Hetlioz
Generic
Name: tasimelteon
Dosage Form: capsule
1. INDICATIONS AND USAGE
Hetlioz is indicated for the
treatment of Non-24-Hour Sleep-Wake Disorder (Non-24).
2. DOSAGE AND ADMINISTRATION
The recommended dosage of
Hetlioz is 20 mg per day taken before bedtime, at the same time every night.
Because of individual
differences in circadian rhythms, drug effect may not occur for weeks or
months.
Hetlioz should be taken
without food [see Clinical Pharmacology (12.3)].
3. DOSAGE FORMS AND STRENGTHS
Capsules: 20 mg size 1 dark
blue opaque, hard gelatin capsules printed with “VANDA 20 mg” in white.
4. CONTRAINDICATIONS
None.
5. WARNINGS AND PRECAUTIONSSomnolence
After taking Hetlioz, patients
should limit their activity to preparing for going to bed. Hetlioz can
potentially impair the performance of activities requiring complete mental
alertness.
6. ADVERSE REACTIONSClinical
Trials Experience
Because clinical trials are
conducted under widely varying conditions, adverse reaction rates observed in
the clinical trials of a drug cannot be directly compared to rates in the
clinical trials of another drug and may not reflect the rates observed in
clinical practice.
A total of 1346 subjects were
treated with at least one dose of Hetlioz, of which 139 were treated for >
26 weeks and 93 were treated for > 1 year.
A 26-week, parallel-arm
placebo-controlled study (Study 1) evaluated Hetlioz (n=42) compared to placebo
(n=42) in patients with Non-24. A randomized-withdrawal, placebo- controlled study
of 8 weeks duration (Study 2) also evaluated Hetlioz (n=10), compared to
placebo (n=10), in patients with Non-24.
In placebo-controlled studies,
6% of patients exposed to Hetlioz discontinued treatment due to an adverse
event, compared with 4% of patients who received placebo.
Table 1 shows the incidence of adverse reactions from Study 1.
|
*Adverse reactions with an incidence > 5% and at
least twice as high on Hetlioz than on placebo are displayed.
|
|
Table 1: Adverse Reactions in Study 1
|
|
|
Hetlioz
N=42
|
Placebo
N=42
|
|
Headache
|
17 %
|
7 %
|
|
Alanine
aminotransferase increased
|
10 %
|
5 %
|
|
Nightmare/abnormal
dreams
|
10 %
|
0 %
|
|
Upper
respiratory tract infection
|
7 %
|
0 %
|
|
Urinary tract
infection
|
7 %
|
2 %
|
7. DRUG INTERACTIONSStrong CYP1A2
Inhibitors (e.g., fluvoxamine)
Avoid use of Hetlioz in
combination with fluvoxamine or other strong CYP1A2 inhibitors because of a
potentially large increase in tasimelteon exposure and greater risk of adverse
reactions [see Clinical Pharmacology (12.3)].
Strong CYP3A4
Inducers (e.g., rifampin)
Avoid use of Hetlioz in
combination with rifampin or other CYP3A4 inducers because of a potentially
large decrease in tasimelteon exposure with reduced efficacy [see Clinical Pharmacology (12.3)].
8. USE IN SPECIFIC POPULATIONSPregnancy
Pregnancy Category C
There are no adequate and
well-controlled studies of Hetlioz in pregnant women. In animal studies,
administration of tasimelteon during pregnancy resulted in developmental
toxicity (embryofetal mortality, neurobehavioral impairment, and decreased
growth and development in offspring) at doses greater than those used
clinically. Hetlioz should be used during pregnancy only if the potential
benefit justifies the potential risks.
In pregnant rats administered
tasimelteon at oral doses of 5, 50, or 500 mg/kg/day during the period of
organogenesis, there were no effects on embryofetal development. The highest
dose tested is approximately 240 times the recommended human dose (RHD) of 20
mg/day, on a mg/m2 basis.
In pregnant rabbits
administered tasimelteon at oral doses of 5, 30, or 200 mg/kg/day during the
period of organogenesis, embryolethality and embryofetal toxicity (reduced
fetal body weight and delayed ossification) were observed at the highest dose
tested. The highest dose not associated with adverse effects (30 mg/kg/day) is
approximately 30 times the RHD on a mg/m2 basis.
Oral administration of
tasimelteon (50, 150, or 450 mg/kg/day) to rats throughout organogenesis and
lactation resulted in persistent reductions in body weight, delayed sexual
maturation and physical development, and neurobehavioral impairment in
offspring at the highest dose tested. Reduced body weight in offspring was also
observed at the mid-dose. The no effect dose (50 mg/kg/day) is approximately 25
times the RHD on a mg/m2 basis.
Nursing
Mothers
It is not known whether this
drug is excreted in human milk. Because many drugs are excreted in human milk,
caution should be exercised when Hetlioz is administered to a nursing woman.
Pediatric Use
Safety and effectiveness in
pediatric patients have not been established.
Geriatric Use
The risk of adverse reactions
may be greater in elderly (>65 years) patients than younger patients because
exposure to tasimelteon is increased by approximately 2-fold compared with
younger patients.
Hepatic
Impairment
Dose adjustment is not
necessary in patients with mild or moderate hepatic impairment. Hetlioz has not
been studied in patients with severe hepatic impairment (Child-Pugh Class C).
Therefore, Hetlioz is not recommended for use in patients with severe hepatic
impairment [see Clinical Pharmacology (12.3)].
Smokers
Smoking causes induction of
CYP1A2 levels. The exposure of tasimelteon in smokers was lower than in non-smokers
and therefore the efficacy of Hetlioz may be reduced in smokers [see Clinical pharmacology (12.3)].
9. DRUG ABUSE AND DEPENDENCEControlled
Substance
Tasimelteon is not a controlled
substance under the Controlled Substances Act.
Abuse
Tasimelteon did not produce
any abuse-related signals in animal behavioral studies. Rats did not
self-administer tasimelteon, suggesting that the drug does not have rewarding
properties. There were also no signs or symptoms indicative of abuse potential
in clinical studies with Hetlioz.
Dependence
Discontinuation of Hetlioz in
humans following chronic administration did not produce withdrawal signs.
Hetlioz does not appear to produce physical dependence.
10. OVERDOSAGE
There is limited premarketing
clinical experience with the effects of an overdosage of Hetlioz.
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 hemodialysis was
effective at clearing Hetlioz 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.
As with the management of any
overdose, the possibility of multiple drug ingestion should be considered.
Contact a poison control center for current information on the management of
overdose.
11. DESCRIPTION
Hetlioz (tasimelteon) is a
melatonin receptor agonist, chemically designated as (1R,
2R)-N-[2-(2,3-dihydrobenzofuran-4-yl)cyclopropylmethyl]propanamide,
containing two chiral centers. The molecular formula is C15H19NO2, and the molecular weight is
245.32. The structural formula is:
Tasimelteon is a white to
off-white crystalline powder. It is very slightly soluble in cyclohexane,
slightly soluble in water and 0.1 N hydrochloric acid, and freely soluble or
very soluble in methanol, 95% ethanol, acetonitrile, isopropanol, polyethylene
glycol 300, propylene glycol and ethyl acetate.
Hetlioz is available in 20 mg
strength capsules for oral administration. Inactive ingredients are: lactose
anhydrous, microcrystalline cellulose, croscarmellose sodium, colloidal silicon
dioxide, and magnesium stearate. Each hard gelatin capsule consists of gelatin,
titanium dioxide, FD&C Blue #1, FD&C Red #3, and FD&C Yellow #6.
12. CLINICAL PHARMACOLOGYMechanism of
Action
The precise mechanism by which
tasimelteon exerts its therapeutic effect in patients with Non-24 is not known.
Tasimelteon is an agonist at melatonin MT1 and MT2 receptors. These
receptors are thought to be involved in the control of circadian rhythms.
Pharmacodynamics
Hetlioz is an agonist at MT1 and MT2 receptors. Hetlioz
exhibits a greater affinity for the MT2 as compared to the MT1 receptor. The most
abundant metabolites of Hetlioz have less than one-tenth of the binding
affinity of the parent molecule for both the MT1 and MT2 receptors.
Pharmacokinetics
The pharmacokinetics of
Hetlioz is linear over doses ranging from 3 to 300 mg (0.15 to 15 times the
recommended daily dosage). The pharmacokinetics of Hetlioz and its metabolites
did not change with repeated daily dosing.
Absorption
The absolute oral
bioavailability is 38.3%. The peak concentration (Tmax) of tasimelteon occurred
approximately 0.5 to 3 hours after fasted oral administration.
When administered with a
high-fat meal, the Cmax of tasimelteon was 44% lower than when given in a fasted
state, and the median Tmax was delayed by approximately 1.75 hours. Therefore,
Hetlioz should be taken without food.
Distribution
The apparent oral volume of
distribution of tasimelteon at steady state in young healthy subjects is
approximately 59 - 126 L. At therapeutic concentrations, tasimelteon is about
90% bound to proteins.
Metabolism
Tasimelteon is extensively
metabolized. 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 and CYP3A4 are the major isozymes involved in the metabolism of
tasimelteon.
Phenolic glucuronidation is
the major phase II metabolic route.
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 feces, 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 Hetlioz does not result in changes in pharmacokinetic parameters or
significant accumulation of tasimelteon.
Studies
in Specific Populations
Elderly
In elderly subjects, tasimelteon exposure increased by approximately two-fold
compared with non-elderly adults.
Gender
The mean overall exposure of tasimelteon was approximately 20-30% greater in
female than in male subjects.
Race
The effect of race on exposure of Hetlioz was not evaluated.
Hepatic
Impairment
The pharmacokinetic profile of a 20 mg dose of Hetlioz was compared among eight
subjects with mild hepatic impairment (Child-Pugh Score ≥5 and ≤6 points),
eight 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.
Hetlioz has not been studied in patients with severe hepatic impairment
(Child-Pugh Class C) and is not recommended in these patients.
Renal
Impairment
The pharmacokinetic profile of a 20 mg dose of Hetlioz was compared among eight
subjects with severe renal impairment (estimated glomerular filtration rate
[eGFR] ≤ 29 mL/min/1.73m2), eight subjects with end-stage renal disease (ESRD) (GFR <
15 mL/min/1.73m2) requiring hemodialysis, and sixteen 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 clearance, and clearance in subjects
with ESRD was comparable to that of healthy subjects. 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 Use in Specific Populations (8.7)].
Drug Interaction Studies
No potential drug interactions
were identified in in vitro studies
with CYP inducers or inhibitors of CYP1A1, CYP1A2, CYP2B6, CYP2C9/2C19, CYP2E1,
CYP2D6 and transporters including P-glycoprotein, OATP1B1, OATP1B3, OCT2, OAT1
and OAT3.
Effect
of Other Drugs on Hetlioz
Drugs that inhibit CYP1A2 and
CYP3A4 are expected to alter the metabolism of tasimelteon.
Fluvoxamine
(strong CYP1A2 inhibitor): 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) [see
Drug Interactions (7.1)].
Ketoconazole
(strong CYP3A4 inhibitor): tasimelteon
exposure increased by approximately 50% when co-administered with ketoconazole
400 mg (after 5 days of ketoconazole 400 mg per day) [see
Drug Interactions (7.2)].
Rifampin
(strong CYP3A4 and moderate CYP2C19 inducer): the exposure of tasimelteon decreased by approximately 90%
when co-administered with rifampin 600 mg (after 11 days of rifampin 600 mg per
day). Efficacy may be reduced when Hetlioz is used in combination with strong
CYP3A4 inducers, such as rifampin [see Drug Interactions
(7.2)].
Effect of Hetlioz on Other Drugs
Midazolam
(CYP3A4 substrate): Administration of
Hetlioz 20 mg once a day for 14 days did not produce any significant changes in
the Tmax, Cmax, or AUC of midazolam or 1-OH midazolam. This indicates there is
no induction of CYP3A4 by tasimelteon at this dose.
Rosiglitazone
(CYP2C8 substrate): Administration of
Hetlioz 20 mg once a day for 16 days did not produce any clinically significant
changes in the Tmax, Cmax, or AUC of rosiglitazone after oral administration of 4 mg.
This indicates that there is no induction of CYP2C8 by tasimelteon at this
dose.
Effect of Alcohol on Hetlioz
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 Hetlioz. There was a trend for an
additive effect of Hetlioz and ethanol on some psychomotor tests.
13. NONCLINICAL
TOXICOLOGYCarcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis
Tasimelteon
was administered orally for up to two years to mice (30, 100, and 300
mg/kg/day) and rats (20, 100, and 250 mg/kg/day). No evidence of carcinogenic
potential was observed in mice; the highest dose tested is approximately 75
times the recommended human dose (RHD) of 20 mg/day, on a mg/m2 basis. In rats, the
incidence of liver tumors was increased in males (adenoma and carcinoma) and
females (adenoma) at 100 and 250 mg/kg/day; the incidence of tumors of the
uterus (endometrial adenocarcinoma) and uterus and cervix (squamous cell
carcinoma) were increased at 250 mg/kg/day. There was no increase in tumors at
the lowest dose tested in rats, which is approximately 10 times the RHD on a
mg/m2 basis.
Mutagenesis
Tasimelteon
was negative in an in vitro bacterial
reverse mutation (Ames) assay, an in vitro cytogenetics
assay in primary human lymphocytes, and an in vivo micronucleus
assay in rats.
Impairment of 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 RHD on a mg/m2 basis.
14. CLINICAL STUDIES
The
effectiveness of Hetlioz in the treatment of Non-24-Hour Sleep-Wake Disorder
(Non-24) was established in two randomized double-masked, placebo-controlled,
multicenter, parallel-group studies (Studies 1 and 2) in totally blind patients
with Non-24.
In
study 1, 84 patients with Non-24 (median age 54 years) were randomized to
receive Hetlioz 20 mg or placebo, one hour prior to bedtime, at the same time
every night for up to 6 months.
Study
2 was a randomized withdrawal trial in 20 patients with Non-24 (median age 55
years) that was designed to evaluate the maintenance of efficacy of Hetlioz
after 12-weeks. Patients were treated for approximately 12 weeks with Hetlioz
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 randomized to receive placebo or continue
treatment with Hetlioz 20 mg for 8 weeks.
Study
1 and Study 2 evaluated the duration and timing of nighttime sleep and daytime
naps via patient-recorded diaries. During Study 1, patient diaries were
recorded for an average of 88 days during screening, and 133 days during
randomization. During Study 2, patient diaries were recorded for an average of
57 days during the run-in phase, and 59 days during the randomized-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 Study 1, patients in the Hetlioz 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. Treatment with
Hetlioz resulted in a significant improvement, compared with placebo, for both
of these endpoints in Study 1 and Study 2 (see Table 2).
|
Table 2: Effects of Hetlioz 20 MG on Nighttime Sleep Time and Daytime
Nap Time in Study 1 and Study 2
|
|
|
Study 1
|
Study 2
|
|
Change from
Baseline
|
Hetlioz
20 MG
N=42
|
Placebo
N=42
|
Hetlioz
20 MG
N=10
|
Placebo
N=10
|
|
Nighttime sleep
time on
25% most symptomatic
nights (minutes)
|
50
|
22
|
-7
|
-74
|
|
Daytime nap time
on
25% most symptomatic
days (minutes)
|
-49
|
-22
|
-9
|
50
|
A responder analysis of
patients with both ≥ 45 minutes increase in nighttime sleep and ≥ 45 minutes
decrease in daytime nap time was conducted in Study 1: 29% (n=12) of patients
treated with Hetlioz, compared with 12% (n=5) of patients treated with placebo
met the responder criteria.
The efficacy of Hetlioz in
treating Non-24 may be reduced in subjects with concomitant administration of
beta adrenergic receptor antagonists.
16. HOW SUPPLIED/STORAGE AND HANDLING
Hetlioz 20 mg capsules are
available as size 1, dark blue opaque, hard gelatin capsules printed with
“VANDA 20 mg” in white, containing 20 mg of tasimelteon per capsule.
·
NDC
43068-220-01 Bottles of
30
Storage
Store Hetlioz 20 mg capsules at controlled room temperature, 25°C (77°F);
excursions permitted to 15°C to 30°C (59°F to 86°F) [See USP Controlled Room
Temperature]. Protect Hetlioz 20 mg capsules from exposure to light and
moisture.
17. PATIENT COUNSELING
INFORMATION
Advise
patients
·
To take Hetlioz before bedtime
at the same time every night.
·
To skip the dose that night if
they cannot take Hetlioz at approximately the same time on a given night.
·
To limit their activities to
preparing for going to bed after taking Hetlioz because Hetlioz can potentially
impair the performance of activities requiring complete mental alertness.
·
That because of individual
differences in circadian rhythms, daily use for several weeks or months may be
necessary before benefit from Hetlioz is observed.
·
To swallow the capsule whole.
Distributed
by:
Vanda Pharmaceuticals Inc.
Washington, D.C. 20037 USA
www.Hetlioz.com
Vanda
and Hetlioz are registered trademarks of Vanda Pharmaceuticals Inc. in the
United States and other countries.
PRINCIPAL DISPLAY PANEL - NDC 43068-220-01
20 mg
Bottle - Composite
PRINCIPAL DISPLAY PANEL - NDC 43068-220-01
20 mg
Bottle - Braille
PRINCIPAL DISPLAY PANEL - NDC 43068-220-01
20 mg
Bottle - Artwork
|
Hetlioz tasimelteon capsule
|
|
Product
Information
|
|
Product Type
|
HUMAN
PRESCRIPTION DRUG LABEL
|
Item Code
(Source)
|
NDC:43068-220
|
|
Route of
Administration
|
ORAL
|
DEA Schedule
|
|
|
|
Active
Ingredient/Active Moiety
|
|
Ingredient
Name
|
Basis of
Strength
|
Strength
|
|
TASIMELTEON (TASIMELTEON)
|
TASIMELTEON
|
20 mg
|
|
|
Inactive
Ingredients
|
|
Ingredient
Name
|
Strength
|
|
ANHYDROUS LACTOSE
|
183.25 mg
|
|
CELLULOSE, MICROCRYSTALLINE
|
75 mg
|
|
CROSCARMELLOSE SODIUM
|
15 mg
|
|
COLLOIDAL SILICON DIOXIDE
|
6 mg
|
|
MAGNESIUM STEARATE
|
0.75 mg
|
|
FD&C BLUE NO. 1
|
0.92 mg
|
|
FD&C RED NO. 3
|
0.03 mg
|
|
FD&C YELLOW NO. 6
|
0.03 mg
|
|
TITANIUM DIOXIDE
|
0.30 mg
|
|
GELATIN
|
74.71 mg
|
|
|
Product
Characteristics
|
|
Color
|
BLUE (DARK
BLUE)
|
Score
|
no score
|
|
Shape
|
CAPSULE
|
Size
|
19mm
|
|
Flavor
|
|
Imprint Code
|
VANDA;20;mg
|
|
Contains
|
|
|
|
|
|
Packaging
|
|
#
|
Item Code
|
Package
Description
|
|
|
1
|
NDC:43068-220-01
|
30 CAPSULE in 1
BOTTLE
|
|
|
|
|
|
Marketing Information
|
|
Marketing
Category
|
Application
Number or Monograph Citation
|
Marketing
Start Date
|
Marketing
End Date
|
|
NDA
|
NDA205677
|
04/04/2014
|
|
|
|
Labeler - Vanda Pharmaceuticals Inc. (133501556)
|
|
|
Establishment
|
|
Name
|
Address
|
ID/FEI
|
Operations
|
|
Patheon Inc.
|
|
005286822
|
ANALYSIS(43068-220),
MANUFACTURE(43068-220), PACK(43068-220)
|
|
Establishment
|
|
Name
|
Address
|
ID/FEI
|
Operations
|
|
Formosa
Laboratories, Inc.
|
|
657846858
|
ANALYSIS(43068-220),
API MANUFACTURE(43068-220)
|
|
|
|
|
|
|
|
|
Establishment
|
|
Name
|
Address
|
ID/FEI
|
Operations
|
|
PPD Development
|
|
838082055
|
ANALYSIS(43068-220)
|
|
Establishment
|
|
Name
|
Address
|
ID/FEI
|
Operations
|
|
SAI Life
Sciences Ltd.
|
|
675977617
|
ANALYSIS(43068-220)
|
|
|
|
|
|
|
|
Revised: 12/2014
Vanda Pharmaceuticals Inc.
