Eszopiclone 2 MG Oral Tablet [Lunesta]
WARNINGS
: Because sleep disturbances may be the presenting manifestation of a physical and/or psychiatric disorder, symptomatic treatment of insomnia should be initiated only after a careful evaluation of the patient.
The failure of insomnia to remit after 7 to 10 days of treatment may indicate the presence of a primary psychiatric and/or medical illness that should be evaluated.
Worsening of insomnia or the emergence of new thinking or behavior abnormalities may be the consequence of an unrecognized psychiatric or physical disorder.
Such findings have emerged during the course of treatment with sedative/hypnotic drugs, including LUNESTA.
Because some of the important adverse effects of LUNESTA appear to be dose-related, it is important to use the lowest possible effective dose, especially in the elderly (see DOSAGE AND ADMINISTRATION ).
A variety of abnormal thinking and behavior changes have been reported to occur in association with the use of sedative/hypnotics.
Some of these changes may be characterized by decreased inhibition (e.g., aggressiveness and extroversion that seem out of character), similar to effects produced by alcohol and other CNS depressants.
Other reported behavioral changes have included bizarre behavior, agitation, hallucinations, and depersonalization.
Complex behaviors such as “sleep-driving” (i.e., driving while not fully awake after ingestion of a sedative-hypnotic, with amnesia for the event) have been reported.
These events can occur in sedative-hypnotic-naïve as well as in sedative-hypnotic-experienced persons.
Although behaviors such as sleep-driving may occur with LUNESTA alone at therapeutic doses, the use of alcohol and other CNS depressants with LUNESTA appears to increase the risk of such behaviors, as does the use of LUNESTA at doses exceeding the maximum recommended dose.
Due to the risk to the patient and the community, discontinuation of LUNESTA should be strongly considered for patients who report a “sleep-driving” episode.
Other complex behaviors (e.g., preparing and eating food, making phone calls, or having sex) have been reported in patients who are not fully awake after taking a sedative-hypnotic.
As with sleep-driving, patients usually do not remember these events.
Amnesia and other neuropsychiatric symptoms may occur unpredictably.
In primarily depressed patients, worsening of depression, including suicidal thoughts and actions (including completed suicides), have been reported in association with the use of sedative/hypnotics.
It can rarely be determined with certainty whether a particular instance of the abnormal behaviors listed above are drug-induced, spontaneous in origin, or a result of an underlying psychiatric or physical disorder.
Nonetheless, the emergence of any new behavioral sign or symptom of concern requires careful and immediate evaluation.
Following rapid dose decrease or abrupt discontinuation of the use of sedative/hypnotics, there have been reports of signs and symptoms similar to those associated with withdrawal from other CNS-depressant drugs (see DRUG ABUSE AND DEPENDENCE ).
LUNESTA, like other hypnotics, has CNS-depressant effects.
Because of the rapid onset of action, LUNESTA should only be ingested immediately prior to going to bed or after the patient has gone to bed and has experienced difficulty falling asleep.
Patients receiving LUNESTA should be cautioned against engaging in hazardous occupations requiring complete mental alertness or motor coordination (e.g., operating machinery or driving a motor vehicle) after ingesting the drug, and be cautioned about potential impairment of the performance of such activities on the day following ingestion of LUNESTA.
LUNESTA, like other hypnotics, may produce additive CNS-depressant effects when coadministered with other psychotropic medications, anticonvulsants, antihistamines, ethanol, and other drugs that themselves produce CNS depression.
LUNESTA should not be taken with alcohol.
Dose adjustment may be necessary when LUNESTA is administered with other CNS-depressant agents, because of the potentially additive effects.
Severe anaphylactic and anaphylactoid reactions Rare cases of angioedema involving the tongue, glottis or larynx have been reported in patients after taking the first or subsequent doses of sedative-hypnotics, including LUNESTA.
Some patients have had additional symptoms such as dyspnea, throat closing, or nausea and vomiting that suggest anaphylaxis.
Some patients have required medical therapy in the emergency department.
If angioedema involves the tongue, glottis or larynx, airway obstruction may occur and be fatal.
Patients who develop angioedema after treatment with LUNESTA should not be rechallenged with the drug.
DRUG INTERACTIONS
Drug Interactions CNS-Active Drugs Ethanol: An additive effect on psychomotor performance was seen with coadministration of eszopiclone and ethanol 0.70 g/kg for up to 4 hours after ethanol administration.
Paroxetine: Coadministration of single doses of eszopiclone 3 mg and paroxetine 20 mg daily for 7 days produced no pharmacokinetic or pharmacodynamic interaction.
Lorazepam: Coadministration of single doses of eszopiclone 3 mg and lorazepam 2 mg did not have clinically relevant effects on the pharmacodynamics or pharmacokinetics of either drug.
Olanzapine: Coadministration of eszopiclone 3 mg and olanzapine 10 mg produced a decrease in DSST scores.
The interaction was pharmacodynamic; there was no alteration in the pharmacokinetics of either drug.
Drugs That Inhibit CYP3A4 (Ketoconazole) CYP3A4 is a major metabolic pathway for elimination of eszopiclone.
The AUC of eszopiclone was increased 2.2-fold by coadministration of ketoconazole, a potent inhibitor of CYP3A4, 400 mg daily for 5 days.
C max and t 1/2 were increased 1.4-fold and 1.3-fold, respectively.
Other strong inhibitors of CYP3A4 (e.g., itraconazole, clarithromycin, nefazodone, troleandomycin, ritonavir, nelfinavir) would be expected to behave similarly.
Drugs That Induce CYP3A4 (Rifampicin) Racemic zopiclone exposure was decreased 80% by concomitant use of rifampicin, a potent inducer of CYP3A4.
A similar effect would be expected with eszopiclone.
Drugs Highly Bound To Plasma Protein Eszopiclone is not highly bound to plasma proteins (52-59% bound); therefore, the disposition of eszopiclone is not expected to be sensitive to alterations in protein binding.
Administration of eszopiclone 3 mg to a patient taking another drug that is highly protein-bound would not be expected to cause an alteration in the free concentration of either drug.
Drugs With A Narrow Therapeutic Index Digoxin: A single dose of eszopiclone 3 mg did not affect the pharmacokinetics of digoxin measured at steady state following dosing of 0.5 mg twice daily for one day and 0.25 mg daily for the next 6 days.
Warfarin: Eszopiclone 3 mg administered daily for 5 days did not affect the pharmacokinetics of ( R )- or ( S )-warfarin, nor were there any changes in the pharmacodynamic profile (prothrombin time) following a single 25 mg oral dose of warfarin.
OVERDOSAGE
: There is limited premarketing clinical experience with the effects of an overdosage of LUNESTA.
In clinical trials with eszopiclone, one case of overdose with up to 36 mg of eszopiclone was reported in which the subject fully recovered.
Individuals have fully recovered from racemic zopiclone overdoses up to 340 mg (56 times the maximum recommended dose of eszopiclone).
Signs And Symptoms Signs and symptoms of overdose effects of CNS depressants can be expected to present as exaggerations of the pharmacological effects noted in preclinical testing.
Impairment of consciousness ranging from somnolence to coma has been described.
Rare individual instances of fatal outcomes following overdose with racemic zopiclone have been reported in European postmarketing reports, most often associated with overdose with other CNS-depressant agents.
Recommended Treatment General symptomatic and supportive measures should be used along with immediate gastric lavage where appropriate.
Intravenous fluids should be administered as needed.
Flumazenil may be useful.
As in all cases of drug overdose, respiration, pulse, blood pressure, and other appropriate signs should be monitored and general supportive measures employed.
Hypotension and CNS depression should be monitored and treated by appropriate medical intervention.
The value of dialysis in the treatment of overdosage has not been determined.
Poison Control Center As with the management of all overdosage, the possibility of multiple drug ingestion should be considered.
The physician may wish to consider contacting a poison control center for up-to-date information on the management of hypnotic drug product overdosage.
DESCRIPTION
: LUNESTA (eszopiclone) is a nonbenzodiazepine hypnotic agent that is a pyrrolopyrazine derivative of the cyclopyrrolone class.
The chemical name of eszopiclone is (+)-(5S)-6-(5-chloropyridin-2-yl)-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b] pyrazin-5-yl 4-methylpiperazine-1-carboxylate.
Its molecular weight is 388.81, and its empirical formula is C 17 H 17 ClN 6 O 3 .
Eszopiclone has a single chiral center with an ( S )-configuration.
It has the following chemical structure: Eszopiclone is a white to light-yellow crystalline solid.
Eszopiclone is very slightly soluble in water, slightly soluble in ethanol, and soluble in phosphate buffer (pH 3.2).
Eszopiclone is formulated as film-coated tablets for oral administration.
LUNESTA tablets contain 1 mg, 2 mg, or 3 mg eszopiclone and the following inactive ingredients: calcium phosphate, colloidal silicon dioxide, croscarmellose sodium, hypromellose, lactose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, titanium dioxide, and triacetin.
In addition, both the 1 mg and 3 mg tablets contain FD&C Blue #2.
Chemical Structure
HOW SUPPLIED
: LUNESTA 3 mg tablets are round, dark blue, film-coated, and identified with debossed markings of S193 on one side, and are supplied as: NDC 63402-193-10 bottle of 100 tablets LUNESTA 2 mg tablets are round, white, film-coated, and identified with debossed markings of S191 on one side, and are supplied as: NDC 63402-191-10 bottle of 100 tablets LUNESTA 1 mg tablets are round, light blue, film-coated, and identified with debossed markings of S190 on one side, and are supplied as: NDC 63402-190-30 bottle of 30 tablets Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].
SUNOVION Manufactured for: Sunovion Pharmaceuticals Inc.
Marlborough, MA 01752 USA For customer service, call 1-888-394-7377.
To report adverse events, call 1-877-737-7226.
For medical information, call 1-800-739-0565.
© 2009, 2010 Sunovion Pharmaceuticals Inc.
All rights reserved.
Lunesta is a registered trademark of Sunovion Pharmaceuticals Inc.
GERIATRIC USE
Geriatric Use A total of 287 subjects in double-blind, parallel-group, placebo-controlled clinical trials who received eszopiclone were 65 to 86 years of age.
The overall pattern of adverse events for elderly subjects (median age = 71 years) in 2-week studies with nighttime dosing of 2 mg eszopiclone was not different from that seen in younger adults (see ADVERSE REACTIONS , Table 2 ).
LUNESTA 2 mg exhibited significant reduction in sleep latency and improvement in sleep maintenance in the elderly population.
INDICATIONS AND USAGE
: LUNESTA is indicated for the treatment of insomnia.
In controlled outpatient and sleep laboratory studies, LUNESTA administered at bedtime decreased sleep latency and improved sleep maintenance.
The clinical trials performed in support of efficacy were up to 6 months in duration.
The final formal assessments of sleep latency and maintenance were performed at 4 weeks in the 6-week study (adults only), at the end of both 2-week studies (elderly only) and at the end of the 6-month study (adults only).
PEDIATRIC USE
Pediatric Use Safety and effectiveness of eszopiclone in children below the age of 18 have not been established.
PREGNANCY
Pregnancy Pregnancy Category C Eszopiclone administered by oral gavage to pregnant rats and rabbits during the period of organogenesis showed no evidence of teratogenicity up to the highest doses tested (250 and 16 mg/kg/day in rats and rabbits, respectively; these doses are 800 and 100 times, respectively, the maximum recommended human dose [MRHD] on a mg/m 2 basis).
In the rat, slight reductions in fetal weight and evidence of developmental delay were seen at maternally toxic doses of 125 and 150 mg/kg/day, but not at 62.5 mg/kg/day (200 times the MRHD on a mg/m 2 basis).
Eszopiclone was also administered by oral gavage to pregnant rats throughout the pregnancy and lactation periods at doses of up to 180 mg/kg/day.
Increased post-implantation loss, decreased postnatal pup weights and survival, and increased pup startle response were seen at all doses; the lowest dose tested, 60 mg/kg/day, is 200 times the MRHD on a mg/m 2 basis.
These doses did not produce significant maternal toxicity.
Eszopiclone had no effects on other behavioral measures or reproductive function in the offspring.
There are no adequate and well-controlled studies of eszopiclone in pregnant women.
Eszopiclone should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
NUSRING MOTHERS
Nursing Mothers It is not known whether LUNESTA is excreted in human milk.
Because many drugs are excreted in human milk, caution should be exercised when LUNESTA is administered to a nursing woman.
INFORMATION FOR PATIENTS
Information For Patients Patients should be instructed to read the accompanying Medication Guide with each new prescription and refill.
The complete text of the Medication Guide is reprinted at the end of this document.
Patients should be given the following information: Patients should be instructed to take LUNESTA immediately prior to going to bed, and only if they can dedicate 8 hours to sleep.
Patients should be instructed not to take LUNESTA with alcohol or with other sedating medications.
Patients should be advised to consult with their physician if they have a history of depression, mental illness, or suicidal thoughts, have a history of drug or alcohol abuse, or have liver disease.
Women should be advised to contact their physician if they become pregnant, plan to become pregnant, or if they are nursing.
DOSAGE AND ADMINISTRATION
: The dose of LUNESTA should be individualized.
The recommended starting dose for LUNESTA for most non-elderly adults is 2 mg immediately before bedtime.
Dosing can be initiated at or raised to 3 mg if clinically indicated, since 3 mg is more effective for sleep maintenance (see PRECAUTIONS ).
The recommended starting dose of LUNESTA for elderly patients whose primary complaint is difficulty falling asleep is 1 mg immediately before bedtime.
In these patients, the dose may be increased to 2 mg if clinically indicated.
For elderly patients whose primary complaint is difficulty staying asleep, the recommended dose is 2 mg immediately before bedtime (see PRECAUTIONS ).
Taking LUNESTA with or immediately after a heavy, high-fat meal results in slower absorption and would be expected to reduce the effect of LUNESTA on sleep latency (see Pharmacokinetics under CLINICAL PHARMACOLOGY ).
Special Populations Hepatic The starting dose of LUNESTA should be 1 mg in patients with severe hepatic impairment.
LUNESTA should be used with caution in these patients.
Coadministration With CYP3A4 Inhibitors The starting dose of LUNESTA should not exceed 1 mg in patients coadministered LUNESTA with potent CYP3A4 inhibitors.
If needed, the dose can be raised to 2 mg.