recommended during concurrent use of tasimelteon and darunavir. Because tasimelteon is partially metabolized via CYP3A4, use with CYP3A4 inhibitors, such as darunavir, may increase exposure to tasimelteon with the potential for adverse reactions.
    Darunavir; Cobicistat: (Moderate) Caution is recommended during concurrent use of tasimelteon and darunavir. Because tasimelteon is partially metabolized via CYP3A4, use with CYP3A4 inhibitors, such as darunavir, may increase exposure to tasimelteon with the potential for adverse reactions.
    Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Moderate) Caution is recommended during concurrent use of tasimelteon and darunavir. Because tasimelteon is partially metabolized via CYP3A4, use with CYP3A4 inhibitors, such as darunavir, may increase exposure to tasimelteon with the potential for adverse reactions.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Major) Concurrent use of tasimelteon and strong inhibitors of CYP3A4, such as ritonavir, should be avoided if possible. Because tasimelteon is partially metabolized via CYP3A4, a large increase in exposure of tasimelteon with the potential for adverse reactions is possible if these drugs are coadministered. During administration of tasimelteon and another potent CYP3A4 inhibitor, tasimelteon exposure increased by about 50%.
    Delavirdine: (Major) Concurrent use of tasimelteon and strong inhibitors of CYP3A4, such as delavirdine, should be avoided if possible. Because tasimelteon is partially metabolized via CYP3A4, a large increase in exposure of tasimelteon with the potential for adverse reactions is possible if these drugs are coadministered. During administration of tasimelteon and another potent CYP3A4 inhibitor, tasimelteon exposure increased by about 50%.
    Deutetrabenazine: (Moderate) Advise patients that concurrent use of deutetrabenazine and drugs that can cause CNS depression, such as tasimelteon, may have additive effects and worsen drowsiness or sedation.
    Dexamethasone: (Moderate) Caution is recommended during concurrent use of tasimelteon and dexamethasone. Because tasimelteon is partially metabolized via CYP3A4, use with CYP3A4 inducers, such as dexamethasone, may reduce the efficacy of tasimelteon.
    Dexchlorpheniramine: (Moderate) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect may occur when it is combined with other CNS depressants including anxiolytics, sedatives, and hypnotics, such as tasimelteon.
    Dexchlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect may occur when it is combined with other CNS depressants including anxiolytics, sedatives, and hypnotics, such as tasimelteon.
    Dextromethorphan; Diphenhydramine; Phenylephrine: (Moderate) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect may occur when it is combined with other CNS depressants including anxiolytics, sedatives, and hypnotics, such as tasimelteon.
    Dihydrocodeine; Guaifenesin; Pseudoephedrine: (Moderate) Concomitant use of opioid agonists with tasimelteon may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking tasimelteon. Limit the use of opioid pain medications with tasimelteon to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Diltiazem: (Moderate) Caution is recommended during concurrent use of tasimelteon and diltiazem. Because tasimelteon is partially metabolized via CYP3A4, use with CYP3A4 inhibitors, such as diltiazem, may increase exposure to tasimelteon with the potential for adverse reactions.
    Dimenhydrinate: (Moderate) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect may occur when it is combined with other CNS depressants including anxiolytics, sedatives, and hypnotics, such as tasimelteon.
    Diphenhydramine: (Moderate) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect may occur when it is combined with other CNS depressants including anxiolytics, sedatives, and hypnotics, such as tasimelteon.
    Diphenhydramine; Hydrocodone; Phenylephrine: (Moderate) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect may occur when it is combined with other CNS depressants including anxiolytics, sedatives, and hypnotics, such as tasimelteon. (Moderate) Concomitant use of opioid agonists with tasimelteon may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking tasimelteon. Limit the use of opioid pain medications with tasimelteon to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Diphenhydramine; Ibuprofen: (Moderate) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect may occur when it is combined with other CNS depressants including anxiolytics, sedatives, and hypnotics, such as tasimelteon.
    Diphenhydramine; Naproxen: (Moderate) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect may occur when it is combined with other CNS depressants including anxiolytics, sedatives, and hypnotics, such as tasimelteon.
    Diphenhydramine; Phenylephrine: (Moderate) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect may occur when it is combined with other CNS depressants including anxiolytics, sedatives, and hypnotics, such as tasimelteon.
    Dorzolamide; Timolol: (Major) The efficacy of tasimelteon in treating circadian rhythm disruptions may be reduced in patients receiving beta-blockers. Because the circadian rhythm of melatonin is regulated by the sympathetic nervous system, administration of beta-blockers may result in a clinically relevant blockade of melatonin secretion.
    Doxylamine: (Moderate) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect may occur when it is combined with other CNS depressants including anxiolytics, sedatives, and hypnotics, such as tasimelteon.
    Doxylamine; Pyridoxine: (Moderate) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect may occur when it is combined with other CNS depressants including anxiolytics, sedatives, and hypnotics, such as tasimelteon.
    Dronedarone: (Moderate) Caution is recommended during concurrent use of tasimelteon and dronedarone. Because tasimelteon is partially metabolized via CYP3A4, use with CYP3A4 inhibitors, such as dronedarone, may increase exposure to tasimelteon with the potential for adverse reactions.
    Efavirenz: (Moderate) Caution is recommended during concurrent use of tasimelteon and efavirenz. Because tasimelteon is partially metabolized via CYP3A4, use with CYP3A4 inhibitors may increase exposure to tasimelteon with the potential for adverse reactions. Because efavirenz may inhibit or induce CYP3A4, the clinical outcome of this combination is unknown.
    Efavirenz; Emtricitabine; Tenofovir: (Moderate) Caution is recommended during concurrent use of tasimelteon and efavirenz. Because tasimelteon is partially metabolized via CYP3A4, use with CYP3A4 inhibitors may increase exposure to tasimelteon with the potential for adverse reactions. Because efavirenz may inhibit or induce CYP3A4, the clinical outcome of this combination is unknown.
    Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Moderate) Caution is recommended during concurrent use of tasimelteon and efavirenz. Because tasimelteon is partially metabolized via CYP3A4, use with CYP3A4 inhibitors may increase exposure to tasimelteon with the potential for adverse reactions. Because efavirenz may inhibit or induce CYP3A4, the clinical outcome of this combination is unknown.
    Elbasvir; Grazoprevir: (Moderate) Administering tasimelteon with elbasvir; grazoprevir may result in elevated tasimelteon plasma concentrations. Tasimelteon is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
    Enzalutamide: (Major) Concurrent use of tasimelteon and strong inducers of CYP3A4, such as enzalutamide, should be avoided. Because tasimelteon is partially metabolized via CYP3A4, a large decrease in exposure is possible with the potential for reduced efficacy. During administration of tasimelteon with another potent inducer of CYP3A4, tasimelteon exposure decreased by about 90%.
    Erythromycin: (Moderate) Caution is recommended during concurrent use of tasimelteon and erythromycin. Because tasimelteon is partially metabolized via CYP3A4, use with CYP3A4 inhibitors, such as erythromycin, may increase exposure to tasimelteon with the potential for adverse reactions.
    Erythromycin; Sulfisoxazole: (Moderate) Caution is recommended during concurrent use of tasimelteon and erythromycin. Because tasimelteon is partially metabolized via CYP3A4, use with CYP3A4 inhibitors, such as erythromycin, may increase exposure to tasimelteon with the potential for adverse reactions.
    Esketamine: (Moderate) Closely monitor patients receiving esketamine and tasimelteon for sedation and other CNS depressant effects. Instruct patients who receive a dose of esketamine not to drive or engage in other activities requiring alertness until the next day after a restful sleep.
    Eslicarbazepine: (Moderate) Caution is recommended during concurrent use of tasimelteon and eslicarbazepine. Because tasimelteon is partially metabolized via CYP3A4, use with CYP3A4 inducers, such as eslicarbazepine, may reduce the efficacy of tasimelteon.
    Esmolol: (Major) The efficacy of tasimelteon in treating circadian rhythm disruptions may be reduced in patients receiving beta-blockers. Because the circadian rhythm of melatonin is regulated by the sympathetic nervous system, administration of beta-blockers may result in a clinically relevant blockade of melatonin secretion.
    Ethanol: (Major) A single dose study indicated a trend towards additive effects of tasimelteon and alcohol on some psychomotor tests. Patients should be cautioned about the potential adverse effects of ethanol ingestion during treatment with tasimelteon.
    Ethotoin: (Major) Concurrent use of tasimelteon and strong inducers of CYP3A4, such as hydantoins, should be avoided. Because tasimelteon is partially metabolized via CYP3A4, a large decrease in exposure is possible with the potential for reduced efficacy. During administration of tasimelteon with another potent inducer of CYP3A4, tasimelteon exposure decreased by about 90%.
    Etravirine: (Moderate) Caution is recommended during concurrent use of tasimelteon and etravirine. Because tasimelteon is partially metabolized via CYP3A4, use with CYP3A4 inducers, such as etravirine, may reduce the efficacy of tasimelteon.
    Fentanyl: (Moderate) Concomitant use of opioid agonists with tasimelteon may cause excessive sedation and somnolence. Limit the use of opioid pain medications with tasimelteon to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Fluconazole: (Moderate) Caution is recommended during concurrent use of tasimelteon and fluconazole. Because tasimelteon is partially metabolized via CYP3A4, use with CYP3A4 inhibitors, such as fluconazole, may increase exposure to tasimelteon with the potential for adverse reactions.
    Fluvoxamine: (Major) Concurrent use of tasimelteon and strong inhibitors of CYP1A2, such as fluvoxamine, should be avoided. Because tasimelteon is partially metabolized via CYP1A2, a large increase in exposure of tasimelteon with the potential for adverse reactions is possible if these drugs are coadministered. During administration of fluvoxamine 50 mg/day for 6 days, the AUC and Cmax of tasimelteon increased by 7-fold and 2-fold, respectively.
    Fosamprenavir: (Major) Concurrent use of tasimelteon and strong inhibitors of CYP3A4, such as amprenavir or fosamprenavir, should be avoided if possible. Because tasimelteon is partially metabolized via CYP3A4, a large increase in exposure of tasimelteon with the potential for adverse reactions is possible if these drugs are coadministered. During administration of tasimelteon and another potent CYP3A4 inhibitor, tasimelteon exposure increased by about 50%.
    Fosphenytoin: (Major) Concurrent use of tasimelteon and strong inducers of CYP3A4, such as hydantoins, should be avoided. Because tasimelteon is partially metabolized via CYP3A4, a large decrease in exposure is possible with the potential for reduced efficacy. During administration of tasimelteon with another potent inducer of CYP3A4, tasimelteon exposure decreased by about 90%.
    Givosiran: (Major) Avoid concomitant use of givosiran and tasimelteon due to the risk of increased tasimelteon-related adverse reactions. If use is necessary, consider decreasing the tasimelteon dose. Tasimelteon is a sensitive CYP1A2 substrate. Givosiran may moderately reduce hepatic CYP1A2 enzyme activity because of its pharmacological effects on the hepatic heme biosynthesis pathway.
    Guaifenesin; Hydrocodone: (Moderate) Concomitant use of opioid agonists with tasimelteon may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking tasimelteon. Limit the use of opioid pain medications with tasimelteon to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Guaifenesin; Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of opioid agonists with tasimelteon may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking tasimelteon. Limit the use of opioid pain medications with tasimelteon to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Homatropine; Hydrocodone: (Moderate) Concomitant use of opioid agonists with tasimelteon may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking tasimelteon. Limit the use of opioid pain medications with tasimelteon to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Hydantoins: (Major) Concurrent use of tasimelteon and strong inducers of CYP3A4, such as hydantoins, should be avoided. Because tasimelteon is partially metabolized via CYP3A4, a large decrease in exposure is possible with the potential for reduced efficacy. During administration of tasimelteon with another potent inducer of CYP3A4, tasimelteon exposure decreased by about 90%.
    Hydrochlorothiazide, HCTZ; Metoprolol: (Major) The efficacy of tasimelteon in treating circadian rhythm disruptions may be reduced in patients receiving beta-blockers. Because the circadian rhythm of melatonin is regulated by the sympathetic nervous system, administration of beta-blockers may result in a clinically relevant blockade of melatonin secretion.
    Hydrochlorothiazide, HCTZ; Propranolol: (Major) The efficacy of tasimelteon in treating circadian rhythm disruptions may be reduced in patients receiving beta-blockers. Because the circadian rhythm of melatonin is regulated by the sympathetic nervous system, administration of beta-blockers may result in a clinically relevant blockade of melatonin secretion.
    Hydrocodone: (Moderate) Concomitant use of opioid agonists with tasimelteon may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking tasimelteon. Limit the use of opioid pain medications with tasimelteon to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Hydrocodone; Ibuprofen: (Moderate) Concomitant use of opioid agonists with tasimelteon may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking tasimelteon. Limit the use of opioid pain medications with tasimelteon to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Hydrocodone; Phenylephrine: (Moderate) Concomitant use of opioid agonists with tasimelteon may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking tasimelteon. Limit the use of opioid pain medications with tasimelteon to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Hydrocodone; Potassium Guaiacolsulfonate: (Moderate) Concomitant use of opioid agonists with tasimelteon may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking tasimelteon. Limit the use of opioid pain medications with tasimelteon to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Hydrocodone; Potassium Guaiacolsulfonate; Pseudoephedrine: (Moderate) Concomitant use of opioid agonists with tasimelteon may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking tasimelteon. Limit the use of opioid pain medications with tasimelteon to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of opioid agonists with tasimelteon may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking tasimelteon. Limit the use of opioid pain medications with tasimelteon to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Hydromorphone: (Moderate) Concomitant use of opioid agonists with tasimelteon may cause excessive sedation and somnolence. Limit the use of opioid pain medications with tasimelteon to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Hydroxyzine: (Moderate) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect may occur when it is combined with other CNS depressants including anxiolytics, sedatives, and hypnotics, such as tasimelteon.
    Ibuprofen; Oxycodone: (Moderate) Concomitant use of opioid agonists with tasimelteon may cause excessive sedation and somnolence. Limit the use of opioid pain medications with tasimelteon to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Imatinib: (Moderate) Caution is recommended during concurrent use of tasimelteon and imatinib, STI-571. Because tasimelteon is partially metabolized via CYP3A4, use with CYP3A4 inhibitors, such as imatinib, may increase exposure to tasimelteon with the potential for adverse reactions.
    Indinavir: (Major) Concurrent use of tasimelteon and strong inhibitors of CYP3A4, such as indinavir, should be avoided if possible. Because tasimelteon is partially metabolized via CYP3A4, a large increase in exposure of tasimelteon with the potential for adverse reactions is possible if these drugs are coadministered. During administration of tasimelteon and another potent CYP3A4 inhibitor, tasimelteon exposure increased by about 50%.
    Isavuconazonium: (Moderate) Concomitant use of isavuconazonium with tasimelteon may result in increased serum concentrations of tasimelteon. Tasimelteon is a substrate of the hepatic isoenzyme CYP3A4; isavuconazole, the active moiety of isavuconazonium, is a moderate inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are used together.
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Concurrent use of tasimelteon and strong inducers of CYP3A4, such as rifampin, should be avoided. Because tasimelteon is partially metabolized via CYP3A4, a large decrease in exposure is possible with the potential for reduced efficacy. During administration of rifampin 600 mg/day for 11 days, the exposure of tasimelteon decreased by about 90%. Rifampin also induces CYP1A2, a secondary metabolic pathway of tasimelteon.
    Isoniazid, INH; Rifampin: (Major) Concurrent use of tasimelteon and strong inducers of CYP3A4, such as rifampin, should be avoided. Because tasimelteon is partially metabolized via CYP3A4, a large decrease in exposure is possible with the potential for reduced efficacy. During administration of rifampin 600 mg/day for 11 days, the exposure of tasimelteon decreased by about 90%. Rifampin also induces CYP1A2, a secondary metabolic pathway of tasimelteon.
    Itraconazole: (Major) Concurrent use of tasimelteon and strong inhibitors of CYP3A4, such as itraconazole, should be avoided if possible. Because tasimelteon is partially metabolized via CYP3A4, a large increase in exposure of tasimelteon with the potential for adverse reactions is possible if these drugs are coadministered. During administration of tasimelteon and another potent CYP3A4 inhibitor, tasimelteon exposure increased by about 50%.
    Ketoconazole: (Major) Concurrent use of tasimelteon and strong inhibitors of CYP3A4, such as ketoconazole, should be avoided if possible. Because tasimelteon is partially metabolized via CYP3A4, a large increase in exposure of tasimelteon with the potential for adverse reactions is possible if these drugs are coadministered. During administration of ketoconazole 40 mg/day for 5 days, tasimelteon exposure increased by about 50%.
    Labetalol: (Major) The efficacy of tasimelteon in treating circadian rhythm disruptions may be reduced in patients receiving beta-blockers. Because the circadian rhythm of melatonin is regulated by the sympathetic nervous system, administration of beta-blockers may result in a clinically relevant blockade of melatonin secretion.
    Letermovir: (Moderate) An increase in the plasma concentration of tasimelteon may occur during concurrent administration with letermovir. In patients who are also receiving treatment with cyclosporine, the magnitude of this interaction may be amplified. Tasimelteon is partially metabolized by CYP3A4. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates is similar to a strong CYP3A4 inhibitor. In a drug interaction study, administration of tasimelteon with another strong CYP3A4 inhibitor increased tasimelteon exposure by approximately 50%.
    Levobetaxolol: (Major) The efficacy of tasimelteon in treating circadian rhythm disruptions may be reduced in patients receiving beta-blockers. Because the circadian rhythm of melatonin is regulated by the sympathetic nervous system, administration of beta-blockers may result in a clinically relevant blockade of melatonin secretion.
    Levobunolol: (Major) The efficacy of tasimelteon in treating circadian rhythm disruptions may be reduced in patients receiving beta-blockers. Because the circadian rhythm of melatonin is regulated by the sympathetic nervous system, administration of beta-blockers may result in a clinically relevant blockade of melatonin secretion.
    Levocetirizine: (Moderate) Concurrent use of cetirizine/levocetirizine with tasimelteon should generally be avoided. Coadministration may increase the risk of CNS depressant-related side effects. If concurrent use is necessary, monitor for excessive sedation and somnolence.
    Levorphanol: (Moderate) Concomitant use of opioid agonists with tasimelteon may cause excessive sedation and somnolence. Limit the use of opioid pain medications with tasimelteon to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Lofexidine: (Moderate) Monitor for excessive sedation during coadministration of lofexidine and tasimelteon. Lofexidine can potentiate the effects of CNS depressants.
    Lopinavir; Ritonavir: (Major) Concurrent use of tasimelteon and strong inhibitors of CYP3A4, such as ritonavir, should be avoided if possible. Because tasimelteon is partially metabolized via CYP3A4, a large increase in exposure of tasimelteon with the potential for adverse reactions is possible if these drugs are coadministered. During administration of tasimelteon and another potent CYP3A4 inhibitor, tasimelteon exposure increased by about 50%.
    Lumacaftor; Ivacaftor: (Major) Lumacaftor; ivacaftor may reduce the efficacy of tasimelteon by significantly decreasing its systemic exposure; avoid concomitant use. Tasimelteon is a CYP3A substrate, 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.
    Meclizine: (Moderate) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect may occur when it is combined with other CNS depressants including anxiolytics, sedatives, and hypnotics, such as tasimelteon.
    Melatonin: (Major) Because of pharmacologic similarities in action as melatonin-receptor agonists, tasimelteon should likely not be coadministered with melatonin. The actions would be expected to be duplicative, and might result in additive side effects. 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 coordination 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 should be advised to avoid dietary supplements containing melatonin.
    Meperidine: (Moderate) Concomitant use of opioid agonists with tasimelteon may cause excessive sedation and somnolence. Limit the use of opioid pain medications with tasimelteon to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Meperidine; Promethazine: (Moderate) Concomitant use of opioid agonists with tasimelteon may cause excessive sedation and somnolence. Limit the use of opioid pain medications with tasimelteon to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Mephobarbital: (Major) Concurrent use of tasimelteon and strong inducers of CYP3A4, such as barbiturates or primidone, should be avoided. Because tasimelteon is partially metabolized via CYP3A4, a large decrease in exposure is possible with the potential for reduced efficacy. During administration of tasimelteon with another potent inducer of CYP3A4, tasimelteon exposure decreased by about 90%. Barbiturates also induce CYP1A2, a secondary metabolic pathway of tasimelteon.
    Methadone: (Moderate) Concomitant use of opioid agonists with tasimelteon may cause excessive sedation and somnolence. Limit the use of opioid pain medications with tasimelteon to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Methohexital: (Major) Concurrent use of tasimelteon and strong inducers of CYP3A4, such as barbiturates or primidone, should be avoided. Because tasimelteon is partially metabolized via CYP3A4, a large decrease in exposure is possible with the potential for reduced efficacy. During administration of tasimelteon with another potent inducer of CYP3A4, tasimelteon exposure decreased by about 90%. Barbiturates also induce CYP1A2, a secondary metabolic pathway of tasimelteon.
    Metoprolol: (Major) The efficacy of tasimelteon in treating circadian rhythm disruptions may be reduced in patients receiving beta-blockers. Because the circadian rhythm of melatonin is regulated by the sympathetic nervous system, administration of beta-blockers may result in a clinically relevant blockade of melatonin secretion.
    Mexiletine: (Moderate) Caution is recommended during concurrent use of tasimelteon and mexiletine. Because tasimelteon is partially metabolized via CYP1A2, use with CYP1A2 inhibitors, such as mexiletine, may increase exposure to tasimelteon and the potential for adverse reactions.
    Mitotane: (Major) Avoid the concomitant use of mitotane with tasimelteon due to decreased tasimelteon exposure and possible decreases in efficacy. Mitotane is a strong CYP3A4 inducer and tasimelteon is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of tasimelteon. During administration of tasimelteon with another potent inducer of CYP3A4, tasimelteon exposure decreased by about 90%.
    Modafinil: (Moderate) Caution is recommended during concurrent use of tasimelteon and modafinil or armodafinil. Because tasimelteon is metabolized via CYP3A4 and CYP1A2, inducers of these isoenzymes, such as modafinil and armodafinil, may reduce the efficacy of tasimelteon.
    Morphine: (Moderate) Concomitant use of opioid agonists with tasimelteon may cause excessive sedation and somnolence. Limit the use of opioid pain medications with tasimelteon to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Morphine; Naltrexone: (Moderate) Concomitant use of opioid agonists with tasimelteon may cause excessive sedation and somnolence. Limit the use of opioid pain medications with tasimelteon to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Nadolol: (Major) The efficacy of tasimelteon in treating circadian rhythm disruptions may be reduced in patients receiving beta-blockers. Because the circadian rhythm of melatonin is regulated by the sympathetic nervous system, administration of beta-blockers may result in a clinically relevant blockade of melatonin secretion.
    Nebivolol: (Major) The efficacy of tasimelteon in treating circadian rhythm disruptions may be reduced in patients receiving beta-blockers. Because the circadian rhythm of melatonin is regulated by the sympathetic nervous system, administration of beta-blockers may result in a clinically relevant blockade of melatonin secretion.
    Nebivolol; Valsartan: (Major) The efficacy of tasimelteon in treating circadian rhythm disruptions may be reduced in patients receiving beta-blockers. Because the circadian rhythm of melatonin is regulated by the sympathetic nervous system, administration of beta-blockers may result in a clinically relevant blockade of melatonin secretion.
    Nefazodone: (Major) Concurrent use of tasimelteon and strong inhibitors of CYP3A4, such as nefazodone, should be avoided if possible. Because tasimelteon is partially metabolized via CYP3A4, a large increase in exposure of tasimelteon with the potential for adverse reactions is possible if these drugs are coadministered. During administration of tasimelteon and another potent CYP3A4 inhibitor, tasimelteon exposure increased by about 50%.
    Nelfinavir: (Moderate) Caution is recommended during concurrent use of tasimelteon and nelfinavir. Because tasimelteon is partially metabolized via CYP3A4, use with CYP3A4 inhibitors, such as nelfinavir, may increase exposure to tasimelteon with the potential for adverse reactions.
    Nevirapine: (Moderate) Caution is recommended during concurrent use of tasimelteon and nevirapine. Because tasimelteon is partially metabolized via CYP3A4, use with CYP3A4 inducers, such as nevirapine, may reduce the efficacy of tasimelteon.
    Nilotinib: (Moderate) Caution is recommended during concurrent use of tasimelteon and nilotinib. Because tasimelteon is partially metabolized via CYP3A4, use with CYP3A4 inhibitors, such as nilotinib, may increase exposure to tasimelteon with the potential for adverse reactions.
    Obeticholic Acid: (Moderate) Obeticholic acid may increase the exposure to concomitant drugs that are CYP1A2 substrates, such as tasimelteon. Therapeutic monitoring is recommended with coadministration.
    Ombitasvir; Paritaprevir; Ritonavir: (Major) Concurrent use of tasimelteon and strong inhibitors of CYP3A4, such as ritonavir, should be avoided if possible. Because tasimelteon is partially metabolized via CYP3A4, a large increase in exposure of tasimelteon with the potential for adverse reactions is possible if these drugs are coadministered. During administration of tasimelteon and another potent CYP3A4 inhibitor, tasimelteon exposure increased by about 50%.
    Oxycodone: (Moderate) Concomitant use of opioid agonists with tasimelteon may cause excessive sedation and somnolence. Limit the use of opioid pain medications with tasimelteon to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Oxymorphone: (Moderate) Concomitant use of opioid agonists with tasimelteon may cause excessive sedation and somnolence. Limit the use of opioid pain medications with tasimelteon to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Penbutolol: (Major) The efficacy of tasimelteon in treating circadian rhythm disruptions may be reduced in patients receiving beta-blockers. Because the circadian rhythm of melatonin is regulated by the sympathetic nervous system, administration of beta-blockers may result in a clinically relevant blockade of melatonin secretion.
    Pentobarbital: (Major) Concurrent use of tasimelteon and strong inducers of CYP3A4, such as barbiturates or primidone, should be avoided. Because tasimelteon is partially metabolized via CYP3A4, a large decrease in exposure is possible with the potential for reduced efficacy. During administration of tasimelteon with another potent inducer of CYP3A4, tasimelteon exposure decreased by about 90%. Barbiturates also induce CYP1A2, a secondary metabolic pathway of tasimelteon.
    Phenobarbital: (Major) Concurrent use of tasimelteon and strong inducers of CYP3A4, such as barbiturates or primidone, should be avoided. Because tasimelteon is partially metabolized via CYP3A4, a large decrease in exposure is possible with the potential for reduced efficacy. During administration of tasimelteon with another potent inducer of CYP3A4, tasimelteon exposure decreased by about 90%. Barbiturates also induce CYP1A2, a secondary metabolic pathway of tasimelteon.
    Phenytoin: (Major) Concurrent use of tasimelteon and strong inducers of CYP3A4, such as hydantoins, should be avoided. Because tasimelteon is partially metabolized via CYP3A4, a large decrease in exposure is possible with the potential for reduced efficacy. During administration of tasimelteon with another potent inducer of CYP3A4, tasimelteon exposure decreased by about 90%.
    Pindolol: (Major) The efficacy of tasimelteon in treating circadian rhythm disruptions may be reduced in patients receiving beta-blockers. Because the circadian rhythm of melatonin is regulated by the sympathetic nervous system, administration of beta-blockers may result in a clinically relevant blockade of melatonin secretion.
    Posaconazole: (Major) Concurrent use of tasimelteon and strong inhibitors of CYP3A4, such as posaconazole, should be avoided if possible. Because tasimelteon is partially metabolized via CYP3A4, a large increase in exposure of tasimelteon with the potential for adverse reactions is possible if these drugs are coadministered. During administration of tasimelteon and another potent CYP3A4 inhibitor, tasimelteon exposure increased by about 50%.
    Primidone: (Major) Concurrent use of tasimelteon and strong inducers of CYP3A4, such as barbiturates or primidone, should be avoided. Because tasimelteon is partially metabolized via CYP3A4, a large decrease in exposure is possible with the potential for reduced efficacy. During administration of tasimelteon with another potent inducer of CYP3A4, tasimelteon exposure decreased by about 90%. Barbiturates also induce CYP1A2, a secondary metabolic pathway of tasimelteon.
    Propranolol: (Major) The efficacy of tasimelteon in treating circadian rhythm disruptions may be reduced in patients receiving beta-blockers. Because the circadian rhythm of melatonin is regulated by the sympathetic nervous system, administration of beta-blockers may result in a clinically relevant blockade of melatonin secretion.
    Ramelteon: (Severe) Because of pharmacologic similarities in action as melatonin-receptor agonists, ramelteon should not be coadministered with tasimelteon. The actions would be expected to be duplicative, and might result in additive side effects, such as somnolence, headache, unusual behaviors or moods, memory impairment, or balance and coordination issues.
    Remifentanil: (Moderate) Concomitant use of opioid agonists with tasimelteon may cause excessive sedation and somnolence. Limit the use of opioid pain medications with tasimelteon to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Rifabutin: (Moderate) Caution is recommended during concurrent use of tasimelteon and rifabutin. Because tasimelteon is partially metabolized via CYP3A4, use with CYP3A4 inducers, such as rifabutin, may reduce the efficacy of tasimelteon.
    Rifampin: (Major) Concurrent use of tasimelteon and strong inducers of CYP3A4, such as rifampin, should be avoided. Because tasimelteon is partially metabolized via CYP3A4, a large decrease in exposure is possible with the potential for reduced efficacy. During administration of rifampin 600 mg/day for 11 days, the exposure of tasimelteon decreased by about 90%. Rifampin also induces CYP1A2, a secondary metabolic pathway of tasimelteon.
    Ritonavir: (Major) Concurrent use of tasimelteon and strong inhibitors of CYP3A4, such as ritonavir, should be avoided if possible. Because tasimelteon is partially metabolized via CYP3A4, a large increase in exposure of tasimelteon with the potential for adverse reactions is possible if these drugs are coadministered. During administration of tasimelteon and another potent CYP3A4 inhibitor, tasimelteon exposure increased by about 50%.
    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 tasimelteon.
    Saquinavir: (Moderate) Caution is recommended during concurrent use of tasimelteon and saquinavir. Because tasimelteon is partially metabolized via CYP3A4, use with CYP3A4 inhibitors, such as saquinavir, may increase exposure to tasimelteon with the potential for adverse reactions.
    Secobarbital: (Major) Concurrent use of tasimelteon and strong inducers of CYP3A4, such as barbiturates or primidone, should be avoided. Because tasimelteon is partially metabolized via CYP3A4, a large decrease in exposure is possible with the potential for reduced efficacy. During administration of tasimelteon with another potent inducer of CYP3A4, tasimelteon exposure decreased by about 90%. Barbiturates also induce CYP1A2, a secondary metabolic pathway of tasimelteon.
    Sedating H1-blockers: (Moderate) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect may occur when it is combined with other CNS depressants including anxiolytics, sedatives, and hypnotics, such as tasimelteon.
    Sotalol: (Major) The efficacy of tasimelteon in treating circadian rhythm disruptions may be reduced in patients receiving beta-blockers. Because the circadian rhythm of melatonin is regulated by the sympathetic nervous system, administration of beta-blockers may result in a clinically relevant blockade of melatonin secretion.
    St. John's Wort, Hypericum perforatum: (Major) Concurrent use of tasimelteon and strong inducers of CYP3A4, such as St. John's Wort, hypericum perforatum, should be avoided. Because tasimelteon is partially metabolized via CYP3A4, a large decrease in exposure is possible with the potential for reduced efficacy. During administration of tasimelteon with another potent inducer of CYP3A4, tasimelteon exposure decreased by about 90%.
    Sufentanil: (Moderate) Concomitant use of opioid agonists with tasimelteon may cause excessive sedation and somnolence. Limit the use of opioid pain medications with tasimelteon to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Suvorexant: (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.
    Tapentadol: (Moderate) Concomitant use of opioid agonists with tasimelteon may cause excessive sedation and somnolence. Limit the use of opioid pain medications with tasimelteon to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Telaprevir: (Major) Concurrent use of tasimelteon and strong inhibitors of CYP3A4, such as telaprevir, should be avoided if possible. Because tasimelteon is partially metabolized via CYP3A4, a large increase in exposure of tasimelteon with the potential for adverse reactions is possible if these drugs are coadministered. During administration of tasimelteon and another potent CYP3A4 inhibitor, tasimelteon exposure increased by about 50%.
    Telithromycin: (Major) Concurrent use of tasimelteon and strong inhibitors of CYP3A4, such as telithromycin, should be avoided if possible. Because tasimelteon is partially metabolized via CYP3A4, a large increase in exposure of tasimelteon with the potential for adverse reactions is possible if these drugs are coadministered. During administration of tasimelteon and another potent CYP3A4 inhibitor, tasimelteon exposure increased by about 50%.
    Telotristat Ethyl: (Major) Avoid coadministration of telotristat ethyl and tasimelteon, as the systemic exposure of tasimelteon may be decreased resulting in reduced efficacy. Tasimelteon 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. The exposure of tasimelteon decreased by approximately 90% when coadministered with a strong CYP3A4 inducer.
    Thiabendazole: (Major) Concurrent use of tasimelteon and strong inhibitors of CYP1A2, such as thiabendazole, should be avoided. Because tasimelteon is partially metabolized via CYP1A2, a large increase in exposure of tasimelteon with the potential for adverse reactions is possible if these drugs are coadministered. During administration of tasimelteon and another potent CYP1A2 inhibitor, the AUC and Cmax of tasimelteon increased by 7-fold and 2-fold, respectively.
    Thiopental: (Major) Concurrent use of tasimelteon and strong inducers of CYP3A4, such as barbiturates or primidone, should be avoided. Because tasimelteon is partially metabolized via CYP3A4, a large decrease in exposure is possible with the potential for reduced efficacy. During administration of tasimelteon with another potent inducer of CYP3A4, tasimelteon exposure decreased by about 90%. Barbiturates also induce CYP1A2, a secondary metabolic pathway of tasimelteon.
    Timolol: (Major) The efficacy of tasimelteon in treating circadian rhythm disruptions may be reduced in patients receiving beta-blockers. Because the circadian rhythm of melatonin is regulated by the sympathetic nervous system, administration of beta-blockers may result in a clinically relevant blockade of melatonin secretion.
    Tipranavir: (Major) Concurrent use of tasimelteon and strong inhibitors of CYP3A4, such as tipranavir, should be avoided if possible. Because tasimelteon is partially metabolized via CYP3A4, a large increase in exposure of tasimelteon with the potential for adverse reactions is possible if these drugs are coadministered. During administration of tasimelteon and another potent CYP3A4 inhibitor, tasimelteon exposure increased by about 50%.
    Tobacco: (Major) Due to partial metabolism of tasimelteon by CYP1A2, drug exposure is decreased by about 40% in smokers compared to non-smokers. Patients should be advised of the potential for reduced efficacy due to tobacco use.
    Tramadol: (Moderate) Concomitant use of opioid agonists with tasimelteon may cause excessive sedation and somnolence. Limit the use of opioid pain medications with tasimelteon to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Trandolapril; Verapamil: (Moderate) Caution is recommended during concurrent use of tasimelteon and verapamil. Because tasimelteon is partially metabolized via CYP3A4, use with CYP3A4 inhibitors, such as verapamil, may increase exposure to tasimelteon with the potential for adverse reactions.
    Trazodone: (Moderate) CNS depressants should be used cautiously in patients receiving trazodone because of additive CNS depressant effects, including possible respiratory depression or hypotension. A dose reduction of one or both drugs may be warranted.
    Triprolidine: (Moderate) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect may occur when it is combined with other CNS depressants including anxiolytics, sedatives, and hypnotics, such as tasimelteon.
    Vemurafenib: (Moderate) Caution is recommended during concurrent use of tasimelteon and vemurafenib. Concurrent use of these agents may have variable effects on tasimelteon exposure. Vemurafenib has inhibitory effects on CYP1A2 and inducing effects on CYP3A4, which are two metabolic pathways of tasimelteon.
    Verapamil: (Moderate) Caution is recommended during concurrent use of tasimelteon and verapamil. Because tasimelteon is partially metabolized via CYP3A4, use with CYP3A4 inhibitors, such as verapamil, may increase exposure to tasimelteon with the potential for adverse reactions.
    Voriconazole: (Major) Concurrent use of tasimelteon and strong inhibitors of CYP3A4, such as voriconazole, should be avoided if possible. Because tasimelteon is partially metabolized via CYP3A4, a large increase in exposure of tasimelteon with the potential for adverse reactions is possible if these drugs are coadministered. During administration of tasimelteon and another potent CYP3A4 inhibitor, tasimelteon exposure increased by about 50%.
    Zileuton: (Moderate) Caution is recommended during concurrent use of tasimelteon and zileuton. Because tasimelteon is partially metabolized via CYP1A2, use with a CYP1A2 inhibitor, such as zileuton, may increase exposure to tasimelteon and the potential for adverse reactions.

    PREGNANCY AND LACTATION

    Pregnancy

    Tasimelteon should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Available postmarketing case reports with use of tasimelteon in pregnant women are not sufficient to evaluate drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. In pregnant rats, no embryofetal developmental toxicity was observed at exposures of up to 50 mg/kg/day (the no-effect dose), or approximately 25 times the human exposure at the maximum recommended human dose (MRHD) of 20 mg/day. Oral administration of tasimelteon at 50, 150, or 450 mg/kg/day to rats throughout organogenesis resulted in persistent reductions in body weight, delayed sexual maturation, and physical development, and neurobehavioral impairment in offspring at the highest dose tested which is approximately 220 times the MRHD based on body surface area. Reduced body weight in offspring was also observed at the mid-dose. It is not known what effect tasimelteon would have during labor or obstetric delivery.

    There are no data on the presence of tasimelteon in human milk, the effects on the breastfed infant, or the effects on milk production. Caution is advisable when administering tasimelteon to a woman who is breast-feeding an infant. Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for tasimelteon and any potential adverse effects on the breastfed infant from tasimelteon or the underlying maternal condition. 

    MECHANISM OF ACTION

    Tasimelteon is a melatonin receptor agonist. The 3 subtypes of mammalian melatonin receptors that have been identified are MT1, MT2, and MT3. Tasimelteon is an agonist at MT1 and MT2, which are located in the suprachiasmatic nucleus (SCN) of the hypothalamus. The SCN functions as the body's internal clock and regulates the 24-hour sleep-wake cycle. The MT1 and MT2 receptors are believed to be involved in the promotion of sleep and the maintenance of the normal circadian rhythm (shift between day and night).

    PHARMACOKINETICS

    Tasimelteon is administered orally and exhibits linear pharmacokinetics over a broad range of doses. The apparent volume of distribution at steady state is approximately 56—126 L. The drug is 90% protein bound. Metabolism occurs primarily through oxidation at multiple sites and oxidative dealkylation resulting in opening of the dihydrofuran ring followed by further oxidation to a carboxylic acid. The major isoenzymes involved in the metabolism of tasimelteon are CYP1A2 and CYP3A4. Phenolic glucuronidation is the major phase II metabolic route. No drug interactions have been identified in vitro with inducers or inhibitors of CYP1A1, CYP1A2, CYP2B6, CYP2C9/2C19, CYP2E1, CYP2D6, P-gP, OATP1B1, OATP1B3, OCT2, OAT1, or OAT3. Tasimelteon exhibits a greater affinity for the melatonin 2 receptor than the melatonin 1 receptor. The major metabolites of tasimelteon have 13-fold or less activity at melatonin receptors than the parent compound. The mean elimination half-life of tasimelteon is 1.3 hours +/- 0.4 hours. The mean elimination half-lives of the primary metabolites range from 1.3 hours +/- 0.5 to 3.7 hours +/- 2.2. Approximately 4% of a dose is excreted in the feces and 80% in the urine. Less than 1% of a dose is excreted in urine as the parent compound.

    Oral Route

    After oral administration in a fasting state, peak concentrations occur about 0.5—3 hours post-dose. Administration with a high-fat meal reduces the Cmax by 44% compared to a fasted state, and the median Tmax is delayed by about 1.75 hours. Therefore, tasimelteon should be taken without food.