Zopiclone (Systemic)



USAN:
zopiclone
VA CLASSIFICATION
Primary: CN309

Commonly used brand name(s): Imovane.

Another commonly used name is:
zopiclonumRP 27267 Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).

*Not commercially available in the U.S.



Category:


Sedative-hypnotic —



Indications

Accepted

Insomnia (treatment)—Zopiclone is indicated for the short-term treatment of insomnia characterized by difficulty in falling asleep, frequent nocturnal awakenings, and/or early morning awakenings. Since sleep disturbances may be the presenting symptom of a physical and/or psychiatric disorder, the patient should be carefully evaluated before pharmacologic treatment is initiated. Insomnia that continues after 7 to 10 days of treatment may indicate the presence of a primary psychiatric and/or medical illness.{01}


Pharmacology/Pharmacokinetics

Physicochemical characteristics:

Chemical group—
    Cyclopyrrolone derivative.{01}
Molecular weight—
    388.82.{01}

Solubility
    Freely soluble in chloroform and methylene chloride; soluble in dimethylformamide and 0.1 N hydrochloric acid; slightly soluble in acetone; nearly insoluble in water, ethanol, or ethyl ether.{01}

Mechanism of action/Effect:

Zopiclone is a non-benzodiazepine hypnotic agent, with marked sedative effects. Although unrelated chemically to the benzodiazepines, it produces similar pharmacological effects.{01}{02}

Although the precise mechanisms have not been completely established, the activity of zopiclone is believed to be related to its binding on the benzodiazepine receptor complex and facilitation of the gamma-aminobutyric acid (GABA) function. It does not appear to bind to sites corresponding exactly to benzodiazepine sites, but rather to sites close by on the receptor complex. Enhanced binding of GABA to the GABA-chloride ionophore complex occurs to a greater extent with benzodiazepines as compared to zopiclone.{02} Zopiclone lacks affinity for the serotonin, GABA1 and GABA2 adrenergic, and dopamine receptors.{01}


Other actions/effects:

In animal studies, zopiclone has demonstrated other central nervous system activity, including anticonvulsant, muscle-relaxant, anti-aggression, and anxiolytic properties.{01}{02} The drug potentiates narcosis induced by ethanol or barbiturates.{01}

Absorption:

Rapidly and well absorbed; >75% bioavailability.{01}

Distribution:

Zopiclone is distributed into human breast milk; its concentration is approximately 50% that of plasma concentrations.{01}

Protein binding:

Moderate (approximately 45%).{01}

Biotransformation:

Extensively metabolized in the liver via decarboxylation (major pathway), demethylation, and side chain oxidation. Metabolites include an N-oxide derivative (weakly active; approximately 12% of a dose) and an N-desmethyl metabolite (inactive; approximately 16%). Approximately 50% of a dose is converted to other inactive metabolites via decarboxylation. Hepatic microsomal enzymes are apparently not involved in zopiclone clearance.{01}{02}


Half-life:


Distribution—:

1.2 hours.{01}



Elimination—:

Approximately 5 hours (range, 3.8 to 6.5 hours); prolonged to 11.9 hours in patients with hepatic insufficiency.{01}



Other—:

Approximately 4.5 hours (N-oxide metabolite).{01}


Time to peak concentration:

Less than 2 hours; increased to 3.5 hours in patients with hepatic insufficiency. {01}

Peak serum concentration:

30 and 60 ng/mL after 3.75 and 7.5 mg doses, respectively.{01}

Elimination:
    Renal, 75% (mostly metabolites, with only 4% to 5% unchanged drug).{01}
    Fecal, 16%.{01}
    Via lungs—metabolites from oxidative decarboxylation partly eliminated as carbon dioxide.{01}
    Hemodialysis—Does not appear to increase plasma clearance.{01}

Accumulation

Repeated daily administration of 7.5 mg orally for 14 days did not lead to accumulation.{01}


Precautions to Consider

Carcinogenicity/Tumorigenicity

An increased incidence of mammary tumors and pulmonary adenocarcinomas occurred in female rats and mice given 100 milligrams of zopiclone per kg of body weight (mg/kg) per day for 2 years{01} In male rats and mice receiving the same high doses, an increased incidence of thyroid and subcutaneous soft tissue tumors was observed.{01}The tumor-producing dose was equivalent to 800 times the usual human dose (0.125 mg/kg), and no effect occurred with doses that were 80 times the usual human dose.{01}

Mutagenicity

Zopiclone showed no evidence of mutagenicity in a wide battery of tests.{01} Urine extracts from zopiclone-treated mice, rats, and humans were not mutagenic.{01} No evidence of mutagenicity was found in the DNA repair assay in rat hepatocytes (William's test), in the Ames test in Salmonella typhimurium and Escherichia coli strains, or in the micronucleus test (mice).{01}

Pregnancy/Reproduction
Fertility—
In rat studies, zopiclone did not affect fertility in doses up to 12 mg/kg.{01} Sterility was induced in male rats given zopiclone 120 mg/kg for 10 weeks prior to mating.{01} Pregnancy rates were slightly lower in female rats given 120 mg/kg for 2 weeks prior to mating (83% compared with 100% in controls).{01} Survival rates were also lower in fetuses of female rats that received zopiclone (120 mg/kg for 2 weeks prior to mating , during pregnancy, and during lactation) than in fetuses of controls. {01}

Pregnancy—
Insufficient data are available to assess the safety of zopiclone during human pregnancy.{01}

Zopiclone was not teratogenic in rats receiving oral doses up to 125 mg/kg from day 5 to day 15 of gestation; however, sternebrae abnormalities, which occur in the strain studied, were found. Similarly, zopiclone was not teratogenic in rabbits receiving oral doses up to 125 mg/kg from day 6 to day 16 of gestation.{01}

Use of zopiclone during pregnancy is not recommended. Women of child-bearing potential should be warned of possible risk to the fetus should pregnancy occur during zopiclone treatment. Ingestion of therapeutic doses of a benzodiazepine hypnotic during the last weeks of pregnancy has resulted in neonatal central nervous system depression; similar effects could be expected to occur with zopiclone. {01}

Postpartum —
Studies of children whose mothers received zopiclone during pregnancy have not been conducted {01}. However, a child born to a mother using benzodiazepines or benzodiazepine-like agents may be at risk for withdrawal symptoms during the postnatal period. {01}

Breast-feeding

Administration of zopiclone during breastfeeding is not recommended.{01} Zopiclone is distributed into human breast milk , reaching concentrations approximately 50% of plasma concentrations.{01}

Pediatrics

Appropriate studies on the relationship of age to the effects of zopiclone have not been performed in children up to 18 years of age.{01} Safety and efficacy have not been established.{01}


Geriatrics


Studies have shown that zopiclone increases absolute bioavailability in elderly subjects (94% versus 77% in young subjects) and prolongs half-life (approximately 7 hours versus 5 hours).{01} Geriatric patients may be more likely to experience drowsiness, dizziness, confusion, impaired coordination, accidental events, or falls while taking zopiclone.{01} Also, elderly subjects may be at particular risk for anterograde amnesia and other memory lapses. {01} The lowest possible dose and careful monitoring should be provided in this population. {01}

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.

» Alcohol {01} or
» CNS depression–producing medications{01}, other (See Appendix II)    (concurrent use with zopiclone may produce additive CNS depressant effects {01} )


Hepatic enzyme inhibitors, including:
Cimetidine{01}
Erythromycin{01}    (inhibitors of cytochrome P450 enzymes may increase the activity of benzodiazepines and benzodiazepine-like medications{01})


Diagnostic interference
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With physiology/laboratory test values
Alanine aminotransferase (ALT [SGPT]) or
Alkaline phosphatase or
Aspartate aminotransferase (AST [SGOT])    (values may be increased)


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Except under special circumstances, this medication should not be used when the following medical problem exists:
» Hypersensitivity to zopiclone{01}
» Respiratory impairment, especially severe pulmonary insufficiency or sleep apnea syndrome    (increased risk of respiratory depression or failure {01})


Risk-benefit should be considered when the following medical problems exist
Alcohol or drug abuse or dependence, history of {01}     (predisposition to dependence may exist)


» Hepatic dysfunction, severe{01}    (plasma concentrations of zopiclone may be enhanced; dosage adjustments should be considered)


History of paradoxical reaction to alcohol and/or sedative medications{01}    (aggressiveness, extroversion, or strange behavior [possibly harmful] may be induced )


Mental depression{01}    (condition may be intensified, resulting in the potential for self-harm{01})


Myasthenic conditions, such as myasthenia gravis{01}    (condition may be exacerbated)


Renal function impairment{01}    (zopiclone clearance may be prolonged)




Side/Adverse Effects
The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence more frequent
    
Confusion — higher incidence in the elderly{01}
    
daytime anxiety and/or restlessness
    
impaired coordination (clumsiness or unsteadiness; difficulty with coordination)—higher incidence in elderly{01}
    
mental depression (mood or mental changes){01}
{01}
Note: Daytime anxiety and/or restlessness may be a manifestation of interdose withdrawal, due to the short elimination half-life of zopiclone.{01}


Incidence less frequent
    
Drowsiness (severe) {01}
    
dyspnea (shortness of breath ; difficult or labored breathing; tightness in chest; wheezing){01}
    
skin rash {01}
    
unusual behavior{01}, including aggressiveness{01}
and extroversion{01} (behavior or mental changes)

{01}
Note: Skin rash may be a sign of hypersensitivity to zopiclone. The medication should be discontinued if a skin rash appears.{01}



Incidence Rare
    
Anterograde amnesia{01} (memory problems)
    
disturbed thinking, including abnormal thoughts
depersonalization
hallucinations
illusions {01}( behavior or mental changes)


Note: Anterograde amnesia may be dose-related; elderly patients seem at particular risk.{01}



Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
    
Amblyopia (impaired vision)
    
anorexia{01} (loss of appetite)
    
asthenia{01} (unusual tiredness or weakness)
    
constipation{01}
    
dizziness {01}
    
dry mouth {01}
    
dyspepsia ( heartburn; indigestion; stomach upset){01}
    
hypotonia{01} (decreased muscle tone)
    
increased appetite{01}
    
speech disorders (difficulty speaking){01}
    
weight loss{01}
{01}

Note: Anorexia may occur more frequently in geriatric patients than in younger patients.{01}

Incidence less frequent
    
Agitation{01}
    
chills
    
limb heaviness (feeling of heaviness of arms and legs)
    
palpitations (fast, irregular, or pounding heartbeat){01}
    
paresthesia (tingling, burning, or prickly sensation){01}
    
sialorrhea{01} (increase in the amount of saliva)
    
sweating, increased{01}
    
tremor{01} ( trembling or shaking of fingers, hands, arms, feet, or legs)
    
vomiting{01}


Note: Agitation, palpitations, sialorrhea, increased sweating, tremor, and vomiting may occur more frequently in geriatric patients than in younger patients.{01}



Those not indicating need for medical attention
Incidence more frequent
    
Coated tongue
    
halitosis (bad breath)
    
taste disturbance (altered sense of taste; bitter (after) taste)
{01}


Those indicating possible withdrawal reaction and/or need for medical attention only if they occur after medication is discontinued
    
Abdominal or stomach cramps {01}
    
anxiety, nervousness, irritability, or restlessness {01}
    
muscle cramps {01}
    
nausea {01}
    
rebound insomnia {01}
    
seizures {01}
    
sweating, increased {01}
    
tremors {01}
    
or vomiting {01}




Overdose
For specific information on the agents used in the management of zopiclone overdose, see:
   • Flumazenil (Systemic) monograph.
For more information on the management of overdose or unintentional ingestion, contact a poison control center (see Poison Control Center Listing).

Clinical effects of overdose
The following effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:
    
Ataxia (clumsiness or unsteadiness ){01}
    
coma (loss of consciousness){01}
    
confusion (mental or mood changes){01}
    
drowsiness {01}
    
lethargy ( unusual tiredness or weakness; sluggishness; reduced physical activity){01}
    
reduced or absent reflexes {01}
    
somnolence, profound (unusual sleepiness){01}


Treatment of overdose


To decrease absorption:
Performing gastric lavage immediately{01}



To enhance elimination :
Performing hemodialysis is NOT expected to enhance elimination of zopiclone.{01}



Specific treatment:
Flumazenil may be useful in reversing sedative and respiratory depressant effects of zopiclone. {01}



Monitoring:
Monitoring respiratory, cardiac, and hemodynamic status{01}



Supportive care:
Providing general supportive therapy as indicated, including administering intravenous fluids and maintaining adequate airway.{01}

Patients in whom intentional overdose is confirmed or suspected should be referred for psychiatric consultation.



Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Zopiclone (Systemic).
In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Hypersensitivity to zopiclone

Pregnancy—Risk to the fetus is unknown





Breast-feeding—Zopiclone is distributed into breast milk (concentration is approximately 50% of plasma concentration); effect on infant is not known





Use in the elderly—Elderly patients are usually more sensitive to the CNS effects of zopiclone
Other medications, especially alcohol and other CNS depressant medications
Other medical problems, especially respiratory impairment (including sleep apnea) , alcohol or drug abuse (or history of), severe hepatic dysfunction , history of paradoxical reaction to sedatives, mental depression, myasthenic conditions, or renal function impairment

Proper use of this medication
» Not taking more zopiclone than the amount prescribed, due to potential for dependency

» Not increasing dose if medication becomes less effective over time; checking with physician

» Proper dosing
Skipping missed dose; not doubling doses

Proper storage

Precautions while using this medication
» Avoiding use of alcohol or other CNS depressants during therapy

» Caution if clumsiness or unsteadiness occurs, especially in the elderly

» Caution if dizziness or drowsiness occurs; not driving, using machines, or doing anything else that requires alertness until effects of zopiclone are known

» Amnesia; avoid by only taking zopiclone when able to get a full night's sleep (7 to 8 hours) before the need to be active again

» Checking with physician if unusual or strange thoughts or behavior develops while taking zopiclone

Checking with physician before discontinuing medication if therapy is prolonged; gradual dosage reduction may be necessary to avoid withdrawal symptoms{01}


Side/adverse effects
Signs of potential side effects, especially confusion; daytime anxiety and/or restlessness; impaired coordination; mental depression; drowsiness (severe); dyspnea; skin rash; unusual behavior including aggressiveness and extroversion; anterograde amnesia; or disturbed thinking, including abnormal thoughts, depersonalization, hallucinations, and illusions


General Dosing Information
Geriatric or debilitated patients or patients with impaired liver function or chronic respiratory insufficiency should receive decreased initial dosage since clearance of zopiclone may be prolonged, enhancing the potential for adverse effects.{01}

Zopiclone should be taken immediately before retiring for the night.{01}

To minimize the occurrence of anterograde amnesia and mental confusion, zopiclone should be taken only when the patient's schedule will allow for a full night's sleep (7 to 8 hours) {01}. Zopiclone should not be taken when there is a need to be awake, active, and functioning in less than 8 hours (such as after an overnight airplane flight of less than 8 hours). {01}

Zopiclone therapy should usually not exceed 7 to 10 consecutive days. Use for more than 2 to 3 consecutive weeks requires complete re-evaluation of the patient.{01}

Following prolonged administration, zopiclone should be withdrawn gradually to lessen the possibility of precipitating withdrawal symptoms {01}.

Potentially suicidal patients, particularly those who use alcohol excessively, should not have access to a large quantity of zopiclone {01}.


Oral Dosage Forms

ZOPICLONE TABLETS

Usual Adult Dose
Insomnia (treatment)
Oral, 5 mg to 7.5 mg at bedtime.{01}


Note: Debilitated patients or patients with hepatic function impairment or chronic respiratory insufficiency—Oral, initially 3.75 mg at bedtime, with dosage adjustments as needed and tolerated up to 7.5 mg.{01}


Usual adult prescribing limits
Up to 7.5 mg a day{01}.

Usual Pediatric Dose
Children up to 18 years of age
Safety and efficacy not established.{01}


Usual Geriatric Dose
Insomnia (treatment)—Oral, initially 3.75 mg at bedtime, with dosage adjustments as needed and tolerated up to 5 to 7.5 mg.{01}

Usual geriatric prescribing limits
Up to 7.5 mg a day.{01}

Strength(s) usually available
U.S.—
Not commercially available.

Canada—


5 mg (Rx) [Imovane (calcium phosphate dibasic) (hydroxypropylmethylcellulose) (lactose) (magnesium stearate) (maize starch) (sodium starch glycolate ) (titanium dioxide)]{01}


7.5 mg (Rx) [Imovane ( scored) (acetic anhydride) ( calcium phosphate) (carnauba wax) (cellulose) (croscarmellose sodium ) (diethyl phthalate) ( FD&C Blue No. 1 aluminum lake) (magnesium stearate ) (titanium dioxide) ( zein)]{01}

Packaging and storage:
Store in a dry place between 15 and 30 °C (59 and 86 °F). Protect from light.{01}

Auxiliary labeling:
   • May cause drowsiness.
   • Avoid alcoholic beverages.



Developed: 05/30/2000



References
  1. Product Information: Imovane®, zopiclone tablets. Rhone-Poulenc Rorer Canada Inc, Saint-Laurent, Quebec, Canada, (PI revised 5/1998) reviewed 5/2000.
  1. Hutchison TA, Shahan DR & Anderson ML (eds): DRUGDEX® System, zopiclone. MICROMEDEX, Inc., Englewood, Colorado (Edition expires 5/31/2000).
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