Hetlioz

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ANNEX I 

 

SUMMARY OF PRODUCT CHARACTERISTICS 



 

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1. NAME OF THE MEDICINAL PRODUCT 

 

HETLIOZ 20 mg hard capsules 

 

 

2. QUALITATIVE AND QUANTITATIVE COMPOSITION 

 

Each hard capsule contains 20 mg tasimelteon. 

 
Excipients with known effect 

 

Each hard capsule contains 183.25 mg of lactose (as anhydrous) and 0.03 mg of Orange Yellow S (E110). 

 

For the full list of excipients, see section 6.1. 

 

 

3. PHARMACEUTICAL FORM 

 

Hard capsule 

 

Dark blue opaque, hard capsule (dimensions 19.4 mm x 6.9 mm) marked with ‘VANDA 20 mg’ in white 

ink.  

 

 

4. CLINICAL PARTICULARS 

 

4.1 Therapeutic indications 

 

HETLIOZ is indicated for the treatment of Non-24-Hour Sleep-Wake Disorder (Non-24) in totally blind 

adults.   

 

 

4.2 Posology and method of administration 

 

Posology 

 

Dose and timing 

The recommended dose is 20 mg (1 capsule) tasimelteon per day taken one hour before bedtime, at the same 

time every night.  

 

 

 

HETLIOZ is intended for chronic use. 

 

Elderly 

No dose adjustment is recommended for individuals older than 65 years of age (see section 5.2). 

 

 

 

Renal impairment 

No dose adjustment is recommended for patients with renal impairment (see section 5.2). 

 

Hepatic impairment 



 

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No dose adjustment is necessary for patients with mild or moderate hepatic impairment (see section 5.2). 

Tasimelteon has not been studied in patients with severe hepatic impairment (Child-Pugh Class C); therefore 

caution is recommended when prescribing tasimelteon to patients with severe hepatic impairment. 

 

Paediatric population 

The safety and efficacy of tasimelteon in children and adolescents aged 0 to 18 years have not been 

established.  No data are available. 

 

Method of administration  

 

Oral use. Hard capsules should be swallowed whole. Avoid breaking as the powder has an unpleasant taste. 

 

Tasimelteon should be taken without food; if patients eat a high-fat meal, it is recommended to wait at least 2 

hours before taking tasimelteon (see section 5.2). 

 

 

4.3 Contraindications 

 

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. 

 

 

4.4 Special warnings and precautions for use 

 

After taking tasimelteon, patients should limit their activity to preparing for going to bed.   

 

 

Caution should be used when administering tasimelteon in combination with fluvoxamine or other strong 

CYP1A2 inhibitors, particularly those which also inhibit other enzymes involved in the clearance of 

tasimelteon because of a potentially large increase in tasimelteon exposure and greater risk of adverse 

reactions (see section 4.5). 

 

Caution should be used when administering tasimelteon in combination with rifampin or other CYP3A4 

inducers because of a potentially large decrease in tasimelteon exposure with reduced efficacy (see section 

4.5). 

Patients should be instructed to initiate tasimelteon treatment without regard to circadian phase.  Physicians 

should evaluate patient response to tasimelteon 3 months after treatment initiation utilising a clinician 

interview to assess their overall functioning with an emphasis on sleep-wake complaints.   

 

 

Excipients 

 

HETLIOZ hard capsules contain lactose. Patients with rare hereditary problems of galactose intolerance,  

total lactase deficiency or glucose-galactose malabsorption should not take this medicinal product. 

 

HETLIOZ hard capsules contain the azo colouring agent Orange Yellow S (E110), which may cause allergic 

reactions.  

 

This medicinal product contains less than 1 mmol sodium (23 mg) per hard capsule, that is to say essentially 

‘sodium-free’. 

 

4.5 Interaction with other medicinal products and other forms of interaction 

 

Potential for other medicinal products to affect tasimelteon 

CYP1A2 and CYP3A4 are enzymes identified to play a role in the metabolism of tasimelteon, with a minor 

role for CYP2C9/C19.  Medicinal products that inhibit CYP1A2 and CYP3A4 have been shown to alter the 

metabolism of tasimelteon in vivo.   



 

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Strong CYP1A2 inhibitors (e.g. fluvoxamine, ciprofloxacin and enoxacin)  

Caution should be used when administering tasimelteon in combination with fluvoxamine or other strong 

CYP1A2 inhibitors such as ciprofloxacin and enoxacin because of a potentially large increase in tasimelteon 

exposure and greater risk of adverse reactions: the AUC0-inf and Cmax of tasimelteon increased by 7-fold and 

2-fold, respectively, when co-administered with fluvoxamine 50 mg (after 6 days of fluvoxamine 50 mg per 

day). This is deemed even more important for strong CYP1A2 inhibitors also inhibiting other enzymes 

involved in the clearance of tasimelteon (e.g. fluvoxamine and ciprofloxacin). 

 

 

Strong CYP3A4 inhibitors (e.g. ketoconazole)  

Tasimelteon exposure was increased by approximately 50% when co-administered with ketoconazole 

400 mg (after 5 days of ketoconazole 400 mg per day).  The clinical relevance of this single factor is unclear, 

but with increased exposure caution is recommended to monitor the patient. 

 

Strong CYP3A4 inducers (e.g. rifampin) 

Use of tasimelteon should be avoided in combination with rifampin or other CYP3A4 inducers because of a 

potentially large decrease in tasimelteon exposure with reduced efficacy: the exposure of tasimelteon 

decreased by approximately 90% when co-administered with rifampin 600 mg (after 11 days of rifampin 

600 mg per day). 

 

Smoking (moderate CYP1A2 inducer) 

Tasimelteon exposure decreased by approximately 40% in smokers compared to non-smokers (see section 

5.2).    The patient should be instructed to cease or reduce smoking while taking tasimelteon. 

 

Beta blockers 

The efficacy of tasimelteon may be reduced in patients with concomitant administration of beta adrenergic 

receptor antagonists. Monitoring of efficacy is recommended where if efficacy is not achieved by a patient 

on beta blocker medication, the physician may consider whether a substitution of another non-beta-blocker 

medication for the beta blocker is warranted or discontinue the use of Hetlioz. 

 

Potential effect of alcohol on tasimelteon 

 

In a study of 28 healthy volunteers, a single dose of ethanol (0.6 g/kg for women and 0.7 g/kg for men) was 

co-administered with a 20 mg dose of tasimelteon. On some psychomotor test measures (intoxication, drunk, 

alertness/drowsiness, balance platform test), there was a trend towards greater effects of tasimelteon plus 

ethanol versus ethanol alone, but the effects were not deemed significant. 

 

4.6 Fertility, pregnancy and lactation 

 

Pregnancy 

 

There are no or limited amount of data from the use of tasimelteon in pregnant women. In animal studies, 

administration of tasimelteon during pregnancy resulted in developmental toxicity (embryofoetal mortality, 

neurobehavioural impairment, and decreased growth and development in offspring) at doses greater than 

those used clinically. As a precautionary measure, it is preferable to avoid the use of tasimelteon during 

pregnancy. 

 

Breast-feeding 

 

It is unknown whether tasimelteon/metabolites are excreted in human milk. A risk to the breast-fed child 

cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain 

from tasimelteon therapy taking into account the benefit of breast-feeding for the child and the benefit of 

therapy for the woman. 

 

Fertility 



 

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There are no data on the effects of tasimelteon on human fertility.  Reproductive and developmental toxicity 

studies showed that oestrous cycles were prolonged in rats treated with high doses of tasimelteon, with no 

effect on mating performance or male fertility, and only a marginal effect on female fertility.  

 

4.7 Effects on ability to drive and use machines 

 

Tasimelteon may cause somnolence, and therefore may have an influence on driving and using machines.  

After taking tasimelteon, patients should limit their activity to preparing to go to bed and not use machines 

because tasimelteon can impair performance of activities requiring complete mental alertness. 

 

 

4.8 Undesirable effects 

 

Summary of the safety profile 

 

The most common adverse reactions (>3%) during clinical trials were headache (10.4%), somnolence 

(8.6%), nausea (4.0%), and dizziness (3.1%).  The most frequently reported adverse reactions were mostly 

mild to moderate in severity and transient in nature. 

 

Adverse reactions leading to discontinuation occurred in 2.3% of tasimelteon-treated patients. The most 

frequent adverse reactions leading to discontinuation were: somnolence (0.23%), nightmare (0.23%), and 

headache (0.17%).  

 

Tabulated list of adverse reactions 

 

The following are adverse reactions that were reported in tasimelteon-treated adult patients, derived from 

patient trials in 1772 patients treated with tasimelteon.  The following terms and frequencies are applied and 

presented by MedDRA System Organ Class: Very common (≥1/10); Common (≥1/100 to <1/10); 

Uncommon (≥1/1,000 to <1/100); Rare (≥1/10,000 to <1/1,000); Very rare (<1/10,000).  Within each 

frequency grouping, adverse reactions are presented in order of decreasing seriousness. 

 

Table 1: Summary of Adverse Drug Reactions 

System Organ Class Very common Common Uncommon 

Psychiatric disorders  
Sleep disorder, insomnia, 

abnormal dreams 
Nightmare 

Nervous system 

disorders 
Headache Somnolence, dizziness Dysguesia 

Ear and labyrinth 

disorders 
  Tinnitus 

Gastrointestinal 

disorders 
 

Dyspepsia, nausea, dry 

mouth 
 

Renal and urinary 

disorders 
  Pollakiuria 

General disorders and 

administrative site 

conditions 

 Fatigue Foggy feeling in head 

Investigations  
Alanine aminotransferase 

increased 

Aspartate aminotransferase 

increased, gamma-glutamyl 

transferase increased 

 

 

Reporting of suspected adverse reactions 

 



 

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Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows 

continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked 

to report any suspected adverse reactions via the national reporting system listed in Appendix V. 

 

 

4.9 Overdose 

 

There is limited clinical experience with the effects of an overdose of tasimelteon.  

 

As with the management of any overdose, general symptomatic and supportive measures should be used, 

along with immediate gastric lavage, where appropriate. Intravenous fluids should be administered as 

needed. Respiration, pulse, blood pressure, and other appropriate vital signs should be monitored, and 

general supportive measures employed. 

 

While haemodialysis was effective at clearing tasimelteon and the majority of its major metabolites in 

patients with renal impairment, it is not known if hemodialysis will effectively reduce exposure in the case of 

overdose. 

 

 

5. PHARMACOLOGICAL PROPERTIES 

 

5.1  Pharmacodynamic properties 

 

Pharmacotherapeutic group: Psycholeptics, melatonin receptor agonists, ATC code: N05CH03 

 

Mechanism of action 

 

Tasimelteon is a circadian regulator that resets the master body clock in the suprachiasmatic nucleus (SCN).  

Tasimelteon acts as a Dual Melatonin Receptor Agonist (DMRA) with selective agonist activity at the MT1 

and MT2 receptors.  These receptors are thought to be involved in the control of circadian rhythms. 

 

The master body clock regulates the circadian rhythms of hormones including melatonin and cortisol and 

aligns/synchronises the physiological processes of the sleep-wake cycle and metabolic and cardiovascular 

homeostasis. 

 

Pharmacodynamic effects 

 

Tasimelteon functions as a DMRA at the MT1 and MT2 receptors.  Tasimelteon exhibits a greater affinity for 

the MT2 as compared to the MT1 receptor. The most abundant metabolites of tasimelteon have less than one-

tenth of the binding affinity of the parent molecule for both the MT1 and MT2 receptors. 

  

Tasimelteon and its most abundant metabolites have no appreciable affinity for more than 160 other 

pharmacologically relevant receptors. This includes the GABA receptor complex, the binding site for 

sedative hypnotics, and receptors that bind neuropeptides, cytokines, serotonin, noradrenaline, acetylcholine, 

and opiates.  

 

 

Clinical efficacy and safety 

The effectiveness of tasimelteon in the treatment of Non-24-Hour Sleep-Wake Disorder (Non-24) was 

established in two randomised, double-masked, placebo-controlled, multicentre, parallel-group studies (SET 

and RESET) in totally blind patients with Non-24. 

 

In SET, 84 patients with Non-24 (median age 54 years) were randomised to receive tasimelteon 20 mg or 

placebo, one hour prior to bedtime, at the same time every night for up to 6 months. 

 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


 

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RESET was a randomised withdrawal trial in 20 patients with Non-24 (median age 55 years) that was 

designed to evaluate the maintenance of efficacy of tasimelteon after 12-weeks. Patients were treated for 

approximately 12 weeks with tasimelteon 20 mg one hour prior to bedtime, at the same time every night. 

Patients in whom the calculated time of peak melatonin level (melatonin acrophase) occurred at 

approximately the same time of day (in contrast to the expected daily delay) during the run-in phase were 

randomised to receive placebo or continue daily treatment with tasimelteon 20 mg for 8 weeks. 

 

SET and RESET assessed entrainment of the master body clock as measured by aMT6s and cortisol.  Both 

studies demonstrated the ability of tasimelteon to entrain the master body clock in patients with Non-24 and 

RESET demonstrated that continued daily dosing of tasimelteon is necessary to maintain entrainment. 

 

 

Entrainment in Non-24-Hour Sleep-Wake Disorder 

 

In SET, tasimelteon entrained circadian rhythms at month 1 at a significantly higher rate than placebo as 

measured by aMT6s and cortisol (20% vs. 2.6 % and 17.5% vs 2.6% respectively). Analyses of entrainment 

at month 7 in a subset of patients demonstrated that 59% of tasimelteon-treated patients entrained by month 7 

indicating that response to treatment may take weeks or months for some patients to respond.  RESET 

demonstrated the maintenance of entrainment with tasimelteon treatment compared to placebo withdrawal 

(aMT6s: 90% vs. 20% and cortisol: 80% vs. 20%). 

 

 

Clinical Response in Non-24-Hour Sleep-Wake Disorder 

 

The effectiveness of tasimelteon in the treatment of clinical symptoms, including the circadian sleep-wake 

cycle and clinical global functioning in patients with Non-24 was established in SET and RESET (Table 3).  

A composite scale of 4 measures of duration and timing of nighttime and daytime sleep and global 

functioning was used to evaluate clinical response in SET.  Entrainment plus a score ≥3 on this scale, called 

Non-24 Clinical Response Scale (N24CRS) was required to be classified as a clinical responder.  The 

components of the scale can be found in Table 2. 

 

Table 2: Non-24 Scale of Clinical Response 

Assessment Threshold of Response 

Nighttime sleep on 25% most symptomatic nights 
>45 minutes increase in average nighttime sleep 

duration 

Daytime sleep on 25% most symptomatic days 
>45 minutes increase in average nighttime sleep 

duration 

Timing of sleep 
>30 minutes increase and a standard deviation <2 

hours during double-masked phase 

CGI-C 
<2.0 from the average of Day 112 and Day 183 

compared to baseline 

 

Clinical response in sleep-wake amount and timing measures 

 

SET and RESET evaluated the duration and timing of nighttime sleep and daytime naps via patient-recorded 

diaries. During SET, patient diaries were recorded for an average of 88 days during screening and 133 days 



 

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during randomisation.  During RESET, patient diaries were recorded for an average of 57 days during the 

run-in phase and 59 days during the randomised-withdrawal phase. 

 

Because symptoms of nighttime sleep disruption and daytime sleepiness are cyclical in patients with Non-24, 

with severity varying according to the state of alignment of the individual patient’s circadian rhythm with the 

24-hour day (least severe when fully aligned, most severe when 12 hours out of alignment), efficacy 

endpoints for nighttime total sleep time and daytime nap duration were based on the 25% of nights with the 

least nighttime sleep, and the 25% of days with the most daytime nap time. In SET, patients in the 

tasimelteon group had, at baseline, an average 195 minutes of nighttime sleep and 137 minutes of daytime 

nap time on the 25% of most symptomatic nights and days, respectively.  The average timing of sleep 

relative to an individual’s desired period for consolidated sleep over at least one circadian period was 

assessed.  Treatment with tasimelteon resulted in a significant improvement, compared with placebo, for all 

of these endpoints in SET and RESET (see Table 3). 

 

Table 3: Effects of Tasimelteon 20 mg Treatment on Clinical Response in Non-24 

 
Tasimelteon 20 mg Placebo 

% 

Difference 
p-value 

SET Study  

Clinical response (Entrainment + N24CRS 

≥3)(1) 
9/38 (23.7) 0/34 (0.0) 23.7 0.0028 

N24CRS ≥ 3(2) 11/38 (28.9) 1/34 (2.9) 26.0 0.0031 

N24CRS ≥ 2(2) 22/38 (57.9) 7/34 (20.6) 37.3 0.0014 

Nighttime sleep on 25% most symptomatic 

nights (minutes)(3) 
56.80 17.08 39.71 0.0055 

Daytime sleep time on 25% most 

symptomatic days (minutes)(3),(4) 
-46.48 -17.87 -28.61 0.0050 

> 45 min improvement in both nighttime 

and daytime sleep (%)(5) 
31.6 8.8 22.8 0.0177 

Timing of sleep (minutes)(1),(3) 35.00 14.48 20.52 0.0123 

RESET Study  

Nighttime sleep on 25% most symptomatic 

nights (minutes)(3) 
-6.74 -73.74 67.00 0.0233 

Daytime sleep time on 25% most 

symptomatic days (minutes)(3),(4) 
-9.31 49.95 -59.25 0.0266 

Timing of sleep (minutes)(1),(3) 19.99 -16.05 36.04 0.0108 
(1) Higher numbers indicates improvement 
(2) Sensitivity Analysis 
(3) P-value was based on analysis of covariance model, units are LS mean minutes 
(4) Lower numbers indicates improvement 
(5) Post-hoc analysis 

 

Response in Clinical Global Functioning Measures 

Patients treated with tasimelteon experienced an overall improvement in clinical global functioning (CGI-

C = 2.6) as compared to patients treated with placebo who showed no improvement status (CGI-C = 3.4) 

compared to the severity of Non-24 at baseline (LS mean difference = -0.8; p=0.0093) (Table 4). The 

effectiveness of tasimelteon to improve clinical global functioning was evaluated in SET.  The Clinical 

Global Impression of Change (CGI-C) is a reflection of the general social, occupational, and health 

functioning of the patient and is evaluated on a 7-point scale, centered at No Change (4), that investigators 



 

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used to rate the patients’ improvement from baseline in symptoms of global functioning. It was rated as:       

1 = very much improved; 2 = much improved; 3 = minimally improved; 4 = no change; 5 = minimally 

worse; 6 = much worse; or 7 = very much worse.  

 

 

Table 4: Clinical Global Functioning in Non-24 Patients 

 Tasimelteon 20 mg Placebo p-value 

CGI-C (LS mean) 2.6 3.4 0.0093 

 

 

See section 4.8 for safety information. 

 

Paediatric population 

 

The European Medicines Agency has deferred the obligation to submit the results of studies with HETLIOZ 

in one or more subsets of the paediatric population who are totally blind with Non-24. See section 4.2 for 

information on paediatric use. 

 

 

5.2 Pharmacokinetic properties 

 

The pharmacokinetics of tasimelteon is linear over doses ranging from 3 to 300 mg (0.15 to 15 times the 

recommended daily dosage). The pharmacokinetics of tasimelteon and its metabolites did not change with 

repeated daily dosing. 

 

Absorption 

 

The peak concentration (Tmax) of tasimelteon occurred approximately 0.5 hours after fasted oral 

administration. The mean absolute oral bioavailability of tasimelteon is 38%. 

 

When administered with a high-fat meal, the Cmax of tasimelteon was 44% lower than when administered in a 

fasted state, and the median Tmax was delayed by approximately 1.75 hours. Therefore, tasimelteon should be 

taken without food; if patients eat a high-fat meal, it is recommended to wait at least 2 hours before taking 

tasimelteon. 

 

Distribution 

 

The apparent oral volume of distribution at steady state of tasimelteon in young healthy subjects is 

approximately 59 - 126 L. At therapeutic concentrations, tasimelteon is about 88.6 – 90.1% bound to 

proteins. 

 

Biotransformation 

 

Tasimelteon is extensively metabolised. Metabolism of tasimelteon consists primarily of oxidation at 

multiple sites and oxidative dealkylation resulting in opening of the dihydrofuran ring followed by further 

oxidation to give a carboxylic acid. CYP1A2 (35.4%) and CYP3A4 (24.3%) are the major enzymes 

identified to play a role in the metabolism of tasimelteon.  CYP2C9 (18.8%) and CYP2C19 (15.1%) also 

contribute to the metabolism of tasimelteon. Tasimelteon clearance does not appear to be affected by 

polymorphisms in these enzymes. 

Phenolic glucuronidation is the major phase II metabolic route. 

 



 

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Major metabolites had 13-fold or less activity at melatonin receptors compared to tasimelteon. 

 

Elimination 

 

Following oral administration of radiolabeled tasimelteon, 80% of total radioactivity was excreted in urine 

and approximately 4% in faeces, resulting in a mean recovery of 84%. Less than 1% of the dose was 

excreted in urine as the parent compound. 

 

The observed mean elimination half-life for tasimelteon is 1.3 ± 0.4 hours. The mean terminal elimination 

half-life ± standard deviation of the main metabolites ranges from 1.3 ± 0.5 to 3.7 ± 2.2. 

 

Repeated once daily dosing with tasimelteon does not result in changes in pharmacokinetic parameters or 

significant accumulation of tasimelteon. 

 

Special populations 

 

Elderly 

In elderly subjects, tasimelteon exposure increased by approximately two-fold compared to non-elderly 

adults.  Due to the overall inter-subject variability of tasimelteon, this increase is not clinically meaningful 

and dose adjustment is not recommended. 

 

Gender 

The mean overall exposure of tasimelteon was approximately 1.6-fold greater in female than in male 

subjects.  Due to the overall inter-subject variability of tasimelteon, this increase is not clinically meaningful 

and dose adjustment is not recommended. 

 

Race 

Race does not affect apparent clearance of tasimelteon. 

 

Hepatic impairment 

The pharmacokinetic profile of a 20 mg dose of tasimelteon was compared among 8 subjects with mild 

hepatic impairment (Child-Pugh Score ≥5 and ≤6 points), 8 subjects with moderate hepatic impairment 

(Child-Pugh Score ≥7 and ≤9 points), and 13 healthy matched controls. Tasimelteon exposure was increased 

less than two-fold in subjects with moderate hepatic impairment. Therefore, no dose adjustment is needed in 

patients with mild or moderate hepatic impairment. Tasimelteon has not been studied in patients with severe 

hepatic impairment (Child-Pugh Class C); therefore caution is recommended when prescribing HETLIOZ to 

patients with severe hepatic impairment. 

 

Renal impairment 

The pharmacokinetic profile of a 20 mg dose of tasimelteon was compared among 8 subjects with severe 

renal impairment (estimated glomerular filtration rate [eGFR] ≤ 29 mL/min/1.73m2), 8 subjects with end-

stage renal disease (ESRD) (GFR < 15 mL/min/1.73m2) requiring hemodialysis, and 16 healthy matched 

controls. There was no apparent relationship between tasimelteon CL/F and renal function, as measured by 

either estimated creatinine clearance or eGFR. Subjects with severe renal impairment had a 30% lower CL/F 

clearance than match controls; however, when variability is taken into account, the different was not 

significant. No dose adjustment is necessary for patients with renal impairment. 

 

Smokers (smoking is a moderate CYP1A2 inducer) 

Tasimelteon exposure decreased by approximately 40% in smokers, compared to non-smokers (see section 

4.5).  The patient should be instructed to cease or reduce smoking while taking tasimelteon. 

 

5.3 Preclinical safety data 

 

Non-clinical data revealed no special hazard for humans based on conventional studies of safety 

pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction and 

development. 



 

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Effects in non-clinical studies were observed only at exposures considered sufficiently in excess of the 

maximum human exposure indicating little relevance to clinical use. 

 

Reproductive toxicology  

 

In pregnant rats administered tasimelteon during the period of organogenesis, there were no effects on 

embryofoetal development. In pregnant rabbits administered tasimelteon during the period of organogenesis, 

embryolethality and embryofoetal toxicity (reduced foetal body weight and delayed ossification) were 

observed at the highest dose tested (200 mg/kg/day).  

 

Oral administration of tasimelteon  to rats throughout organogenesis and lactation resulted in persistent 

reductions in body weight, delayed sexual maturation and physical development,  neurobehavioural 

impairment in offspring at the highest dose tested, andreduced body weight in offspring at the mid-dose 

tested. The no effect dose (50 mg/kg/day) is approximately 25 times the RHD on a mg/m2 basis. 

 

Carcinogenesis 

 

No evidence of carcinogenic potential was observed in mice; the highest dose tested is approximately 75 

times the RHD of 20 mg/day, on a mg/m2 basis. In rats, the incidence of liver tumours was increased in 

males (adenoma and carcinoma) and females (adenoma) at 100 and 250 mg/kg/day; the incidence of tumours 

of the uterus (endometrial adenocarcinoma) and uterus and cervix (squamous cell carcinoma) were increased 

at 250 mg/kg/day. There was no increase in tumours at the lowest dose tested in rats, which is approximately 

10 times the recommended human doseon a mg/m2 basis. 

 

 

6. PHARMACEUTICAL PARTICULARS 

 

6.1 List of excipients 

 

Hard capsule core 

 

Lactose anhydrous 

Microcrystalline cellulose  

Croscarmellose sodium 

Silica, colloidal anhydrous 

Magnesium stearate 

 

Hard capsule shell 

 

Gelatin  

Titanium dioxide  

Brilliant Blue FCF  

Erythrosine  

Orange Yellow S (E 110) 

 

White printing ink 

 

Shellac  

Propylene glycol  

Sodium hydroxide 

Povidone Titanium dioxide  

 

6.2 Incompatibilities 

 

Not applicable.  



 

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6.3 Shelf life 

 

3 years 

 

After first opening of the bottle: 30 days 

 

6.4 Special precautions for storage 

 

This medicinal product does not require any special temperature storage conditions.  

Store in the original container and keep the bottle tightly closed in order to protect from moisture and light.   

 

6.5 Nature and contents of container 

 

High density polyethylene (HDPE) bottle containing 30 hard capsules with polypropylene child-resistant 

closures containing polypropylene resin induction seals. Each bottle also contains a 1.5 g silica gel desiccant 

canister and polyester dunnage.   

Pack size: 30 hard capsules.. 

 

6.6 Special precautions for disposal 

 

Any unused medicinal product or waste material should be disposed of in accordance with local 

requirements.  

 

 

7. MARKETING AUTHORISATION HOLDER 

 

Vanda Pharmaceuticals Germany GmbH 

Französische Str. 12, c/o Satellite Office 

10117 Berlin 

Germany 

 

 

 

8. MARKETING AUTHORISATION NUMBER(S)  

 

EU/1/15/1008/001 

 

 

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 

 

Date of first authorisation: 3 July 2015 

Date of latest renewal:  

 

 

10. DATE OF REVISION OF THE TEXT 

 

 

Detailed information on this medicinal product is available on the website of the European Medicines 

Agency http://www.ema.europa.eu. 

 

http://www.ema.europa.eu/


 

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ANNEX II 

 

A. MANUFACTURER RESPONSBILE FOR BATCH RELEASE 

 

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 

 

C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION 

 

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 



 

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A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE  

 

Name and address of the manufacturer responsible for batch release 

 

Hälsa Pharma GmbH 

Hafenweg 18-20 

48155 Münster  

Germany 

 

B. CONDITIONS OR RESTRICTIONS 

 

Medicinal product subject to medical prescription 

 

 

C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION 

 

 

The requirements for submission of PSURs for this medicinal product are set out in the list of Union 

reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and any 

subsequent updates published on the European medicines web-portal . 

 

 

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE 

OF THE MEDICINAL PRODUCT 

 

 Risk Management Plan (RMP) 

 

The MAH shall perform the required pharmacovigilance activities and interventions detailed in the agreed 

RMP presented in Module 1.8.2 of the Marketing Authorisation and any agreed subsequent updates of the 

RMP. 

 

An updated RMP should be submitted: 

 At the request of the European Medicines Agency; 

 Whenever the risk management system is modified, especially as the result of new information being 

received that may lead to a significant change to the benefit/risk profile or as the result of an 

important (pharmacovigilance or risk minimisation) milestone being reached. 

 



 

15 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

ANNEX III 

 

LABELLING AND PACKAGE LEAFLET 



 

16 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

A. LABELLING 



 

17 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 

 

CARTON FOR 30-COUNT BOTTLE 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

HETLIOZ 20 mg hard capsules 

tasimelteon 

 

 

2. STATEMENT OF ACTIVE SUBSTANCE(S) 

 

Each hard capsule contains 20 mg of tasimelteon. 

 

 

3. LIST OF EXCIPIENTS 

 

Contains lactose and Orange Yellow S (E110). 

See leaflet for further information. 

 

 

4. PHARMACEUTICAL FORM AND CONTENTS 

 

Hard capsule  

 

30 hard capsules 

 

 

5. METHOD AND ROUTE(S) OF ADMINISTRATION 

 

Read the package leaflet before use. 

Oral use. 

 

 

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF 

THE SIGHT AND REACH OF CHILDREN 

 

Keep out of the sight and reach of children. 

 

 

7. OTHER SPECIAL WARNING(S), IF NECESSARY 

 

Do not swallow the desiccant.  

 

8. EXPIRY DATE 

 

EXP  

 

Use within 30 days after first opening. 

 

Open date:  

 

9. SPECIAL STORAGE CONDITIONS 

 



 

18 

Store in the original container and keep the bottle tightly closed in order to protect from moisture and light. 

 

 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR 

WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 

 

 

 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 

 

Vanda Pharmaceuticals Germany GmbH 

Französische Str. 12, c/o Satellite Office 

10117 Berlin 

Germany 
 

 

 

12. MARKETING AUTHORISATION NUMBER(S)  

 

EU/1/15/1008/001 

 

 

13. BATCH NUMBER 

 

Lot 

 

 

14. GENERAL CLASSIFICATION FOR SUPPLY 

 

 

 

15. INSTRUCTIONS ON USE 

 

 

 

16. INFORMATION IN BRAILLE 

 

HETLIOZ 

20 mg 

 
 

17. UNIQUE IDENTIFIER – 2D BARCODE 

 

2D barcode carrying the unique identifier included. 

 

18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 

 

PC  

SN  

NN 



 

19 

 

 

PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING 

 

LABEL FOR 30-COUNT BOTTLE 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

HETLIOZ 20 mg hard capsules 

tasimelteon 

 

 

2. STATEMENT OF ACTIVE SUBSTANCE(S) 

 

Each hard capsule contains 20 mg of tasimelteon. 

 

 

3. LIST OF EXCIPIENTS 

 

Contains lactose and Orange Yellow S (E110). 

See leaflet for further information. 

 

 

4. PHARMACEUTICAL FORM AND CONTENTS 

 

Hard capsule 

 

30 hard capsules 

 

 

5. METHOD AND ROUTE(S) OF ADMINISTRATION 

 

Read the package leaflet before use. 

Oral use. 

 

 

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF 

THE SIGHT AND REACH OF CHILDREN 

 

Keep out of the sight and reach of children. 

 

 

7. OTHER SPECIAL WARNING(S), IF NECESSARY 

 

 

8. EXPIRY DATE 

 

EXP  

 

 

9. SPECIAL STORAGE CONDITIONS 

 



 

20 

Store in the original container and keep the bottle tightly closed in order to protect from moisture and light. 

 

 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR 

WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 

 

 

 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 

 

 

 

12. MARKETING AUTHORISATION NUMBER(S)  

 

EU/1/15/1008/001 

 

13. BATCH NUMBER 

 

Lot 

 

 

14. GENERAL CLASSIFICATION FOR SUPPLY 

 

 

 

15. INSTRUCTIONS ON USE 

 

 

 

16. INFORMATION IN BRAILLE 

 

HETLIOZ  

20 mg 

 
 

17. UNIQUE IDENTIFIER – 2D BARCODE 

 

 

18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 

 

 

 

 

 

 

 

 

 

 



 

21 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

B. PACKAGE LEAFLET 



 

22 

Package leaflet: Information for the patient 
 

HETLIOZ 20 mg hard capsules 

tasimelteon 

 

 

Read all of this leaflet carefully before you start taking this medicine because it contains important 

information for you. 
- Keep this leaflet. You may need to read it again.  
- If you have any further questions, ask your doctor or pharmacist. 
- This medicine has been prescribed for you only. Do not pass it on to others.  It may harm them, even if 

their signs of illness are the same as yours. 

- If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects 

not listed in this leaflet.  See section 4. 

 

 

What is in this leaflet 
 

1. What HETLIOZ is and what it is used for  

2. What you need to know before you take HETLIOZ  

3. How to take HETLIOZ  

4. Possible side effects  

5. How to store HETLIOZ 

6. Contents of the pack and other information 

 

 

1. What HETLIOZ is and what it is used for 

 

HETLIOZ contains the active substance tasimelteon.  This type of medicine is called a “melatonin agonist” 

that acts as a regulator of daily body rhythms. 

 

It is used to treat Non-24-Hour Sleep-Wake Disorder (Non-24) in adults who are totally blind. 

 

How HETLIOZ works 

In sighted people, the change in light levels between day and night helps to synchronise internal body 

rhythms, including feeling sleepy at night and being active during the day. The body controls these rhythms 

through many pathways including increases and decreases in the production of the hormone melatonin.  

 

Patients with Non-24 who are totally blind cannot see light, so their body rhythms shift out of alignment with 

the 24-hour world, resulting in periods of feeling sleepy during the day and the inability to sleep at night. The 

active substance in HETLIOZ, tasimelteon, is able to act as a time-keeper for the body rhythms and resets 

them each day.  It aligns body rhythms with the usual 24-hour day and night cycle and so improve sleep 

patterns. Because of individual differences in each person’s body rhythms, it could take weeks or up to 3 

months for an improvement in symptoms to be noticed.  

 

 

2. What you need to know before you take HETLIOZ  
 

Do not take HETLIOZ if 
You are allergic to tasimelteon or any of the other ingredients of this medicine (listed in section 6). 

  

Warnings and precautions 

After taking HETLIOZ, you should get ready to go to bed and only carry out activities that you would 

normally do before going to bed. 

 

 

Children and adolescents 



 

23 

Do not give HETLIOZ to children under the age of 18 years.  This is because HETLIOZ has not been tested 

in people under 18 years of age and the effects are unknown.  

 

Other medicines and HETLIOZ 
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines.  This 

includes:  

- medicines known to reduce the activity of an enzyme called ‘CYP1A2’.  An example is 
fluvoxamine, which is used to treat depression and obsessive compulsive disorder (OCD).   

- medicines known to reduce the activity of an enzyme called ‘CYP3A4’.  An example is 
ketoconazole, which is used to treat fungal infections. 

- medicines known to increase the activity of an enzyme called ‘CYP3A4’.  An example is rifampicin, 
which is used to treat tuberculosis (TB). 

- medicines known to reduce the activity of an enzyme called ‘CYP2C19’.  An example is 
omeprazole, which is used to treat hearburn and gastroesophageal reflux disease (GERD). 

- medicines called “beta blockers” used to treat high blood pressure and other heart problems.  Some 
examples include atenolol, metoprolol, and propanolol. 

 

If any of the above applies to you (or you are not sure), talk to your doctor or pharmacist before taking 

HETLIOZ. 

 

Pregnancy and breast-feeding 

If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your 

doctor or pharmacist for advice before taking this medicine.  As a precautionary measure, it is preferable to 

avoid the use of tasimelteon during pregnancy.  If you become pregnant while taking HETLIOZ, consult 

your doctor immediately as it is recommended not to take HETLIOZ while you are pregnant or breast 

feeding. 

 

HETLIOZ contains lactose 

If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before 

taking this medicine. 

 

HETLIOZ contains Orange Yellow S (E110) 

Tell your doctor if you have an allergy to Orange Yellow S (E110).  HETLIOZ contains Orange Yellow S 

(E110) which may cause allergic reactions. 

 

HETLIOZ contains sodium  

This medicinal product contains less than 1 mmol sodium (23 mg) per capsule, that is to say essentially 

‘sodium-free’. 

 

 

 

3. How to take HETLIOZ 

 

Always take this medicine exactly as your doctor or pharmacist has told you.  Check with your doctor or 

pharmacist if you are not sure. 

 

How much to take 

The recommended dose is one capsule every night, taken one hour before you go to bed. Try to take the 

medicine at the same time every night.  Because of individual differences in each person’s body rhythms, it 

could take weeks or months for you to notice an improvement in your symptoms.  Therefore, your doctor 

may ask you to take HETLIOZ for up to 3 months before checking if it is working for you. 

 

Taking HETLIOZ 

- Take the medicine by mouth. 
- Swallow the capsule whole.  



 

24 

- It is best to take HETLIOZ on an empty stomach as food can reduce the amount of the medicine that 
is absorbed into your body.  If you eat a high-fat meal close to the time you would normally take the 

medicine, it is best to wait 2 hours before taking HETLIOZ.  

- To open the bottle, push the cap down and turn counter-clockwise. 
 

If you take more HETLIOZ than you should 

If you accidentally take more HETLIOZ than your doctor recommended, contact your doctor at once or 

contact the nearest hospital for advice. Keep the bottle with you so that you can easily describe what you 

have taken. 

 

If you forget to take HETLIOZ 
- Skip the missed dose.  Take your next dose at the usual time the next day. Do not take a double dose. 

  

If you stop taking HETLIOZ 

Do not stop taking HETLIOZ without talking to your doctor. 

- If HETLIOZ is not taken every night, the body rhythms will lose alignment with the usual 24-hour 
day and night cycle again.  This means that  symptoms will come back. 

 

If you have any further questions on the use of this medicine, ask your doctor or pharmacist. 

 

4. Possible side effects 
 

Like all medicines, this medicine can cause side effects, although not everybody gets them. The following 

side effects may happen with this medicine. 

 

Very common: may affect more than 1 in 10 people 

- headache 

 

Common: may affect up to 1 in 10 people 

- change in sleeping pattern 
- difficulty in sleeping 
- dizziness 
- dry mouth 
- tiredness 
- indigestion 
- feeling sick in the stomach 
- blood tests which show changes in the way the liver is working (alanine aminotransferase) 
- unusual dreams 
- sleepiness 

 

Uncommon: may affect up to 1 in 100 people 

- abnormal or change in taste 

- blood tests which show changes in the way the liver is working (aspartate aminotransferase and 

gamma-glutamyl transferase) 

- increase in daytime urination 

- nightmares 

- ringing in the ears 

- feeling foggy in the head 

 

Reporting of side effects 

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed 

in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix 

V. By reporting side effects, you can help provide more information on the safety of this medicine. 

 

 

5. How to store HETLIOZ 

 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc
http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


 

25 

- Keep this medicine out of the sight and reach of children. 
- Do not use this medicine after the expiry date which is stated on the bottle and the carton after EXP. 

The expiry date refers to the last day of that month. 

- This medicine does not require any special temperature storage conditions.  
- Store in the original container and keep the bottle tightly closed in order to protect from moisture and 

light. 

- Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 
throw away medicines you no longer use. These measures will help protect the environment. 

 

 

6. Contents of the pack and other information 

 

What HETLIOZ contains  

- The active substance is tasimelteon.  Each hard capsule contains 20 mg of tasimelteon. 
- The other ingredients are lactose anhydrous, microcrystalline cellulose, croscarmellose sodium, silica, 

colloidal anhydrous, and magnesium stearate.   

- The hard capsule shell consists of gelatin, titanium dioxide , Brilliant Blue FCF , Erythrosine , and 
Orange Yellow S (E 110).  

- The white printing ink contains shellac, propylene glycol, sodium hydroxide, povidone  and titanium 
dioxide. 

 

What HETLIOZ looks like and contents of the pack 

HETLIOZ hard capsules are opaque dark blue printed with “VANDA 20 mg” in white.  Each bottle has a 

child-resistant cap and contains 30 hard capsules.  

 

Marketing Authorisation Holder 

Vanda Pharmaceuticals Germany GmbH 

Französische Str. 12, c/o Satellite Office 

10117 Berlin 

Germany 

 

Manufacturer 

Hälsa Pharma GmbH 

Hafenweg 18-20 

48155 Münster  

Germany 

 

 

For any information about this medicine, please contact the local representative of the Marketing 

Authorisation Holder: 

 

België/Belgique/Belgien 
Vanda Pharmaceuticals Germany GmbH 

Tél/Tel: +49 (0)89 3803772-0 

Lietuva 
Vanda Pharmaceuticals Germany GmbH 

Tel. +49 (0)89 3803772-0 

 

България 

Vanda Pharmaceuticals Germany GmbH 

Teл: +49 (0)89 3803772-0 

 

Luxembourg/Luxemburg 
Vanda Pharmaceuticals Germany GmbH 

Tél/Tel: +49 (0)89 3803772-0 

Česká republika 
Vanda Pharmaceuticals Germany GmbH 

Tel: +49 (0)89 3803772-0 

Magyarország 

Vanda Pharmaceuticals Germany GmbH 

Tel.: +49 (0)89 3803772-0 

Danmark 
Vanda Pharmaceuticals Germany GmbH 

Tlf: +49 (0)89 3803772-0 

Malta 

Vanda Pharmaceuticals Germany GmbH 

Tel: +49 (0)89 3803772-0 

 



 

26 

Deutschland 
Vanda Pharmaceuticals Germany GmbH 

Tel: +49 (0)89 3803772-0 

 

Nederland 
Vanda Pharmaceuticals Germany GmbH 

Tel: +49 (0)89 3803772-0 

Eesti 

Vanda Pharmaceuticals Germany GmbH 

Tel: +49 (0)89 3803772-0 

Norge 
Vanda Pharmaceuticals Germany GmbH 

Tlf: +49 (0)89 3803772-0 

 

Ελλάδα 
Vanda Pharmaceuticals Germany GmbH 

T: +49 (0)89 3803772-0 

Österreich 
Vanda Pharmaceuticals Germany GmbH 

Tel: +49 (0)89 3803772-0 

 

España 

Vanda Pharmaceuticals Germany GmbH 

Tel: +49 (0)89 3803772-0 

Polska 

Vanda Pharmaceuticals Germany GmbH 

Tel.: +49 (0)89 3803772-0 

 

France 

Vanda Pharmaceuticals Germany GmbH 

Tél: +49 (0)89 3803772-0 

Portugal 
Vanda Pharmaceuticals Germany GmbH 

Tel: +49 (0)89 3803772-0 

 

Hrvatska 
Vanda Pharmaceuticals Germany GmbH 

Tel: +49 (0)89 3803772-0 

 

România 

Vanda Pharmaceuticals Germany GmbH 

Tel: +49 (0)89 3803772-0 

 

Ireland 
Vanda Pharmaceuticals Germany GmbH 

Tel: +49 (0)89 3803772-0 

 

Slovenija 
Vanda Pharmaceuticals Germany GmbH 

Tel: +49 (0)89 3803772-0 

 

Ísland 

Vanda Pharmaceuticals Germany GmbH 

Sími: +49 (0)89 3803772-0 

Slovenská republika 

Vanda Pharmaceuticals Germany GmbH 

Tel: +49 (0)89 3803772-0 

 

Italia 
Vanda Pharmaceuticals Germany GmbH 

Tel: +49 (0)89 3803772-0 

Suomi/Finland 
Vanda Pharmaceuticals Germany GmbH 

Puh/Tel: +49 (0)89 3803772-0 

 

Κύπρος 

Vanda Pharmaceuticals Germany GmbH 

T: +49 (0)89 3803772-0 

Sverige 

Vanda Pharmaceuticals Germany GmbH 

Tel: +49 (0)89 3803772-0 

 

Latvija 

Vanda Pharmaceuticals Germany GmbH 

+49 (0)89 3803772-0 

United Kingdom 

Vanda Pharmaceuticals Germany GmbH 

Tel: +49 (0)89 3803772-0 

 

 

This leaflet was last revised in  
 

 

Other sources of information 

 

Detailed information on this medicine is available on the European Medicines Agency web site: 

http://www.ema.europa.eu.  

 

http://www.ema.europa.eu/

	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET