Tasimelteon (Hetlioz) for non-24 hour sleep-wake disorder

Tasimelteon (Hetlioz) is a novel drug and the first of its kind that has been approved by the FDA for the treatment of non-24-hour sleep-wake disorder. The Europeans have approved it for the treatment of non-24-hour sleep-wake disorder only in totally blind people. It has not been approved in Europe in sighted people. Non-24 hour sleep-wake disorder is only seen in totally blind patients. However, it may rarely affect sighted individuals as well.

The symptoms of non-24-hour sleep-wake disorder include:

Difficulty to fall asleep at night.
Sleep time gradually gets delayed.
Getting up later in the morning
The sleep does not relieve fatigue and is not restful.
This also results in daytime sleepiness.
The sleep pattern may be disturbed or the patient may develop insomnia
Depression and anxiety

Other hypnotic drugs used to treat insomnia include:

Benzodiazepines, zolpidem, zaleplon, and zopiclone.

Tasimelteon (Hetlioz) dose in Adults

Tasimelteon (Hetlioz) dose in the treatment of Non-24-hour sleep-wake disorder:

20 mg orally once a day at a fixed scheduled time each night prior to going to bed.

Tasimelteon (Hetlioz) dose in Childrens

It has not been studied in children.

Pregnancy Risk Factor C

It has not been studied in pregnant females. Animal studies have shown adverse fetal events with its use.

Tasimelteon use during breastfeeding:

The excretion of the drug into breastmilk is not known.
The manufacturer recommends using it with caution in breastfeeding mothers.

Tasimelteon (Hetlioz) dose in Kidney Disease:

Adjustment in the dose is not necessary.

Tasimelteon (Hetlioz) dose in Liver Disease:

Mild or moderate impairment:
- Adjustment in the dose is not required.
Severe hepatic impairment:
- Although the manufacturer has not recommended any adjustment in the dose, it should be avoided in patients with severe liver disease.

Tasimelteon (Hetlioz) side effects (common):

Central nervous system:
- Headache

(Tasimelteon) Hetlioz Side Effects (Less common):

Central nervous system:
- Abnormal dreams
Genitourinary:
- Urinary tract infection
Hepatic:
- Increased serum ALT
Respiratory:
- Upper respiratory tract infection

Contraindication to Tasimelteon (Hetlioz) include:

The manufacturer has not mentioned any contraindications to its use.

Warnings and Precautions

CNS depression:
- It may cause CNS depression. Patients who perform tasks that require mental alertness such as driving and operating heavy machinery should take the drug with caution.
Hepatic impairment:
- Patients with severe hepatic impairment should take the drug with extreme caution or preferably avoid it.

Tasimelteon (Hetlioz): Drug Interaction

Risk Factor C (Monitor therapy)
Abiraterone Acetate	May increase the serum concentration of CYP1A2 Substrates (High risk with Inhibitors).
Alcohol (Ethyl)	CNS Depressants may enhance the CNS depressant effect of Alcohol (Ethyl).
Alizapride	May enhance the CNS depressant effect of CNS Depressants.
Bosentan	May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).
Brexanolone	CNS Depressants may enhance the CNS depressant effect of Brexanolone.
Brimonidine (Topical)	May enhance the CNS depressant effect of CNS Depressants.
Broccoli	May decrease the serum concentration of CYP1A2 Substrates (High risk with Inducers).
Bromopride	May enhance the CNS depressant effect of CNS Depressants.
Cannabidiol	May enhance the CNS depressant effect of CNS Depressants.
Cannabis	May decrease the serum concentration of CYP1A2 Substrates (High risk with Inducers).
Cannabis	May enhance the CNS depressant effect of CNS Depressants.
Chlorphenesin Carbamate	May enhance the adverse/toxic effect of CNS Depressants.
CNS Depressants	May enhance the adverse/toxic effect of other CNS Depressants.
CYP1A2 Inducers (Moderate)	May decrease the serum concentration of CYP1A2 Substrates (High risk with Inducers).
CYP1A2 Inhibitors (Moderate)	May decrease the metabolism of CYP1A2 Substrates (High risk with Inhibitors).
CYP3A4 Inducers (Moderate)	May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).
CYP3A4 Inhibitors (Strong)	May increase the serum concentration of Tasimelteon.
Cyproterone	May decrease the serum concentration of CYP1A2 Substrates (High risk with Inducers).
Deferasirox	May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).
Deferasirox	May increase the serum concentration of CYP1A2 Substrates (High risk with Inhibitors).
Dimethindene (Topical)	May enhance the CNS depressant effect of CNS Depressants.
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.
Dronabinol	May enhance the CNS depressant effect of CNS Depressants.
Erdafitinib	May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).
Esketamine	May enhance the CNS depressant effect of CNS Depressants.
HydrOXYzine	May enhance the CNS depressant effect of CNS Depressants.
Ivosidenib	May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).
Kava Kava	May enhance the adverse/toxic effect of CNS Depressants.
Lofexidine	May enhance the CNS depressant effect of CNS Depressants. Management: Drugs listed as exceptions to this monograph are discussed in further detail in separate drug interaction monographs.
Magnesium Sulfate	May enhance the CNS depressant effect of CNS Depressants.
Melatonin	May enhance the sedative effect of Hypnotics (Nonbenzodiazepine).
MetyroSINE	CNS Depressants may enhance the sedative effect of MetyroSINE.
Minocycline	May enhance the CNS depressant effect of CNS Depressants.
Mirtazapine	CNS Depressants may enhance the CNS depressant effect of Mirtazapine.
Nabilone	May enhance the CNS depressant effect of CNS Depressants.
Obeticholic Acid	May increase the serum concentration of CYP1A2 Substrates (High risk with Inhibitors).
Peginterferon Alfa-2b	May increase the serum concentration of CYP1A2 Substrates (High risk with Inhibitors).
Piribedil	CNS Depressants may enhance the CNS depressant effect of Piribedil.
Pramipexole	CNS Depressants may enhance the sedative effect of Pramipexole.
ROPINIRole	CNS Depressants may enhance the sedative effect of ROPINIRole.
Rotigotine	CNS Depressants may enhance the sedative effect of Rotigotine.
Rufinamide	May enhance the adverse/toxic effect of CNS Depressants. Specifically, sleepiness and dizziness may be enhanced.
Sarilumab	May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).
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.
Siltuximab	May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).
Teriflunomide	May decrease the serum concentration of CYP1A2 Substrates (High risk with Inducers).
Tetrahydrocannabinol	May enhance the CNS depressant effect of CNS Depressants.
Tetrahydrocannabinol and Cannabidiol	May enhance the CNS depressant effect of CNS Depressants.
Tobacco (Smoked	May decrease the serum concentration of Tasimelteon.
Tocilizumab	May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).
Trimeprazine	May enhance the CNS depressant effect of CNS Depressants.
Risk Factor D (Consider therapy modification)
Blonanserin	CNS Depressants may enhance the CNS depressant effect of Blonanserin.
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 at lower doses in patients already receiving CNS depressants.
Chlormethiazole	May enhance the CNS depressant effect of CNS Depressants. Management: Monitor closely for evidence of excessive CNS depression. The chlormethiazole labeling states that an appropriately reduced dose should be used if such a combination must be used.
Dabrafenib	May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). 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).
Droperidol	May enhance the CNS depressant effect of CNS Depressants. Management: Consider dose reductions of droperidol or of other CNS agents (eg, opioids, barbiturates) with concomitant use. Exceptions to this monograph are discussed in further detail in separate drug interaction monographs.
Flunitrazepam	CNS Depressants may enhance the CNS depressant effect of Flunitrazepam.
HYDROcodone	CNS Depressants may enhance the CNS depressant effect of HYDROcodone. Management: Avoid concomitant use of hydrocodone and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug.
Lorlatinib	May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Avoid concurrent use of lorlatinib with any CYP3A4 substrates for which a minimal decrease in serum concentrations of the CYP3A4 substrate could lead to therapeutic failure and serious clinical consequences.
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.
Opioid Agonists	CNS Depressants may enhance the CNS depressant effect of Opioid Agonists. Management: Avoid concomitant use of opioid agonists and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug.
OxyCODONE	CNS Depressants may enhance the CNS depressant effect of OxyCODONE. Management: Avoid concomitant use of oxycodone and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug.
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.
Pitolisant	May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Combined use of pitolisant with a CYP3A4 substrate that has a narrow therapeutic index should be avoided. Other CYP3A4 substrates should be monitored more closely when used with pitolisant.
St John's Wort	May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling.
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.
Tapentadol	May enhance the CNS depressant effect of CNS Depressants. Management: Avoid concomitant use of tapentadol and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug.
Vemurafenib	May increase the serum concentration of CYP1A2 Substrates (High risk with Inhibitors). Management: Consider alternatives to such combinations whenever possible, particularly if the CYP1A2 substrate has a relatively narrow therapeutic index. Drugs listed as exceptions to this monograph are discussed in separate drug interaction monographs.
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.
Risk Factor X (Avoid combination)
Azelastine (Nasal)	CNS Depressants may enhance the CNS depressant effect of Azelastine (Nasal).
Bromperidol	May enhance the CNS depressant effect of CNS Depressants.
CYP1A2 Inhibitors (Strong	May increase the serum concentration of Tasimelteon.
CYP3A4 Inducers (Strong)	May decrease the serum concentration of Tasimelteon.
Orphenadrine	CNS Depressants may enhance the CNS depressant effect of Orphenadrine.
Oxomemazine	May enhance the CNS depressant effect of CNS Depressants.
Paraldehyde	CNS Depressants may enhance the CNS depressant effect of Paraldehyde.
Sodium Oxybate	Hypnotics (Nonbenzodiazepine) may enhance the CNS depressant effect of Sodium Oxybate.
Thalidomide	CNS Depressants may enhance the CNS depressant effect of Thalidomide.

Monitor:

None required.

How to administer Tasimelteon (Hetlioz)?

It is administered orally without meals and preferably at the same timed each night prior to bedtime.
If the dose can not be taken at the scheduled time, the dose should be missed.
After taking the drug, activities should be limited to preparing for getting into the bed to sleep.
The capsule should be swallowed whole and should not be chewed or crushed.

Mechanism of action of Tasimelteon (Hetlioz):

Tasimelteon (Hetlioz) is an agonist of melatonin receptors (MT-1 and MT-2).
The receptor affinity is greater for MT-2 than MT-1. MT-1 receptor activation causes sleepiness while MT-2 receptor activation regulates the circadian rhythm.

The onset of action: It takes weeks to months for the full effect to be seen.

Absorption: Meals high in fats reduces the systemic absorption by 44% and delays the time for the drug to get absorbed.

Protein binding: About 90% of the drug is protein-bound.

Metabolism: It is extensively metabolized by the liver via the process of oxidation (primarily through CYP1A2 and CYP3A4).

Bioavailability of the drug is about 38%

The half-life elimination is 1 to 2 hours.

The time to reach peak serum concentration is about 0.5 - 3 hours (and increased to 1.75 hours with a high fat-meals.

Excretion: 80% of the drug is excreted via urine.