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Tasimelteon


General


Pronunciation

(tas i MEL tee on)


Brand Names: U.S.

  • Hetlioz

Indications


Use: Labeled Indications

Non-24-hour sleep-wake disorder: Treatment of non-24-hour sleep-wake disorder (non-24). Note: Efficacy was established in totally blind patients with non-24-hour sleep-wake disorder.


Contraindications


There are no contraindications listed in the manufacturers labeling.


Dosing and Administration


Dosing: Adult

Note: Effect may not occur for weeks or months due to differences in circadian rhythms.

Non-24-hour sleep-wake disorder: Adults: Oral: 20 mg once daily at the same time each night before bedtime.


Dosing: Renal Impairment

No dosage adjustment necessary.


Dosing: Hepatic Impairment

Mild or moderate impairment: No dosage adjustment necessary.

Severe impairment: There are no dosage adjustments provided in manufacturer 's labeling (has not been studied). Use is not recommended.


Administration

Administer orally without food. Should be taken at the same time every night before bedtime. Swallow capsule whole. After administration, activities should be limited to preparing for sleep. If the dose cannot be taken at approximately the same time on a given night, that dose should be skipped.


Dietary Considerations

Avoid or limit ethanol.


Storage

Store at 25 ‚ °C (77 ‚ °F); excursions are permitted between 15 ‚ °C and 30 ‚ °C (59 ‚ °F and 86 ‚ °F). Protect from light and moisture.


Dosage Forms/Strengths


Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Capsule, Oral:

Hetlioz: 20 mg [contains brilliant blue fcf (fd&c blue #1), fd&c yellow #6 (sunset yellow)]


Drug Interactions

Abiraterone Acetate: May increase the serum concentration of CYP1A2 Substrates. Monitor therapy

Alcohol (Ethyl): CNS Depressants may enhance the CNS depressant effect of Alcohol (Ethyl). Monitor therapy

Azelastine (Nasal): CNS Depressants may enhance the CNS depressant effect of Azelastine (Nasal). Avoid combination

Blonanserin: CNS Depressants may enhance the CNS depressant effect of Blonanserin. Consider therapy modification

Bosentan: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Brimonidine (Topical): May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Buprenorphine: CNS Depressants may enhance the CNS depressant effect of Buprenorphine. Management: Consider reduced doses of other CNS depressants, and avoiding such drugs in patients at high risk of buprenorphine overuse/self-injection. Initiate buprenorphine patches (Butrans brand) at 5 mcg/hr in adults when used with other CNS depressants. Consider therapy modification

Cannabis: May decrease the serum concentration of CYP1A2 Substrates. Monitor therapy

Cannabis: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

CNS Depressants: May enhance the adverse/toxic effect of other CNS Depressants. Monitor therapy

CYP1A2 Inhibitors (Moderate): May decrease the metabolism of CYP1A2 Substrates. Monitor therapy

CYP1A2 Inhibitors (Strong): May increase the serum concentration of Tasimelteon. Avoid combination

CYP3A4 Inducers (Moderate): May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

CYP3A4 Inducers (Strong): May decrease the serum concentration of Tasimelteon. Avoid combination

CYP3A4 Inhibitors (Strong): May increase the serum concentration of Tasimelteon. Monitor therapy

Cyproterone: May decrease the serum concentration of CYP1A2 Substrates. Monitor therapy

Dabrafenib: May decrease the serum concentration of CYP3A4 Substrates. Management: Seek alternatives to the CYP3A4 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Consider therapy modification

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Deferasirox: May increase the serum concentration of CYP1A2 Substrates. Monitor therapy

Dimethindene: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Doxylamine: May enhance the CNS depressant effect of CNS Depressants. Management: The manufacturer of Diclegis (doxylamine/pyridoxine), intended for use in pregnancy, specifically states that use with other CNS depressants is not recommended. Monitor therapy

Dronabinol: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Droperidol: May enhance the CNS depressant effect of CNS Depressants. Management: Consider dose reductions of droperidol or of other CNS agents (e.g., opioids, barbiturates) with concomitant use. Consider therapy modification

Flunitrazepam: CNS Depressants may enhance the CNS depressant effect of Flunitrazepam. Consider therapy modification

HYDROcodone: CNS Depressants may enhance the CNS depressant effect of HYDROcodone. Management: Consider starting with a 20% to 30% lower hydrocodone dose when using together with any other CNS depressant. Dose reductions in the other CNS depressant may also be warranted. Consider therapy modification

HydrOXYzine: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Kava Kava: May enhance the adverse/toxic effect of CNS Depressants. Monitor therapy

Magnesium Sulfate: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Methotrimeprazine: CNS Depressants may enhance the CNS depressant effect of Methotrimeprazine. Methotrimeprazine may enhance the CNS depressant effect of CNS Depressants. Management: Reduce adult dose of CNS depressant agents by 50% with initiation of concomitant methotrimeprazine therapy. Further CNS depressant dosage adjustments should be initiated only after clinically effective methotrimeprazine dose is established. Consider therapy modification

MetyroSINE: CNS Depressants may enhance the sedative effect of MetyroSINE. Monitor therapy

Minocycline: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Mirtazapine: CNS Depressants may enhance the CNS depressant effect of Mirtazapine. Monitor therapy

Nabilone: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Obeticholic Acid: May increase the serum concentration of CYP1A2 Substrates. Monitor therapy

Orphenadrine: CNS Depressants may enhance the CNS depressant effect of Orphenadrine. Avoid combination

Osimertinib: May increase the serum concentration of CYP3A4 Substrates. Osimertinib may decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Osimertinib: May decrease the serum concentration of CYP1A2 Substrates. Monitor therapy

OxyCODONE: CNS Depressants may enhance the CNS depressant effect of OxyCODONE. Management: When oxycodone is combined with another CNS depressant, a dose reduction of one or both agents should be considered. The extended release oxycodone starting dose should be reduced 50% to 67% when initiated in patients already receiving CNS depressants. Consider therapy modification

Paraldehyde: CNS Depressants may enhance the CNS depressant effect of Paraldehyde. Avoid combination

Peginterferon Alfa-2b: May increase the serum concentration of CYP1A2 Substrates. Monitor therapy

Perampanel: May enhance the CNS depressant effect of CNS Depressants. Management: Patients taking perampanel with any other drug that has CNS depressant activities should avoid complex and high-risk activities, particularly those such as driving that require alertness and coordination, until they have experience using the combination. Consider therapy modification

Piribedil [INT]: CNS Depressants may enhance the CNS depressant effect of Piribedil [INT]. Monitor therapy

Pramipexole: CNS Depressants may enhance the sedative effect of Pramipexole. Monitor therapy

ROPINIRole: CNS Depressants may enhance the sedative effect of ROPINIRole. Monitor therapy

Rotigotine: CNS Depressants may enhance the sedative effect of Rotigotine. Monitor therapy

Rufinamide: May enhance the adverse/toxic effect of CNS Depressants. Specifically, sleepiness and dizziness may be enhanced. Monitor therapy

Selective Serotonin Reuptake Inhibitors: CNS Depressants may enhance the adverse/toxic effect of Selective Serotonin Reuptake Inhibitors. Specifically, the risk of psychomotor impairment may be enhanced. Monitor therapy

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Sodium Oxybate: Hypnotics (Nonbenzodiazepine) may enhance the CNS depressant effect of Sodium Oxybate. Avoid combination

St Johns Wort: May decrease the serum concentration of CYP3A4 Substrates. Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

Suvorexant: CNS Depressants may enhance the CNS depressant effect of Suvorexant. Management: Dose reduction of suvorexant and/or any other CNS depressant may be necessary. Use of suvorexant with alcohol is not recommended, and the use of suvorexant with any other drug to treat insomnia is not recommended. Consider therapy modification

Tapentadol: May enhance the CNS depressant effect of CNS Depressants. Management: Start tapentadol at a dose of one-third to one-half of the normal dose if being initiated in a patient who is taking another drug with CNS depressant effects. Monitor closely for evidence of excessive CNS depression. Consider therapy modification

Teriflunomide: May decrease the serum concentration of CYP1A2 Substrates. Monitor therapy

Tetrahydrocannabinol: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Thalidomide: CNS Depressants may enhance the CNS depressant effect of Thalidomide. Avoid combination

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Trimeprazine: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Vemurafenib: May increase the serum concentration of CYP1A2 Substrates. Management: Consider alternatives to such combinations whenever possible, particularly if the CYP1A2 substrate has a relatively narrow therapeutic index. Consider therapy modification

Zolpidem: CNS Depressants may enhance the CNS depressant effect of Zolpidem. Management: Reduce the Intermezzo brand sublingual zolpidem adult dose to 1.75 mg for men who are also receiving other CNS depressants. No such dose change is recommended for women. Avoid use with other CNS depressants at bedtime; avoid use with alcohol. Consider therapy modification


Adverse Reactions


>10%: Central nervous system: Headache (17%)

1% to 10%:

Central nervous system: Abnormal dreams (10%)

Genitourinary: Urinary tract infection (7%)

Hepatic: Increased serum ALT (10%)

Respiratory: Upper respiratory tract infection (7%)


Warnings/Precautions


Special Populations: Renal Function Impairment

Patients with severe renal impairment (GFR <15 mL/minute/1.73 m2) had a 30% lower clearance compared to healthy patients; clearance in patients with end-stage renal disease was comparable to that of healthy subjects.


Special Populations: Hepatic Function Impairment

Tasimelteon exposure was increased less than 2-fold in patients with moderate hepatic impairment (Child-Pugh Score ≥7 and ≤9 points).


Special Populations: Elderly

In elderly subjects, tasimelteon exposure increased by ~2-fold compared with younger adults.


Special Populations: Gender

The mean overall exposure of tasimelteon was ~20% to 30% greater in female than in male subjects.


Special Populations Note

Cigarette smoking: Exposure decreased by ~40% in smokers, compared to nonsmokers.


Warnings/Precautions

Concerns related to adverse effects:

- CNS depression: May cause CNS depression impairing physical and mental capabilities; patients must be cautioned about performing tasks that require mental alertness (operating machinery or driving).

Disease-related concerns:

- Hepatic impairment: Use is not recommended in patients with severe hepatic impairment.

Concurrent drug therapy issues:

- Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special populations:

- Elderly: Use with caution in the elderly; exposure is increased; may increase the risk of adverse events.

- Smokers: Smoking causes induction of CYP1A2 levels; tasimelteon exposure is decreased in smokers compared to nonsmokers, which may reduce tasimelteon efficacy.


Pregnancy Risk Factor

C


Pregnancy Considerations

Adverse events were observed in some animal reproduction studies.


Actions


Pharmacology

Agonist of melatonin receptors MT1 and MT2 (greater affinity for the MT2 receptor than the MT1 receptor). Agonism of MT1 is thought to preferentially induce sleepiness, while MT2 receptor activation preferentially influences regulation of circadian rhythms.


Absorption

High-fat meals delayed Tmax and maximum serum concentration was reduced by 44%


Distribution

Vd: ~59 to 126 L


Metabolism

Hepatic (extensive); oxidative metabolism primarily through CYP1A2 and CYP3A4. Phenolic glucuronidation is the major phase II metabolic route.


Excretion

Urine (80%; <1% as unchanged drug); feces (~4%)


Onset of Action

Effect may take weeks or months (due to individual differences in circadian rhythms)


Time to Peak

Fasting: ~0.5 to 3 hours (increased by ~1.75 hours with a high-fat meal)


Half-Life Elimination

~1 to 2 hours


Protein Binding

~90%


Patient and Family Education


Patient Education

- Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

- Patient may experience headache, nightmares, cough, pharyngitis, rhinorrhea, or rhinitis. Have patient report immediately to prescriber painful urination or difficult urination (HCAHPS).

- Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

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