INDICATIONS
HETLIOZ IS INDICATED FOR THE TREATMENT OF NON-24-HOUR SLEEP-WAKE DISORDER (NON-24).
HOW SUPPLIED
DOSAGE FORMS AND STRENGTHS
CAPSULES: 20 MG SIZE 1 DARK BLUE OPAQUE, HARD GELATIN CAPSULES PRINTED WITH "VANDA 20 MG" IN WHITE.
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.
DISTRIBUTED BY: VANDA PHARMACEUTICALS INC. WASHINGTON, D.C. 20037 USA WWW.HETLIOZ.COM. REVISED: DEC 2014
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] .
SIDE EFFECTS
CLINICAL 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.
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 %
*ADVERSE REACTIONS WITH AN INCIDENCE > 5% AND AT LEAST TWICE AS HIGH ON HETLIOZ THAN ON PLACEBO ARE DISPLAYED.
READ THE HETLIOZ (TASIMELTEON CAPSULES) SIDE EFFECTS CENTER FOR A COMPLETE GUIDE TO POSSIBLE SIDE EFFECTS
OVERDOSE
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.
CLINICAL PHARMACOLOGY
MECHANISM OF ACTION
THE PRECISE MECHANISM BY WHICH TASIMELTEON EXERTS ITS THERAPEUTIC EFFECT IN PATIENTS WITH NON24 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] .
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] .
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].
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] .
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.
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
CHANGE FROM BASELINE STUDY 1 STUDY 2
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.