a) ZOPICLONE: The most common adverse effect of zopiclone is taste alteration (ie, bitter taste) due to the salivary excretion of the drug (Prod Info Imovane(R), zopiclone, 2000; Inman et al, 1993; Brun, 1988; Marc-Aurele et al, 1987; Campbell et al, 1987).
b) ESZOPICLONE: During placebo-controlled clinical trials, an unpleasant taste, as a dose-dependent effect, was reported in 8% (n=72), 17% (n=104), and 34% (n=105) of patients who received 1 mg, 2 mg, and 3 mg of eszopiclone, respectively (Prod Info Lunesta (TM), 2004).

a) CASE REPORT: Following a mixed overdose ingestion, including zopiclone 127.5 mg, a man developed transient first degree AV heart block. He fully recovered following gastric lavage and observation (Regouby et al, 1990).

a) CASE REPORT: A 52-year-old man with a history of depression, hypertension and alcohol abuse, intentionally ingested 60 mg of eszopiclone over a 10 hour period, and sought care initially because of a severe headache. Initial physical exam and laboratory evaluation were essentially normal, with the exception of elevated liver enzymes. Approximately 14 hours after admission the patient experienced a ventricular fibrillation cardiac arrest. Following successful resuscitation, ECG revealed ST elevation in leads III, AVF, and V3-V6. Cardiac catheterization revealed 100% occlusion of the right coronary artery by vasospasm without significant underlying coronary artery disease. Treatment included intracoronary nitroglycerin. The patient was discharged to home on day 12 with an implantable cardioverter/defibrillator (Miller et al, 2006).

a) Respiratory depression or dyspnea may occur as an adverse effect, particularly in patients with compromised respiratory function, and may occur following a significant overdose (Prod Info Imovane(R), zopiclone, 2000).
b) Overdoses result in hypoventilation due CNS depression. This effect may be worsened with a multiple drug ingestion that includes other respiratory depressants. Zopiclone and suriclone also produce a lowering of blood pressure due to depression of the central sympathetic regulatory mechanism with resultant lowering of cerebral perfusion and worsening of respiratory failure. Occlusion of the airways when in supine position may occur due to deep sedation and muscle relaxation. Fatalities are likely the result of respiratory failure (Bramness et al, 2001).
c) CASE REPORT: A 72-year-old female, with respiratory debilitation due to bronchogenic carcinoma, died after an intentional ingestion of 200 to 350 mg of zopiclone. The cause of death was reported as respiratory failure (Bramness et al, 2001).

a) Noncardiogenic pulmonary edema, probably secondary to hypoxia, may rarely result following an overdose of these drugs, which may then lead to respiratory failure and death in severe cases (Bramness et al, 2001).

a) Adverse effects of zopiclone include residual sequelae of morning drowsiness/sedation and psychomotor impairment which have been reported occasionally following 7.5 mg nightly doses (Alderman et al, 2001; Ansoms et al, 1991; Autret et al, 1987; Campbell et al, 1987; Goa & Heel, 1986; Lader & Denney, 1983). These effects occur more frequently with the use of higher doses (10 mg or more) (Goa & Heel, 1986; Lader & Denney, 1983). Other common adverse effects include asthenia, dizziness, confusion, memory impairment, feeling of drunkenness, euphoria, anxiety, depression, impaired coordination, hypotonia, and speech disorder (Prod Info Imovane(R), zopiclone, 2000).

a) SOMNOLENCE/STUPOR

a) Twenty-five cases of neuropsychiatric reactions related to zopiclone resembling psychosis have been reported to the Committee on Safety of Medicines in the United Kingdom since marketing of the drug in 1989. Auditory or visual hallucinations were reported in 5 cases and behavioral disturbances in 10, including cases of aggression. Amnesia was also reported in several patients. Most cases occurred shortly after initiation of therapy and resolved upon withdrawal (Anon, 1990). Details of these cases are lacking.

a) Tremor has been reported as a rare adverse effect of zopiclone, and appears to be more prevalent in elderly patients (Prod Info Imovane(R), zopiclone, 2000).

a) Dose-related memory loss has been reported shortly following therapeutic doses of zopiclone and eszopiclone (Prod Info Lunesta (TM), 2004; Fava, 1996; Goa & Heel, 1986; Fossen et al, 1983).
b) CASE REPORT: Global amnesic syndrome has been reported in a patient taking zopiclone for over 2 years. The symptoms appeared 3 months after a dosage increase from 7.5 to 15 mg at bedtime and consisted of a failure to recollect activities performed during late night awakenings and late morning episodes (Fava, 1996).

a) Rebound insomnia has been reported following withdrawal of zopiclone when given for even short periods (5 to 14 days) to healthy volunteers and insomniac patients (Anon, 1990; Tyrer, 1990; Lader & Frcka, 1987; Goa & Heel, 1986). Bianchi & Musch (1990) reported no rebound effect concerning sleep induction time, sleep duration, or number of nocturnal awakenings in 12 patients following discontinuation after 2 weeks of zopiclone therapy.

a) ESZOPICLONE: During a 6-week placebo-controlled study, headaches were reported in 21% (n=104) and 17% (n=105) of non-elderly adults who received 2 mg and 3 mg of eszopiclone, respectively, as compared with 13% in the placebo group (n=99) (Prod Info Lunesta (TM), 2004).

a) CASE REPORT: Severe headache was reported in a patient with a history of depression that ingested 60 mg of eszopiclone over a 10 hour period (Miller et al, 2006).
b) Headache and dizziness were reported in a woman who developed methemoglobinemia and acute tubular necrosis after ingesting 2250 mg of zopiclone in a suicide attempt (Kung et al, 2008).

a) Headache and dizziness were reported in a woman who developed methemoglobinemia and acute tubular necrosis after ingesting 2250 mg of zopiclone in a suicide attempt (Kung et al, 2008).

a) Adverse effects of zopiclone have included vomiting, anorexia, and sialorrhea, which appear to be more prevalent in geriatric patients (Prod Info Imovane(R), zopiclone, 2000).

a) Sporadic reports of abnormal laboratory tests following zopiclone therapeutic use have included increases in AST, ALT or alkaline phosphatase values (Prod Info Imovane(R), zopiclone, 2000).

a) CASE REPORT: Methemoglobinemia (blood methemoglobin concentration 19.4%) and acute tubular necrosis developed in a 53-year-old woman who presented with headache, dizziness, and cyanosis 60 hours after ingesting 2250 mg of zopiclone in a suicide attempt. The serum creatinine concentration peaked at 5.4 mg/dL 80 hours after the ingestion and normalized on day 9 following supportive care. On day 2, urine beta2-microglobulin was 6.2 mcg/mL (normal, less than 0.2 mcg/mL) (Kung et al, 2008).

a) SUMMARY: Individuals have developed methemoglobinemia following relatively large ingestions (up to 3750 mg) of zopiclone but have recovered without sequelae following methylene blue therapy and supportive care (Chan, 2014; Fung et al, 2008; Kung et al, 2008).
b) CASE REPORT: Methemoglobinemia (blood methemoglobin concentration 19.4%) and acute tubular necrosis developed in a 53-year-old woman who presented with headache, dizziness, and cyanosis 60 hours after ingesting 2250 mg of zopiclone in a suicide attempt. Following supportive care and methylene blue therapy, her condition improved, and she was discharged 4 days after presentation (Kung et al, 2008).
c) CASE REPORTS: A 43-year-old woman developed methemoglobinemia after ingesting 100 tablets of 7.5 mg zopiclone. Her methemoglobin concentration peaked at 23.8% at 16 hours postingestion. Another patient, a 30-year-old woman developed methemoglobinemia after ingesting 150 to 200 tablets of 7.5 mg zopiclone. Her methemoglobin concentration peaked at 10.4%, 53 hours after zopiclone ingestion. Following supportive care and methylene blue therapy, both patients recovered completely (Fung et al, 2008).
d) CASE REPORTS: In a review, methemoglobinemia developed in 2 adults after ingesting greater than 200 to 500 tablets of 7.5 mg zopiclone. In the first patient, the methemoglobin level peaked at 4.2% and her level dropped to 1.1% within 6 hours and she remained asymptomatic. The second patient had a history of chronic insomnia and took up to 20 tablets of zopiclone 7.5 mg at night. During one episode she took 500 tablets of zopiclone 7.5 mg (total, 3750 mg ) over 5 hours. She presented 9 hours after ingestion with dizziness, cyanosis, asymptomatic T-wave inversion and a methemoglobin level of 24.5%. Methylene blue was administered (50 mg) and her level dropped to 4.1% about 40 minutes later. She recovered without sequelae (Chan, 2014).

a) CASE REPORT: Hemolytic anemia developed in a 46-year-old woman after ingesting 50 to 100 tablets of 7.5 mg zopiclone. Laboratory results revealed oxidative hemolysis with anemia (hemoglobin 9 g/dL 7 hours postingestion; reference range, 11.6 to 15.5 g/dL), anisocytosis, polychromasia, spherocytosis, bite cells, increased unconjugated bilirubin and lactate dehydrogenase, lower haptoglobin, and reticulocytosis. One month postingestion, laboratory tests revealed hemoglobin of 11.9 g/dL and total bilirubin of 0.24 mg/dL (reference range, 0.3 to 1.2 mg/dL) (Fung et al, 2009).

a) Dermatologic adverse effects of zopiclone have included rash, skin spots, and sweating. These effects are rare. Rash may be a drug hypersensitivity reaction (Prod Info Imovane(R), zopiclone, 2000).

a) Monitor cardiac, CNS, and respiratory function in all symptomatic patients. Any fatalities would likely be a result of depression of the CNS and/or respiratory centers.

a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.

a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
b) ADVERSE EFFECTS/CONTRAINDICATIONS

a) Most patients will require little more than monitoring and positioning to maintain the airway and avoid aspiration.

a) Severe toxicity generally occurs if other sedating agents are also ingested. Intubate patients with any difficulty maintaining their airway or who are at risk for aspiration. Hypotension is generally mild and responds to fluids. METHEMOGLOBINEMIA: Monitor methemoglobin levels; levels above 20% to 30% may produce symptoms. Symptomatic patients should be treated with methylene blue. Administer oxygen therapy while preparing methylene blue.

a) Flumazenil has been used to reverse sedation due to zopiclone or eszopiclone. However, since toxicity is so mild, it is rarely required. Routine use of flumazenil is NOT recommended. Flumazenil may be useful in establishing a diagnosis in a patient with CNS depression and possibly in preventing the need for respiratory support. Flumazenil should not be administered to patients with cardiac arrhythmias, seizures or a history of seizures, signs/symptoms of a cyclic antidepressant intoxication, or a suspected multidrug ingestion.
b) For initial management of a known or suspected zopiclone overdose, the recommended initial dose of flumazenil is 0.2 mg (2 mL of a 0.1 mg/mL solution) administered intravenously over 30 seconds. If the desired level of consciousness is not obtained after waiting 30 seconds, a further dose of 0.3 mg (3 mL of a 0.1 mg/mL solution) can be administered over another 30 seconds. Further doses of 0.5 mg (5 mL of a 0.1 mg/mL solution) can be administered over 30 seconds at 1-minute intervals up to a cumulative dose of 3 mg. Once doses of 3 mg have been reached without clinical response, additional flumazenil is not likely to have any effect. On rare occasions, patients with a partial response at 3 mg may require additional titration up to a total dose of 5 mg (administered slowly in the same manner) (Prod Info ROMAZICON(R) injection, 2007).
c) MECHANISM: Flumazenil can block the central effects of benzodiazepines by competitive interaction at the receptor level; likewise the effects of nonbenzodiazepine agonists at benzodiazepine receptors, such as zopiclone are also blocked (Prod Info ROMAZICON(R) injection, 2007).
d) In the event of resedation, repeated doses may be given at 20-minute intervals if needed. For repeat treatment, no more than 1 mg (given as 0.5 mg/min) should be given at any one time and no more than 3 mg should be given in any one hour.
e) Reversal with an excessively high dose of flumazenil may produce anxiety, agitation, increased muscle tone, hyperesthesia and possibly seizures. Seizures have been treated with barbiturates, benzodiazepines and phenytoin, generally with prompt resolution of the seizures.

a) CASE REPORT: A 27-year-old man was found unresponsive approximately 1.5 hours after ingesting 14 to 20 zopiclone 7.5 mg tablets (105 to 150 mg). On arrival at the ED he was lethargic but able to follow commands. A temporary reversal of sedation occurred after he was treated with 0.2 mg IV of flumazenil (Cienki et al, 2005).
b) CASE SERIES: The Poison Control Center of Taiwan reported that 25 of 119 zopiclone overdoses received flumazenil, and 20 of the 25 cases had positive urine confirmation of zopiclone exposure. The median ingested dose was 210 mg. Seventeen of the 20 cases responded to flumazenil therapy, and the need for intubation was avoided in 6 of these patients. However, re-sedation was noted in 9 of the patients who initially responded to flumazenil, and 3 cases did not respond to flumazenil at all (Yang & Deng, 2008).

a) Flumazenil is contraindicated in patients with known hypersensitivity to benzodiazepines or flumazenil, patients suspected of tricyclic antidepressant overdose, and in those who have been given benzodiazepines for control of a life-threatening condition. Flumazenil should not be used until the effects of neuromuscular blocking agents have worn off (Prod Info ROMAZICON(R) IV injection, 2004).
b) Precipitation of seizures may occur in epileptic patients or in those ingesting epileptogenic co-ingestants (Bismuth et al, 1985).
c) TRICYCLIC ANTIDEPRESSANTS: Flumazenil is NOT recommended for use when patients show signs of tricyclic toxicity; the patient should be allowed to remain sedated (with respiratory and other support) until the tricyclic signs abate. Concurrent ingestion of large doses of tricyclics may predispose patients to seizures upon flumazenil administration.

a) Infuse 10 to 20 milliliters/kilogram of isotonic fluid and keep the patient supine. If hypotension persists, administer dopamine or norepinephrine. Consider central venous pressure monitoring to guide further fluid therapy.

a) DOSE: Begin at 5 micrograms per kilogram per minute progressing in 5 micrograms per kilogram per minute increments as needed (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). If hypotension persists, dopamine may need to be discontinued and a more potent vasoconstrictor (eg, norepinephrine) should be considered (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
b) CAUTION: If ventricular dysrhythmias occur, decrease rate of administration (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). Extravasation may cause local tissue necrosis, administration through a central venous catheter is preferred (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).

a) PREPARATION: 4 milligrams (1 amp) added to 1000 milliliters of diluent provides a concentration of 4 micrograms/milliliter of norepinephrine base. Norepinephrine bitartrate should be mixed in dextrose solutions (dextrose 5% in water, dextrose 5% in saline) since dextrose-containing solutions protect against excessive oxidation and subsequent potency loss. Administration in saline alone is not recommended (Prod Info norepinephrine bitartrate injection, 2005).
b) DOSE

a) To minimize barotrauma and other complications, use the lowest amount of PEEP possible while maintaining adequate oxygenation. Use of smaller tidal volumes (6 mL/kg) and lower plateau pressures (30 cm water or less) has been associated with decreased mortality and more rapid weaning from mechanical ventilation in patients with ARDS (Brower et al, 2000). More treatment information may be obtained from ARDS Clinical Network website, NIH NHLBI ARDS Clinical Network Mechanical Ventilation Protocol Summary, http://www.ardsnet.org/node/77791 (NHLBI ARDS Network, 2008)

a) Determine the methemoglobin concentration and evaluate the patient for clinical effects of methemoglobinemia (ie, dyspnea, headache, fatigue, CNS depression, tachycardia, metabolic acidosis). Treat patients with symptomatic methemoglobinemia with methylene blue (this usually occurs at methemoglobin concentrations above 20% to 30%, but may occur at lower methemoglobin concentrations in patients with anemia, or underlying pulmonary or cardiovascular disorders). Administer oxygen while preparing for methylene blue therapy.

a) INITIAL DOSE/ADULT OR CHILD: 1 mg/kg IV over 5 to 30 minutes; a repeat dose of up to 1 mg/kg may be given 1 hour after the first dose if methemoglobin levels remain greater than 30% or if signs and symptoms persist. NOTE: Methylene blue is available as follows: 50 mg/10 mL (5 mg/mL or 0.5% solution) single-dose ampules (Prod Info PROVAYBLUE(TM) intravenous injection, 2016) and 10 mg/1 mL (1% solution) vials (Prod Info methylene blue 1% intravenous injection, 2011). REPEAT DOSES: Additional doses may be required, especially for substances with prolonged absorption, slow elimination, or those that form metabolites that produce methemoglobin. NOTE: Large doses of methylene blue may cause methemoglobinemia or hemolysis (Howland, 2006). Improvement is usually noted shortly after administration if diagnosis is correct. Consider other diagnoses or treatment options if no improvement has been observed after several doses. If intravenous access cannot be established, methylene blue may also be given by intraosseous infusion. Methylene blue should not be given by subcutaneous or intrathecal injection (Prod Info methylene blue 1% intravenous injection, 2011; Herman et al, 1999). NEONATES: DOSE: 0.3 to 1 mg/kg (Hjelt et al, 1995).
b) CONTRAINDICATIONS: G-6-PD deficiency (methylene blue may cause hemolysis), known hypersensitivity to methylene blue, methemoglobin reductase deficiency (Shepherd & Keyes, 2004)
c) FAILURE: Failure of methylene blue therapy suggests: inadequate dose of methylene blue, inadequate decontamination, NADPH dependent methemoglobin reductase deficiency, hemoglobin M disease, sulfhemoglobinemia, or G-6-PD deficiency. Methylene blue is reduced by methemoglobin reductase and nicotinamide adenosine dinucleotide phosphate (NADPH) to leukomethylene blue. This in turn reduces methemoglobin. Red blood cells of patients with G-6-PD deficiency do not produce enough NADPH to convert methylene blue to leukomethylene blue (do Nascimento et al, 2008).
d) DRUG INTERACTION: Concomitant use of methylene blue with serotonergic drugs, including serotonin reuptake inhibitors (SRIs), selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), norepinephrine-dopamine reuptake inhibitors (NDRIs), triptans, and ergot alkaloids may increase the risk of potentially fatal serotonin syndrome (U.S. Food and Drug Administration, 2011; Stanford et al, 2010; Prod Info methylene blue 1% IV injection, 2011).

a) DOSE: 2 to 4 mg/kg intravenously over 5 minutes. Dose may be repeated in 30 minutes (Nemec, 2011; Lindenmann et al, 2006; Kiese et al, 1972).
b) SIDE EFFECTS: Hypotension with rapid intravenous administration. Vomiting, diarrhea, excessive sweating, hypotension, dysrhythmias, hemolysis, agranulocytosis and acute renal insufficiency after overdose (Dunipace et al, 1992; Hix & Wilson, 1987; Winek et al, 1969; Teunis et al, 1970; Marquez & Todd, 1959).
c) CONTRAINDICATIONS: G-6-PD deficiency; may cause hemolysis.

a) The recommended starting dose is 1 mg orally immediately before bedtime. If clinically indicated, the dose may be increased to 2 or 3 mg. MAX dose: 3 mg/day (Prod Info LUNESTA(R) oral tablets, 2014).

a) ZOPICLONE: 5 to 7.5 mg orally at bedtime is recommended in the treatment of insomnia; prolonged use (longer than 10 days) should be avoided; dose adjustments are not required in renal insufficiency or in the elderly (Prod Info Imovane(R), zopiclone, 2000; Goa & Heel, 1986).

1) Clinical effects of overdoses are expected to be consistent with its pharmacological activity and may include somnolence, confusion and coma with reduced or absent reflexes.

1) In another case, a 48-year-old woman ingested 100 tablets of zopiclone 7.5 mg and developed drowsiness, cyanosis and a methemoglobin level of 12%. Treatment included intubation and ventilation. An initial dose of methylene blue reduced the methemoglobin level to 6.7% but it rebounded to 20.5% about 8 hours later. A second dose of methylene blue was administered which decreased the methemoglobin level to 10% about 22 hours post ingestion. Levels gradually declined but they were measurable for up to 90 hours post ingestion (Chan, 2014).

a) ZOPICLONE - Following a single 7.5 mg dose, peak plasma concentrations of 60 to 70 mcg/L are reported within 0.5 to 1.5 hours after the dose (Pounder & Davies, 1994).
b) ZOPICLONE - Mannaert et al (1996) reported that therapeutic plasma concentrations varied from 10 to 100 ng/mL (Mannaert et al, 1996).
c) ZOPICLONE - Blood concentrations of 18.4 to 35.2 ng/mL are reported following a single 7.5 mg dose (Van Bocxlaer et al, 1996).

a) Methemoglobinemia and acute tubular necrosis developed In a woman after ingesting 2250 mg of zopiclone in a suicide attempt. On admission (60 hours after ingestion), her serum zopliclone concentration was 1690 ng/mL. Following supportive care, her condition improved, and she was discharged 4 days after presentation (Kung et al, 2008).
b) Royer-Morrot et al (1992) reported a survivor of a 300 mg zopiclone overdose who had a plasma level of 1.6 mcg/L (1600 ng/mL) at 4.5 hours after the dose (Royer-Morrot et al, 1992).
c) In a post-mortem case, an estimated fatal dose of 150 mg of zopiclone resulted in zopiclone blood concentrations (1.2 mcg/mL) approximately 20-fold greater than the expected peak plasma level after a single oral dosage (Pounder & Davies, 1994).
d) A 27-year-old man developed lethargy after ingesting 14 to 20 zopiclone 7.5 mg tablets (105 to 150 mg). His serum zopiclone levels were 0.073 mg/L at 4.25 hr, 0.02 mg/L at 6.75 hr, 0.005 mg/L at 12 hr and undetectable at 17 hours after ingestion (therapeutic range 0.018-0.038 mg/L) (Cienki et al, 2005).
e) In a fatality involving the ingestion of an unknown quantity of pentazocine and zopiclone by a 26-year-old female, a postmortem zopiclone blood concentration of 1.18 mcg/mL was reported (Van Bocxlaer et al, 1996).
f) In a fatality following a mixed ingestion, zopiclone was found in the serum in a concentration of 0.5 mcg/mL. Serum levels of phenobarbital were 8.6 mcg/mL, chlorpromazine 0.2 mcg/mL, and promethazine 0.3 mcg/mL. Zopiclone was reported as the probable cause of death in this case (Yamazaki et al, 1998).
g) A postmortem femoral blood zopiclone concentration of 1.9 mg/L (4.8 mcmol/L) was reported following the death of a 72-year-old woman who ingested between 200 and 350 mg. No other drugs were detected (Bramness et al, 2001).
h) Zopiclone does not appear to undergo significant postmortem redistribution (Pounder & Davies, 1994; Pounder & Davies, 1996).
i) Following a drug interaction between nefazodone and zopiclone, elevated plasma concentrations of the S-enantiomer and the R-enantiomer of zopiclone were reported as 107 and 20.6 ng/mL, respectively. Two weeks after discontinuing nefazodone, plasma concentrations of the S- and R-enantiomers decreased to 16.9 and 1.45 ng/mL, respectively (Alderman et al, 2001).

a) 541 mg/kg ((RTECS, 2001))

a) 2174 mg/kg ((RTECS, 2001))

a) 888 mg/kg ((RTECS, 2001))

a) 295 mg/kg ((RTECS, 2001))

a) 827 mg/kg ((RTECS, 2001))

a) 540 mg/kg ((RTECS, 2001))