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PubMed2001

Possible interaction of zopiclone and nefazodone.

OBJECTIVE: To describe a case in which concurrent treatment with nefazodone was associated with an elevation in the plasma concentration of zopiclone, possibly resulting in enhanced hypnosedative efficacy. CASE REPORT: An 86-year-old white woman was treated with nefazodone for depression. Zopiclone was also introduced for the management of insomnia, but she subsequently experienced morning drowsiness. The concentration of zopiclone in plasma was subsequently measured eight hours after administration on two occasions, during nefazodone therapy and after its withdrawal. After discontnuation of nefazodone, the plasma concentration of the S-enantiomer of zopiclone decreased from 107 to 16.9 ng/mL, while the R-enantiomer plasma concentration decreased from 20.6 to 1.45 ng/mL. DISCUSSION: Nefazodone is a relatively potent inhibitor of CYP3A4, a hepatic isoenzyme thought to play a major role in the metabolic elimination of zopiclone. The substantial decrease in the plasma zopiclone concentrations observed after withdrawal of nefazodone likely reflects a drug interaction. Despite the normally short elimination half-life of zopiclone, the residual sedation initially observed in this case suggests that the interaction may have clinical significance. CONCLUSIONS: The features observed in this case suggest the possibility of a drug-drug interaction between nefazodone and zopiclone. Further prospective investigation is required to elucidate the nature and magnitude of this effect.

Aged↗

PubMed2005

Eszopiclone for insomnia.

OBJECTIVE: To review the pharmacology, pharmacokinetics, efficacy data, and adverse effects of eszopiclone in the treatment of transient and chronic insomnia in adult and geriatric patients. DATA SOURCES: A MEDLINE literature search (1966-May 2005) was conducted to retrieve articles and abstracts involving eszopiclone. The manufacturer of the drug provided a general summary of clinical data and abstracts of unpublished Phase III clinical trials. STUDY SELECTION AND DATA EXTRACTION: All articles identified from the data sources were reviewed, and information deemed relevant was included for this review. DATA SYNTHESIS: Food and Drug Administration approval of eszopiclone was based on 6 double-blind, placebo-controlled trials. Five trials published in abstract or study form were reviewed. The sixth trial was not available for evaluation. An open-label continuation trial was also reviewed. All studies showed statistically significant improvements in sleep parameters in adult and elderly patients treated for insomnia with eszopiclone. CONCLUSIONS: The results of the 5 available double-blind, placebo-controlled studies (and 1 open-label, 6-month extension) showed that eszopiclone was safe and effective in the treatment of transient and chronic insomnia in adult and geriatric patients. Tolerance with long-term exposure (6 mo) and rebound insomnia were not observed. The results of the 6-month, open-label extension trial demonstrated that improvements in sleep parameters were sustained. Future studies comparing eszopiclone with other non benzodiazepine sedative-hypnotics (eg, zolpidem, zaleplon) are needed with cost data to clearly define the role of eszopiclone in the pharmacotherapy of chronic insomnia.

Azabicyclo Compounds↗

PubMed2006

Eszopiclone for the treatment of insomnia.

Eszopiclone, a single-isomer, non-benzodiazepine hypnotic agent, is approved for use in the US for the treatment of insomnia for patients who have difficulty falling asleep (sleep latency) as well as for those who have difficulty staying asleep (sleep maintenance). Efficacy in sleep maintenance has not been consistently demonstrated with previous hypnotics, and long-term efficacy and safety data are lacking for these agents. In clinical trials, eszopiclone 3 mg significantly improved objective and subjective sleep measures in transient and chronic insomnia in adults. Nightly treatment with eszopiclone 1 mg effectively induced sleep in elderly patients and the 2-mg dose effectively induced and maintained sleep. The ability of eszopiclone 2 mg to significantly improve next-day functioning and daytime alertness (as demonstrated by a reduction in the number and duration of naps) in the elderly is an important finding in clinical trials, and is unique to the class of hypnotic agents for the treatment of insomnia. Eszopiclone was well tolerated in clinical trials < or = 12 months duration, with no clinically significant evidence of pharmacological tolerance, rebound insomnia or dependence. The most frequently reported adverse event was unpleasant taste. Eszopiclone is the only non-benzodiazepine sedative-hypnotic (in the Schedule IV class under the Controlled Substances Act) to be evaluated as a long-term treatment for chronic insomnia.

Adult↗

PubMed2001

Effects of zopiclone on blood glucose level, serum lipid concentration and clot lysis time in normoglycemic and normolipidemic rats.

In normoglycemic and normolipidemic rats the i.p. injection of zopiclone induced an acceleration of fibrinolysis in a dose-dependent bell shaped manner and various changes of the blood glucose level. Total lipids, total cholesterol and triglyceride serum levels remained unaffected by doses of 1.25, 2.5 and 15.0 mg/kg, with the exception of the medium dose (5.0 mg/kg) and the next dose (10.0 mg/kg) which lowered them very significantly.

Animals↗

PubMed2000

Phytonadione therapy in a multiple-drug overdose involving warfarin.

We cared for a patient who ingested an unknown amount of acetaminophen with zopiclone and warfarin. The only liver function test that was abnormal was an increased international normalized ratio (INR), which remained elevated despite treatment with subcutaneous phytonadione and a prolonged infusion of N-acetylcysteine. An interaction between acetaminophen and warfarin may have decreased the hepatic metabolism of warfarin. The patient received numerous antibiotics that may have contributed to the increased INR. The prolonged elevation of INR also may have been due to infrequent administration of phytonadione.

Acetaminophen↗

PubMed1984

Some toxic properties of a carcinogenic pyrrolizidine alkaloid, petasitenine.

Some toxic properties of petasitenine, a hepatocarcinogenic pyrrolizidine alkaloid, were confirmed in 3 parts of studies. Electron microscopic observation of rat liver on the stage of acute toxicity following administration of a toxic dose of petasitenine disclosed the distinctive changes i.e., nucleolar segregation, degradation of endoplasmic reticulum such as formation of concentric whorls in the liver cells. Biochemical test for the mitochondrial function in the isolated mitochondria from rat liver cells revealed on inhibitory effects of petasitenine in the respiratory system, indicating that minor changes of mitochondria on the pyrrolizidine alkaloid may be induced by some other indirect factor. Investigation for the effect of petasitenine on the cell cycle of the cultured cell line from the human carcinoma showed some inhibitory effects in the appearance of cells in S-phase or M-phase, suggesting a possibility that toxicity of petasitenine will be developed in the tissues other than the liver or in the species apart from rodents.

Animals↗

PubMed2006

Eszopiclone.

PURPOSE: The pharmacology, pharmacokinetics, indications, clinical efficacy, adverse effects, drug interactions, dosing, and administration of eszopiclone are discussed. SUMMARY: The pharmacology of eszopiclone is not well understood. Eszopiclone is the S-isomer of racemic zopiclone. The relative bioavailability of oral racemic zopiclone is about 80%. Eszopiclone is rapidly absorbed after oral administration, with peak serum concentrations ranging from 1 to 1.3 hours. The efficacy of eszopiclone has been evaluated in healthy adults, including elderly patients, for the treatment of transient and chronic insomnia. Compared with placebo, eszopiclone has been shown to considerably reduce sleep induction and improve sleep maintenance, duration, quality, and depth, as well as next-day functioning. The most common adverse effects reported are unpleasant taste, headache, and dry mouth. Dosing should be individualized, and the lowest effective dose should be used to minimize the risk of adverse events. The recommended starting dosage for nonelderly patients is 2 mg immediately before bedtime, with adjustment to 3 mg if clinically indicated. Dosage adjustment is necessary in patients with severe hepatic disease and in those receiving concomitant potent cytochrome P-450 isoenzyme 3A4 inhibitors. No dosage adjustment is required for patients with renal dysfunction. The cost of eszopiclone is 3.70 dollars per tablet for all dosage strengths (1-, 2-, and 3-mg tablets). CONCLUSION: Its favorable adverse-effect profile and approved labeling for the treatment of chronic insomnia makes eszopiclone a viable alternative for insomnia treatment. Published data are limited, however, and more clinical trials, including comparator studies, are needed to further evaluate the use of this drug.

Adult↗

PubMedDate not supplied

Prescribing short-acting hypnosedatives. Current recommendations from a safety perspective.

The duration of action of hypnosedative drugs is mainly determined by their pharmacokinetic properties. The ideal drug should induce sleep within 30 min and maintain a normal pattern of sleep for 6 to 8h, with little or no residual effects the next morning. Clinically, 4 types of insomnia can be distinguished: prolonged latency, 1 to 2 long periods of wakefulness, frequent short awakenings and early morning awakening. An ultra-short-acting drug (2 to 3h), such as triazolam, is useful for prolonged latency. Temazepam, lormetazepam and loprazolam provide more prolonged effects (8 to 10h). These benzodiazepines are not free of daytime adverse effects, particularly drowsiness, dependency potential, rebound insomnia and habituation to the drug effect. Zopiclone and zolpidem are new nonbenzodiazepine hypnotics that are as effective as benzodiazepines but without the problems associated with the latter. They produce a more normal electroencephalogram sleep pattern and so would seem to approach to the ideal hypnosedative for the future. However only further clinical trials and widespread use in practice will determine whether they will live up to this potential.

Azabicyclo Compounds↗

PubMed1999

A comparative assessment of the risks and benefits of zopiclone: a review of 15 years' clinical experience.

Zopiclone is a cyclopyrrolone hypnosedative that is chemically unrelated to the benzodiazepines but nevertheless potentiates gamma-aminobutyric acid-mediated neuronal inhibition, and has demonstrated proven efficacy and good tolerability in the treatment of insomnia over 15 years of use. Zopiclone is indicated for short term use, and should not be prescribed for more than 4 weeks. This review compares the efficacy of zopiclone with that of a number of commonly used short-, medium- and long-acting benzodiazepines. Zopiclone at dosages of 7.5 mg/day has demonstrated efficacy equivalent and in some cases greater to that of flurazepam 30 mg/day, nitrazepam 5 mg/day, flunitrazepam 1 to 2 mg/day, temazepam 20 mg/day, triazolam 0.125 to 0.5 mg/day and midazolam 15 mg/day. Zopiclone-treated patients reported themselves to be less impaired by daytime sedation than patients treated with the medium- and long-acting hypnosedatives flurazepam, nitrazepam and flunitrazepam. Zopiclone and temazepam showed similar effects on daytime behaviour while zopiclone appeared to have somewhat better effects on daytime well-being than the short-acting triazolam and midazolam. There has been no clinical comparison with the frequently used medium-acting benzodiazepines lormetazepam and brotizolam and the imidazopyridine hypnosedative zolpidem. Data from clinical trials, pooled analyses and postmarketing surveillance including over 30,000 patients showed that with the exception of bitter taste (reported by <10% of zopiclone recipients), the tolerability profile of zopiclone is similar to that of placebo. Clinical trials found no evidence for significant rebound insomnia and indicated that the risk of withdrawal reactions with therapeutic doses of zopiclone is very low. In addition, to date, dependency appears very low, although abuse potential should be considered following a history of addiction or psychiatric illness. Evaluation of the accumulated evidence from over 2.5 billion units dispensed in more than 30 countries indicates that zopiclone is effective, well tolerated and an excellent alternative to benzodiazepines in the short term treatment of insomnia.

Animals↗

PubMedDate not supplied

Zopiclone. A review of its pharmacological properties and therapeutic efficacy as an hypnotic.

Zopiclone is a cyclopyrrolone which is chemically unrelated to the benzodiazepines and is thought to act on the GABAA receptor complex at a site distinct from, but closely related to, the benzodiazepine binding site. The hypnotic efficacy of zopiclone administered as single oral doses has been demonstrated in patients undergoing next-day surgery and in patients with insomnia, and these studies have established an optimal dose of 7.5mg for elderly patients. Using this dose, clinical studies have shown that zopiclone improved sleep in elderly patients to a similar extent as triazolam 0.125 to 0.5mg, flurazepam 15mg, and nitrazepam 5mg. Studies that also included younger patients have shown that zopiclone 7.5mg is at least as effective as triazolam 0.25 or 0.5mg, and on most sleep parameters is comparable to temazepam 20mg, nitrazepam 5mg, flunitrazepam 2mg, and flurazepam 20mg. Zopiclone causes minimal impairment to psychomotor performance and mental alertness the morning after night-time administration. The drug is generally well tolerated by patients of all ages; the most frequently reported adverse effects being bitter taste and dry mouth. Treatment withdrawal due to adverse effects is seldom required and reports of rebound insomnia after zopiclone withdrawal are rare. While symptoms of physical dependence have not been observed in clinical studies, there have been isolated reports of physical dependence in patients with a history of substance abuse. Although the latter finding should be kept in mind, it appears that zopiclone has a low dependence liability. Thus, with its short duration of action and good tolerability profile, zopiclone is a well established alternative to the benzodiazepine hypnotics and may be particularly beneficial in those patients unable or unwilling to tolerate the residual effects associated with many other hypnotic agents.

Aged↗

PubMed1995

Clinical pharmacokinetics of zopiclone.

Zopiclone is a cyclopyrrolone hypnotic agent. It possesses a chiral centre and is commercially available as a racemic mixture. Methods involving high performance liquid chromatography (HPLC), gas chromatography, capillary electrophoresis (CE) and high performance thin layer chromatography have been developed for the quantitation of zopiclone and its 2 main metabolites in biological samples. For the chiral determination of the enantiomers of zopiclone and its metabolites, HPLC and CE methods are available. After oral administration, zopiclone is rapidly absorbed, with a bioavailability of approximately 80%. The plasma protein binding of zopiclone has been reported to be between 45 and 80%. Zopiclone is rapidly and widely distributed to body tissues including the brain, and is excreted in urine, saliva and breast milk. Zopiclone is partly metabolised in the liver to form an inactive N-demethylated derivative and an active N-oxide metabolite. In addition, approximately 50% of the administered dose is decarboxylated and excreted via the lungs. Less than 7% of the administered dose is renally excreted as unchanged zopiclone. In urine, the N-demethyl and N-oxide metabolites account for 30% of the initial dose. The terminal elimination half-life (t1/2z) of zopiclone ranges from 3.5 to 6.5 hours. The pharmacokinetics of zopiclone in humans are stereoselective. After oral administration of the racemic mixture, Cmax (time to maximum plasma concentration), AUC (area under the plasma time-concentration curve) and t1/2z values are higher for the dextrorotatory enantiomer owing to the slower total clearance and smaller volume of distribution (corrected by the bioavailability), compared with the levorotatory enantiomer. In urine, the concentrations of the dextrorotatory enantiomers of the N-demethyl and N-oxide metabolites are higher than those of the respective antipodes. The pharmacokinetics of zopiclone are altered by aging and are influenced by renal and hepatic functions. Drug interactions have been observed with erythromycin, trimipramine and carbamazepine.

Azabicyclo Compounds↗

PubMed1986

Zopiclone. A review of its pharmacodynamic and pharmacokinetic properties and therapeutic efficacy as an hypnotic.

Zopiclone is the first of the cyclopyrrolones, a new class of psychotherapeutic agents possessing a pharmacological profile of high efficacy and low toxicity similar to that of the benzodiazepines. Binding is thought to occur to the benzodiazepine receptor complex, or to a site closely linked to this complex. Although zopiclone exhibits anticonvulsant, muscle relaxant and anxiolytic properties in animals, it finds better use as an hypnotic because of marked sedating effects. In clinical trials, zopiclone (usually 7.5 mg) improved sleep in chronic insomniacs similarly to nitrazepam 5 mg, flurazepam 15 to 30 mg, triazolam 0.5 mg and temazepam 20 mg, but in a single study was slightly less effective than flunitrazepam 2 mg in some evaluation criteria. Sleep induction before surgical procedures in hospitalised patients is satisfactory with zopiclone, but when the drugs are administered a few hours before surgery, diazepam appears to be more effective in alleviating preoperative anxiety. Minimal impairment of psychomotor skills and mental acuity occurs in the morning after a bedtime dose of zopiclone, which has a short half-life of about 5 hours and no long acting metabolites. No serious side effects have been reported in the relatively small number of patients studied to date; the development of 'bitter taste' does not deter patients from continuing therapy. Thus, with its short duration of action zopiclone is a useful alternative to other hypnotics, especially in patients intolerant of residual effects the morning after taking an hypnotic.

Anti-Anxiety Agents↗

PubMed1998

Zopiclone. An update of its pharmacology, clinical efficacy and tolerability in the treatment of insomnia.

Zopiclone is a non-benzodiazepine hypnotic which was first reviewed in Drugs in 1986. At that time, zopiclone had shown hypnotic efficacy superior to that of placebo, but had not been extensively compared with benzodiazepine hypnotics in patients with insomnia. A much larger body of clinical data is now available, allowing a more detailed evaluation than was previously possible. Together with results from earlier studies, subsequent clinical trials have shown that zopiclone is generally at least as effective as the benzodiazepines (regardless of duration of action) in the treatment of insomnia, although comparisons between zopiclone and flurazepam have produced inconsistent results. Tolerance to the effects of zopiclone was not seen in short term clinical trials (< or = 4 weeks); data from longer term studies are conflicting and the potential for tolerance during long term zopiclone treatment is therefore unclear. Zopiclone has a relatively low propensity to cause residual clinical effects (such as difficulty in waking or reduced morning concentration). Rebound of insomnia to a level below that at baseline can occur after withdrawal of zopiclone, but, on the basis of data from short term studies, does not appear to be common. Data from prescription-event monitoring suggest that zopiclone does not have a high dependence potential (at least in those who are not regular drug abusers/addicts). Zopiclone is well tolerated in both the elderly and younger patients with insomnia. A bitter aftertaste is usually the most common adverse event, but is relatively infrequent (3.6% in the largest available postmarketing study). Thus, zopiclone is now firmly established as an effective and well tolerated hypnotic agent. Although the available data on rebound insomnia and dependence liability are encouraging, potential differences between zopiclone and the benzodiazepines in these respects may have little clinical relevance in the context of short term intermittent use of hypnotics, as it currently recommended. A low propensity for rebound insomnia and dependence might prove valuable during long term hypnotic therapy (which, although not recommended, is a clinical reality). However, the risk-benefit profile of zopiclone in this context remains unknown. Nevertheless, zopiclone is clearly a suitable alternative to the benzodiazepines for the short term treatment of insomnia.

Azabicyclo Compounds↗

PubMed1996

Clinical management of patients with insomnia. The role of zopiclone.

Insomnia, especially when chronic, is associated with disturbances in daytime well-being and performance, resulting in a poor quality of life for those affected. Zopiclone has been proven as a drug that favourably balances sleep induction and maintenance as well as an improvement in daytime well-being (efficacy) with a low potential for adverse effects (safety) in the symptomatic treatment of insomnia. Management of chronic insomnia with zopiclone needs a multidimensional approach involving the proper diagnosis of possible underlying causes, and combined use of causal treatment, general sleep hygiene measures, basic elements of psychological treatment and adjunctive medication. It is recommended that therapy with the nonbenzodiazepine hypnotic zopiclone should conform to the guidelines for the use of hypnotics, which are valid for all benzodiazepine receptor agonists.

Azabicyclo Compounds↗

PubMed1996

Health-related quality of life in patients with insomnia treated with zopiclone.

Insomnia can cause impaired productivity and absenteeism from work, increased risk of accidents, and impaired quality of family and social life. Thus, it can compromise quality of life in affected individuals and result in costs to society as a whole. The nonbenzodiazepine hypnotic zopiclone is effective and well tolerated in the treatment of insomnia. Importantly, it also has minimal effects on next-day performance and psychological function. 458 patients treated with zopiclone for 14 days showed significantly greater improvement compared with placebo recipients in sleep evaluation questions and scores for activity, social and professional quality-of-life aspects. After 8 weeks, the improvement in scores for sleep, activity and social questions remained significantly higher in patients who had received zopiclone compared with placebo recipients. No significant differences were observed between 167 patients who had been taking zopiclone for at least 12 months and a control group of 381 persons with no sleep problems in virtually all of the 5 aspects of the quality-of-life questionnaire. Some important aspects such as relationships and professional life were not modified by zopiclone. When insomnia is treated appropriately, compared with no treatment, patients' feelings about their quality of life are improved and, furthermore, do not appear to differ significantly from perceptions of quality of life in those without sleep-related problems.

Azabicyclo Compounds↗

PubMed2001

A general model of the effects of sleep medications on the risk and cost of motor vehicle accidents and its application to France.

BACKGROUND: Although various prescription drugs may be equally effective in promoting sleep, some may lead to substantial impairment in psychomotor functioning and an increased risk of motor vehicle accidents. OBJECTIVE: To develop a general model to evaluate the potential effects of sleep medications on motor vehicle accidents and costs, and apply the model to the French setting. METHODS: Impairment in driving performance, as evaluated by randomised controlled open-road studies using the standard deviation of a vehicle's lateral position (SDLP), a measure of weaving, was expressed in terms of equivalent blood alcohol (ethanol) concentration (BAC). Epidemiological data were then used to relate BAC to the excess risk of motor vehicle accidents. Although a non-impairing medication would not increase risk, a medication that produces mild impairment in driving performance (a change of 2.5 cm in SDLP, equivalent to 0.05% BAC) would increase motor vehicle accident risk by 25%. One that leads to moderate impairment (an SDLP change of 4.5 cm, equivalent to 0.08% BAC) would roughly double this risk, and a severely impairing medication (an SDLP change of 7 cm, equivalent to 0.12% BAC) would result in up to a 5-fold increase in motor vehicle accident risk. For application to the French setting, a hypothetical cohort of 100,000 adult drivers with insomnia was assumed to be treated for 14 days either with zaleplon 10 mg, a new sleep medication that has been shown not to significantly impair driving performance, or zopiclone 7.5 mg, which has been shown to cause moderate impairment. RESULTS: Compared with zaleplon, use of zopiclone over 14 days in France would be expected to result in 503 excess accidents per 100,000 drivers at an additional cost of 158 French francs (31 US dollars) per person (1996 values). CONCLUSIONS: Our model illustrates the extent to which non-impairing sleep medications could reduce the burden posed by motor vehicle accidents. Our model is designed to be general, and thus can serve as the basis for similar investigations.

Accidents, Traffic↗

PubMed2002

Efficacy and safety of tianeptine in major depression: evidence from a 3-month controlled clinical trial versus paroxetine.

OBJECTIVE: This study was performed to compare the efficacy and safety of tianeptine and paroxetine in the treatment of major depression. Anxiolytic drug use was systematically reported to provide an indirect evaluation of the anxiolytic activity of both treatments. Zopiclone use was assessed to provide an indirect evaluation of the possible hypnotic activity of both treatments. DESIGN AND SETTING: This was a 3-month controlled, randomised, double-blind clinical trial which involved 82 centres in France. PATIENTS: 277 outpatients who met DSM-IV criteria for major depression. INTERVENTIONS: Patients were treated with either tianeptine (12.5mg three times daily) or paroxetine (20mg once daily plus two placebo capsules). The drug dosages could be doubled after 3 weeks if required by the patient's medical state. MAIN OUTCOME MEASURES AND RESULTS: There was a significant decrease in the Montgomery-Asberg Depression Rating Scale score in both groups (from 28.9 at baseline to 11 at endpoint in the tianeptine group, and from 29.6 to 11.6 in the paroxetine group) after 3 months of treatment. No significant difference was evident between the groups. Secondary criteria confirmed the antidepressant efficacy of both medications, with no difference between tianeptine and paroxetine (Hamilton Depression Rating Scale global score at endpoint, Clinical Global Impression final scores, number of responders, delay-to-response, rate of dosage doubling at day 21). The anxiolytic and hypnotic consumption rates decreased in both groups, with no significant difference between the groups. There was no significant difference in clinical safety parameters. CONCLUSION: Tianeptine appears to be as effective and as safe as paroxetine for the ambulatory treatment of major depression.

Adolescent↗

PubMed2003

Clinically important drug interactions with zopiclone, zolpidem and zaleplon.

Insomnia, an inability to initiate or maintain sleep, affects approximately one-third of the American population. Conventional benzodiazepines, such as triazolam and midazolam, were the treatment of choice for short-term insomnia for many years but are associated with adverse effects such as rebound insomnia, withdrawal and dependency. The newer hypnosedatives include zolpidem, zaleplon and zopiclone. These agents may be preferred over conventional benzodiazepines to treat short-term insomnia because they may be less likely to cause significant rebound insomnia or tolerance and are as efficacious as the conventional benzodiazepines. This review aims to summarise the published clinical drug interaction studies involving zolpidem, zaleplon and zopiclone. The pharmacokinetic and pharmacodynamic interactions that may be clinically important are highlighted. Clinical trials have studied potential interactions of zaleplon, zolpidem and zopiclone with the following types of drugs: cytochrome P450 (CYP) inducers (rifampicin), CYP inhibitors (azoles, ritonavir and erythromycin), histamine H(2) receptor antagonists (cimetidine and ranitidine), antidepressants, antipsychotics, antagonists of benzodiazepines and drugs causing sedation. Rifampicin significantly induced the metabolism of the newer hypnosedatives and decreased their sedative effects, indicating that a dose increase of these agents may be necessary when they are administered with rifampicin. Ketoconazole, erythromycin and cimetidine inhibited the metabolism of the newer hypnosedatives and enhanced their sedative effects, suggesting that a dose reduction may be required. Addition of ethanol to treatment with the newer hypnosedatives resulted in additive sedative effects without altering the pharmacokinetic parameters of the drugs. Compared with some of the conventional benzodiazepines, fewer clinically important interactions appear to have been reported in the literature with zaleplon, zolpidem and zopiclone. The fact that these drugs are newer to the market and have not been as extensively studied as the conventional benzodiazepines may be the reason for this. Another explanation may be a difference in CYP metabolism. While triazolam and midazolam are biotransformed almost entirely via CYP3A4, the newer hypnosedatives are biotransformed by several CYP isozymes in addition to CYP3A4, resulting in CYP3A4 inhibitors and inducers having a lesser effect on their biotransformation.

Acetamides↗