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) THERAPEUTIC CLASS: Pyrazolopyrimidine Hypnotic, Non-benzodiazepine PREPARED BY: Mina Kim, PharmD DATE OF REVIEW: Table 1: Non-benzodiazepine Hypnotics Generic Brand Manufacturer Zaleplon Sonata® King Pharmaceuticals Zolpidem Ambien CR® Sanofi-Aventis CR Zolpidem Ambien® Various Eszopiclone Lunesta® Sepracor Ramelteon Rozerem® Takeda Pharmaceuticals Formulary No No Yes No No
BACKGROUND: Insomnia is a sleep disorder characterized by insufficient or inadequate sleep despite adequate opportunity to sleep. Patients may experience one or more of the following symptoms: • Difficulty initiating or maintaining sleep • Poor-quality sleep • Frequent or early awakening • Inadequate total sleep time (TST) All of these symptoms may result in the patient experiencing daytime sleepiness, general tiredness, irritability, and changes in alertness and cognitive function. According to the National Academy of Sciences Institute of Medicine, insomnia affects as many as 70 million U.S. adults and about 30 million people suffer from chronic insomnia. Insomnia is classified as either primary or secondary insomnia. Primary insomnia is caused by an unknown etiology and is not found to be directly associated with any other health conditions. Secondary insomnia, also referred to as “comorbid insomnia” by the National Institute of Health State of the Science, is associated with other health conditions/diseases. Insomnia may also be considered transient, lasting 2-3 nights in a single week; acute (short-term), lasting 1-4 weeks; or chronic, lasting longer than a month. Acute insomnia can occur due to various reasons including life stress (e.g. job loss, death of a loved one, divorce), illness, or jet lag. Chronic insomnia is frequently associated with psychiatric or medical conditions. Medications, such as anticonvulsants, bronchodilators, stimulants, steroids, etc., may also cause insomnia. The treatment of insomnia involves both pharmacologic and nonpharmacologic therapies. Pharmacologic interventions, especially in the treatment of transient and
In healthy patients. effort should be made to identify and treat any underlying causes of insomnia. leading to altered conduction across the cell membrane. an influx of chloride ions occurs. inhibitory neurotransmitters in the central nervous system. This drug has not been shown to increase total sleep time or decrease the number of awakenings. and psychomotor functioning. Nonclinical studies have shown zaleplon to bind selectively to the brain omega-1 (α1β1γ2) receptor on the alpha subunit PHARMACOKINETICS: The pharmacokinetics of zaleplon has been investigated in more than 500 health subjects (young and elderly). In all situations. The alpha subunits found on GABAA receptors are highly concentrated in areas of the CNS responsible for cognition. The alpha1 subunit primarily mediates sleep. and the alpha3 and alpha5 subunits regulate anticonvulsant activity. neuronal cell hyperpolarization and action potential inhibition. the pharmacokinetic profile was examined after single doses up to 60mg and once-daily administration of 15mg and 30mg for 10 days. decrease sleep latency and improve sleep maintenance Ramelteon Treatment of insomnia characterized by difficulty with sleep onset CLNICAL PHARMACOLOGY: Nonbenzodiazepine receptor agonists modulate the activity of gamma-aminobutric acid (GABA). Pharmacologic treatment includes nonbenzodiazepine benzodiazepine receptor agonists. at the receptor. memory. and 1 gamma1 subunits.acute insomnia. By binding to the GABAA receptor complex. primarily 2 alpha1. should be reserved for those who have failed nonpharmacologic treatment. nursing mothers. GABAA receptor accounts for more than half of the GABA receptors in the brain and is made up of protein subunits. and patients with hepatic or renal disease. the alpha2 subunit mediates anxiolysis and muscle-relaxant effects. . benzodiazepine receptor agonists. a melatonin receptor agonist. shown to decrease sleep latency Eszopiclone Treatment of insomnia. trazodone. and ramelteon. . Table 2: FDA-Approved Indications for Nonbenzodiazepine Agents Agent Approved Indication Zaleplon Short-term treatment of insomnia. 2 beta2. INDICATIONS: Zaleplon is indicated for the short-term treatment of insomnia and it has been shown to decrease the time to sleep onset for up to 30 days in controlled clinical trials. not been shown to increase total sleep time or decrease the number of awakenings Zolpidem Treatment of insomnia characterized by difficulties with sleep onset CR and/or sleep maintenance Zolpidem Short-term treatment of insomnia characterized by difficulties with sleep initiation.
After oral administration.75 Duration (h) 1–4 2.8 (%) Tmax (h) 1 1. Elimination occurs quickly with a mean terminal-phase elimination half-life (t1/2) of approximately 1 hour. It is not sensitive to changes in protein binding as its in vitro plasma protein binding is approximately 60% ± 15% and is independent of zaleplon concentration over 10 ng/mL–1000 ng/mL.5 52 – 59 82 Metabolism Hepatic Hepatic Hepatic Hepatic Excretion Renal/Feca Renal and biliary Renal Renal l Food When zaleplon was administered with a high-fat/heavy meal.5 1 0.6 Protein Binding 60 92. Zaleplon is also uniformly distributed throughout the blood without extensive distribution into red blood cells with a blood to plasma ratio of 1. the absorption of zaleplon was prolonged and the tmax was delayed to approximately 2 hour with the Cmax being reduced by ~35%. Table 3: Pharmacokinetics of Zaleplon and Other Nonbenzodiazepine Receptor Agonists Agent Zaleplon Zolpidem Zolpidem Eszopiclone Ramelteon CR Bioavailability 30 70 70 80 1. zaleplon is primarily metabolized by aldehyde oxidase to 5oxo-zaleplon. Although it is well absorbed. Zaleplon also undergoes extensive high first-pass metabolism with a hepatic extraction ratio of 0. has been found in the urine.6 1. which is subsequently converted rapidly to 5-oxo-desethylzaleplon. has a volume of distribution of ~1. Special Populations Age Not significantly different from those of young healthy patients .4 L/kg following IV administration and extensive distribution into extravascular tissue. Both of these oxidative metabolites are converted to glucoronides and eliminated in the urine. zaleplon is also metabolized by CYP3A4 to desethylzaleplon.5 – 6 6–8 6–7 t1/2 (h) 1 2. Within 48 hours. an additional 17% was found in the feces. Zaleplon.Zaleplon is rapidly and almost completely absorbed following oral administration with time to peak concentration (tmax) occurring approximately 1 hour after oral administration. The oral and IV plasma clearance of zaleplon is 3 L/h/kg and 1 L/h/kg respectively.8 6 1 – 2. mostly as 5-oxo-zaleplon. To a lesser extent. By the end of 6 days. 70% of the administered dose. a lipophilic compound. the bioavailability is only approximately 30% due to significant presystemic metabolism. Less than 1% of the dose administered is excreted unchanged in the urine. mostly as zaleplon metabolites and glucoronides.7.6 2.
In patients with decompensated cirrhotic livers. CLINICAL EFFICACY: Table 4: Commonly Assessed Efficacy End Points in Clinical Trials Efficacy Assessment Definition Sleep onset latency The amount of time between the participant’s lying down and sleep onset Number of The number of wake periods lasting at least 1 minute and awakenings occurring after the onset of persistent sleep Wake time after sleep The amount of time spent awake in bed following the onset attainment of sleep Total sleep time The total time spent asleep in bend Sleep efficiency The amount of time spent asleep as a percentage of the total time spent in bed . Hepatic Zaleplon is primarily metabolized by the liver and undergoes significant presystemic metabolism. diet. the effect of race on the pharmacokinetics of zaleplon has not been well established. This may have occurred due to different body weights.Gender No significant difference between men and women Race Pharmacokinetics was studied in Japanese subjects and in this group Cmax and AUC was increased by 37% and 64% respectively. etc. Overall. environment. It is recommended to reduce the dose in patients with mild to moderate hepatic impairment and to avoid use in severe hepatic impairment. there were marked increases in Cmax and AUC. This medication has not been studied in patients with severe renal impairment. Renal No dose adjustment needed in mild to moderate renal impairment as <1% of the administered dose is renally excreted.
number of awakenings. zaleplon 10 mg (N=121).+3 of placebo run=out period Safety assessments based on reports of adverse events and physical examinations. restless less • Median sleep duration was significantly longer at weeks 1-4 with zolpidem (p≤0. and neurologic impairment assessments Adverse Effects: • No significant differences in adverse events between treatment groups and placebo Commona Treatment-Emergent Adverse Events Reported in Any Active Treatment Group at Twice the Rate or More of That Reported in the Placebo Group Zaleplon Zolpidem Placebo 5 10 20 10 N=126 N = 121 N = 120 N = 124 N = 122 Body System N % N % N % N % N % Body as a whole Abdominal pain 4 3 1 <1 11 9 7 6 7 6 Asthenia 4 3 6 5 10 8 6 5 6 5 Nervous system Amnesia 3 2 1 <1 5 4 5 4 6 5 Paresthesia 3 2 1 <1 9 8 6 5 4 3 Somnolence 1 <1 3 2 6 5 3 2 6 5 Respiratory system Pharyngitis 4 3 5 4 2 2 2 2 9 7 Special senses Taste perversion 4 3 3 2 7 6 5 4 1 <1 a Reported by ≥5% of patients in any treatment group Limitations: Although zaleplon and zolpidem were both studied in this trial.001) versus Purpose: syndrome. zaleplon 20mg (N=124). Farr I. et al. and sleep quality Treatment Groups: • Zaleplon 5. or a major psychiatric disorder To compare the placebo while zaleplon 20 mg prolonged sleep duration only at weeks 1. double-blind treatment period (28 nights). mild nonpsychotic psychiatric disorder based on the Diagnosis placebo (p≤0. Inclusion Criteria: Primary Endpoints: Randomized.05) • Age 18-65 years • Zolpidem caused significant rebound insomnia and withdrawal symptoms versus placebo Published • Any race (p≤0. 5mg (N=122). or placebo (N=126) under double-blind conditions. no statistical comparisons were made between the two drugs Conclusion: Zaleplon is well suited for people who have trouble falling asleep. a Novel Nonbenzodiazepine Hypnotic Design Methods Results Multicenter. • Meet criteria for primary insomnia or insomnia associated with • Median sleep latency was significantly reduced at weeks 1-4 with zaleplon 10 and 20 mg versus Double-Blind. vital signs.• Zaleplon 5 mg and zolpidem 10 mg significantly decreased median sleep latency only during Controlled R) weeks 1-3 versus placebo (p≤0. 10.05) Placebo and Statistical Manual of Mental Disorders.05) 4 weeks Exclusion Criteria: • No statistical difference in withdrawal symptoms between zaleplon treatment group and placebo • Experienced transient insomnia.05) in outpatients with DSM-III-R insomnia and also using Zolpidem 10mg as an active comparator Population: Total of 615 patients were randomly assigned to receive either zaleplon. single-blind placebo run-in period (7 nights). 2. or insomnia group on any night after the treatment study period ended Study Size: associated with sleep-wake schedule or the use of alcohol/drugs 615 adults Secondary Endpoints: • History or current manifestations of sleep apnea.05) or the Zung Self-Rating Depression Scale was >49 of 3 doses of • No significant difference in number of awakenings between all treatment groups and placebo zaleplon with Primary Endpoints: • Sleep quality was significantly improved at weeks 1-4 with zolpidem 10 mg versus placebo those of placebo • Patient’s assessment of sleep latency (p≤0. electrocardiograms.05) while zaleplon 10 and 20 mg improved sleep quality only during week 1 (p≤0.+2. laboratory determinations. single-blind placebo run-out period (3 nights) • Presleep and Postsleep questionnaires • • Postsleep questionnaire to assess rebound insomnia Withdrawal effects evaluated with Benzodiazepine Withdrawal Symptom Questionnaire completed morning after the last night of placebo run-in period (baseline) and 2 and 4 weeks of doubleblind treatment. Ruther E.05) during the first night after the study ended Duration of • Nonpregnant women • Zaleplon 10 and 20 mg caused significantly more rebound insomnia for the number of Study: awakenings in patients during the second night after the study ended (p≤0. zolpidem 10mg (N=122). This medication has a favorable safety profile with no rebound insomnia or withdrawal effect after discontinuation of treatment • . Third Edition (DSM-III. Sleep Latency is Shortened During 4 Weeks of Treatment with Zaleplon. and after nights +1. situational insomnia. and 4 versus placebo • Patients whose raw score on the Zung Self-Rating Anxiety Scale efficacy and safety (p ≤ 0. 20 mg • • Zolpidem 10 mg Placebo Assessments • 4 phases: prestudy washout period (1-3 weeks). • • Rebound insomnia and withdrawal effects Adverse effects Secondary Endpoints: • Patient’s assessment of sleep duration.Elie R.
• No placebo control difficulties getting neuroleptics. zaleplon (cephalgia Assess the • Patients currently being treated by zolpidem or zaleplon requiring analgesic treatment. Gandon J. previous history of recurrent episodes of insomnia. barbiturates or • No washout period between nights to sleep between hypnotics • Patients were mostly individuals with transient insomnia and thus results cannot be zolpidem or generalized to patients with chronic insomnia zaleplon Primary Endpoints: • Patients were identified and included based on clinical judgment of physicians • Preference for insomniacs between single dose of 10 mg zaleplon Population: and zolpidem 53 patients with a Conclusion: history of Patients with intermittent insomnia tended to prefer zolpidem on both nocturnal and diurnal Secondary Endpoints: recurrent episodes assessments • Assess sleep quality and quality of the following day of insomnia and currently • Safety complaining of difficulties in Treatment Groups: falling asleep were • Zolpidem-zaleplon sequence (N = 25) included into a • Zaleplon-zolpidem sequence (N = 28) study by 12 general Assessments practitioners • Assess patient’s preference between the two investigational drugs using a questionnaire filled by the patient in the evening of the day following the second night of administration of the drugs • Leeds sleep evaluation questionnaire to assess the quality of sleep (getting to sleep.Allain H. anxiety and mood) Adverse effects recorded in case report form . abdominal fullness. anxiolytics. consciousness.0001) with zolpidem compared with zaleplon. H1 antihistamines. impaired concentration. no difference between ease of waking up and • Current episode having lasted more than 3 weeks Single-dose cross behavior following wakefulness over study • Any secondary insomnia resulting from medical or psychiatric • No significant difference in sleep duration between both drugs causes Study Size: • Day quality: significant increase on the quality of sleep with zolpidem compared with zaleplon • Patients who followed a continuous treatment with the same 53 adults (p<0.0001). quality of sleep. dynamism. leg complaints). headache. Le Breton S. Bentue-Ferrer D. mood or hypnotic for more than six months drowsiness duration • Patients who took hypnotic drugs the day before inclusion Purpose: • Safety: zolpidem (sluggish tongue. Preference of insomniac patients between a single dose of zolpidem 10 mg versus zaleplon 10 mg Design Methods Results Multicenter. • Age between 40 and 65 years Double Blind. dynamism.08) although 62% of patients preferred investigator: patient displayed insomnia with difficulty falling zolpidem asleep. Inclusion Criteria: No statistical differences between the two groups at baseline Randomized. vertigo) preference of Night-shift work insomniac patients • Limitations: complaining of • Current medical treatment including antidepressants. Polard E. and behavior following wakefulness) • Sleep duration • • Quality of the day using six 100 mm visual analogue scales filled on the evening of the day following each of the two administration (quality of sleep. drowsiness.03) and quality of sleep Exclusion Criteria: Study: (p<0. anxiety. Primary Endpoints: • Clinical examination judged compatible with the study by the Cross Over • No statistical difference between the two groups (p=0. and Published justified for treatment with hypnotics Secondary Endpoints: Duration of • Sleep quality: significantly greater increase in getting to sleep (p=0. ease of waking from sleep. no significant difference on consciousness. drowsiness – including duration.
Primary Endpoints: month history of primary insomnia as defined by the Diagnostic Placebo • Sleep latency was significantly reduced by zolpidem during weeks 1 (p≤0.001) usual sleep time ≤ 6.05).05) and total sleep time (p<0. A Novel Nonbenzodiazepine Hypnotic.001) but not during week 1 Duration of Study: • Median total sleep time with zolpidem was significantly prolonged at weeks 1 (p<0. single-blind placebo post-treatment period (7 days) • Daily sleep questionnaires • • Safety assessments based on reports of adverse events and results of routine physical examinations. and electrocardiograms Rebound insomnia assessed from sleep data derived from postsleep questionnaires completed after the first placebo discontinuation night . restless leg syndrome. recording of vital signs. Walsh J. number of awakenings. Increase in total sleep time tended to increase as well with the 10-mg dose during the 2 weeks of treatment with zaleplon with no change seen with the lower dose. Zolpidem decreased subjective sleep latency and increased subjective total sleep time but more residual effects/rebound insomnia was seen compared to placebo.Ancoli-Israel S. sleep quality) Secondary Endpoints: • Safety assessments • somnolence and rhinitis. or if their sleep complaint Purpose: 1 (p<0. Side effect and rebound insomnia was minimal in this population. Fujimori M. • Elderly (≥65 years of age) men and women with at least a 3Double-Blind.01) and Statistical Manual of Mental Disorders. Effectively Treats Insomnia In Elderly Patients Without Causing Rebound Effects Design Methods Results Multicenter. pain. Assessments • 3 phases: single-blind placebo screening/baseline week (7 days). no significant difference between either zaleplon dose and placebo in terms of CNS adverse events. Fourth Edition (DSMControlled IV) at study entry versus placebo • History must have included a usual sleep latency of 30 minutes or • Zaleplon 10 mg significantly reduced sleep latency for both study weeks versus both placebo Published more and either 3 or more awakenings per night on average or a (p≤0.5 hours • Zaleplon 5 mg significantly reduced sleep latency during week 2 (p<0.01) and 2 (p<0.001) compared to placebo • Rebound insomnia Treatment Groups: • Zaleplon 5 or 10 mg • • Zolpidem 5 mg Placebo Conclusion: Zaleplon 10 mg was shown to consistently shorten subjective sleep latency in elderly patients with insomnia while zaleplon 5mg was shown to be effective only in week 2. laboratory determinations.05) • If physical examination or routine clinical laboratory assessments effectiveness and while zolpidem showed significance during both weeks of treatment (p<0.01) versus placebo • Pre-existing medical condition that would affect the study results • Zaleplon 10 mg demonstrated total sleep time that was significantly longer than placebo only Study Size: • If the raw score on the Zung Self-Rating Anxiety and Depression during week 1 (p<0. double-blind treatment period (14 days).05) 549 adults Scale administered during screening were ≥ 50 • Only zolpidem-treated patients experienced significantly reduced nighttime awakenings at weeks • Sleep apnea.05) versus placebo was considered to be secondary to nicotine use To study the • Zaleplon 10 mg showered significantly better median sleep quality during the first week (p<0.001) and zolpidem (p<0. Population: 549 elderly patients (≥65 years of age) with insomnia Primary Endpoints: • Efficacy variables collected from daily postsleep questionnaires (sleep latency.001) safety of zaleplon included a clinically important abnormality for treatment in • Caffeine-containing beverage was ≥ 5 cups/day or if they drank Secondary Endpoints: the elderly caffeine-containing beverages late in the day • Safety assessment: most common treatment-emergent adverse events were headache.001) and 2 Exclusion Criteria: 2 weeks (p<0. no clinically important physical or neurologic examination findings Rebound insomnia: zaleplon 5 and 10 mg showed no significant difference from placebo on discontinuation night 1 while zolpidem 5 mg displayed significantly higher rebound insomnia with sleep latency (p<0. Zaleplon. CNS adverse events were significantly greater for zolpidem compared to placebo (p<0. Inclusion Criteria: No statistical differences between the two groups Randomized.05) and 2 (p<0. total sleep time. Mangano R.
randomized. incomplete block crossover study 36 healthy subjects Study Drug Zaleplon 10 mg or Zolpidem 10mg or Placebo Key Findings Assessment of residual effects of treatment administered at 5. and memory function (immediate and delayed free recall and Sternberg memory scanning) compared to placebo Zolpidem 10 mg showed significant residual effects on DST and memory (immediate and delayed free recall) after administration of up to 5 h before waking and choice reaction time. Zaleplon did not significantly impair psychomotor performance.Reference Danjou et al (2000) Study Design Double-blind. placebo-controlled. cross over study 31 patients with mild to moderate COPD Zaleplon 10 mg or Zolpidem 10 mg or Placebo . critical flicker fusion threshold and Sternberg memory scanning after administration up to 4 h before waking No p values were provided Both treatments reduced objective sleep latency versus placebo: zaleplon (21 min) versus zolpidem (37. 3. 4.5 min) Only zolpidem improved objective total sleep time and reduced the number of awakenings after onset No difference in oxygen saturation were observed between treatments George et al (1999) Double-blind. choice reaction time. digit symbol substitution test. or 2 h before morning awakening No residual effects were demonstrated after zaleplon 10 mg when administered as little as 2 hours before waking. randomized. arousal and cognitive function on critical flicker fusion.
somnolence. depression. arthralgia. pruritis. migraine. rash. conjunctivitis. dyspepsia. dizziness. including severe reactions DRUG INTERACTIONS Zaleplon is metabolized primarily by aldehyde oxidase and to a lesser extent CYP3A4. dry mouth. abnormal thinking. and eye pain. anxiety. arthritis. Table 4 reports incidence of treatment-emergent adverse events for a pool of three 28-night and one 35-night placebo-controlled Sonata study at doses of 5 or 10mg and 200 mg. nausea. bronchitis. . Table 4: Incidence(%) of Treatment-Emergent Adverse Events in Long-Term (28 and 35 Nights) Placebo-Controlled Clinical Trials of Zaleplon Body System Placebo Zaleplon 5 or 10 mg Zaleplon 20 mg (n = 344) (n = 569) (n = 297) Body as a whole Abdominal Pain 3 6 6 Asthenia 5 5 7 Headache 35 30 42 Digestive System Anorexia <1 <1 2 Nausea 7 6 8 Nervous system Amnesia 1 2 4 Confusion <1 <1 1 Depersonalization <1 <1 2 Dizziness 7 7 9 Hypoesthesia <1 <1 2 Paresthesia 1 3 3 Somnolence 4 5 5 Tremor 1 2 2 Special senses Abnormal vision <1 <1 2 Eye pain 2 4 3 Hyperacusis <1 1 2 Parosmia <1 <1 2 Urogenital system Dysmenorrhea 2 3 4 Common adverse reactions found in pre-marketing evaluation of Sonata in addition to the above adverse events: back pain. constipation. asthenia. fever. taste perversion Postmarketing reports: Anaphylactic/anaphylactoid reactions. chest pain.ADVERSE REACTIONS: Common adverse effects found in patients taking zaleplon were headache. nervousness. abdominal pain. Inhibitors and inducers of these enzymes are expected to affect the clearance of this medication. myalgia.
Complex behaviors such as “sleep driving. Abnormal thinking and behavioral changes have been reported to occur with the use of sedative/hypnotics.” Other complex behaviors (e. administration of rifampin (600 mg every 24 hours for 14 days) reduced zaleplon Cmax and AUC by approximately 80%. or taking zaleplon is doses higher than the maximum recommended dose. zaleplon should be administered at the lowest possible effective dose. Alternative non-CYP3A4 substrate hypnotic agents should be considered in patients taking CYP3A4 inducers such as rifampin. especially in the elderly. Drugs that Inhibit Both Aldehyde Oxidase and CYP3A4 Cimetidine: Cimetidine inhibits both enzymes involved in the metabolism of zaleplon and concomitant administration of zaleplon (10 mg) and cimetidine (800 mg) produced an 85% increase in the mean Cmax and AUC of zaleplon.Drugs that Induce CYP3A4 Rifampin: Although CYP3A4 is a minor metabolizing enzyme of zaleplon. phenytoin. Zaleplon has been shown to have minimal effects on the kinetics of CNS-active drugs (ethanol. drugs with narrow therapeutic indexes (warfarin and digoxin). bizarre behavior. Rapid dose decrease or abrupt discontinuation of this medication may lead to signs/symptoms of withdrawal. drugs highly bound to plasma protein. imipramine. preparing and eating food. and venlafaxine). It is recommended to discontinue zaleplon in the presence of “sleep driving. hallucinations. or having sex) and emergence of any new behavioral symptom of concern should receive careful and immediate evaluation.g. An initial dose of zaleplon 5 mg should be given to patients who are also taking cimetidine. CONTRAINDICATIONS: Hypersensitivity to zaleplon or any excipients in the formulations WARNINGS: Insomnia that does not remit after 7-10 days of treatment may indicate the presence of an underlying psychiatric or medical disorder attributing to the insomnia. drugs that inhibit CYP3A4. There is an increase risk for this behavior with the alcohol intake.” driving while not fully awake after ingestion of a sedative/hypnotic. drugs that inhibit aldehyde oxidase (diphenhydramine). have been reported to occur. and drugs that alter renal function (ibuprofen). and phenobarbital. agitation. These changes include decreased inhibition. paroxetine. CYP3A4 inducers may lead to the ineffectiveness of zaleplon. Also due to the dose related adverse effects that may occur. use of concomitant CNS depressants. thioridazine. Although not harmful. . and depersonalization. carbamazepine. making phone calls.
Additive CNS-depressant effects may occur when administered with other psychotropic medications. and lightheadedness. Controlled trials of acute administration of zaleplon 10 mg in patients with mild to moderate COPD or moderate obstructive sleep apnea showed no evidence of problems from respiratory depression. Like any other hypnotic. This product also contains FD&C Yellow No. anesthetics. 5 (tartrazine) which may cause allergictype reactions in susceptible patients. or nausea and vomiting suggestive of anaphylaxis have been reported by patients taking zaleplon. narcotic analgesics. No dose adjustments are recommended in patients with mild to moderate renal impairment while no adequate studies have been conducted in patients with severe renal impairment. throat closing. Zaleplon should also be administered with caution in patients with signs/symptoms of depression. and other drugs that produce CNSdepression. It is recommended to reduce the zaleplon dose to 5mg in patients with mild to moderate hepatic impairment while avoiding use in patients with severe hepatic impairment. or larynx) and symptoms such as dyspnea. A staring dose of 5 mg is recommended for elderly patients to decrease possible side effects and due to the concern of increased risk of impaired motor/cognitive performance or unusual sensitivity to sedative/hypnotic drugs. Patients should not be rechallenged if such events occur upon administration of this medication. this medication is a CNS-depressant and patients should be cautioned against engaging in hazardous activities requiring mental alertness or motor coordination. antihistamines. Increased risk of suicidal tendencies may be present with intentional overdosage being common. glottis. caution should still be taken in patients with compromised respiration and careful monitoring should take place. Taking this medication while still up may result in short-term memory impairment. hallucinations. However. . ethanol. Rare cases of angioedema (tongue. Note should also be made that potential impairment may occur the day following ingestion of zaleplon. Careful monitoring along with using the least amount of drug possible should be prescribed for the patient at one time. anticonvulsants. impaired coordination.Zaleplon has a rapid onset of action and should be ingested immediately prior to going to bed or after the patient has gone to bed and has experienced difficulty falling asleep. dizziness. PRECAUTIONS: Zaleplon should be ingested immediately prior to going to bed or after the patient has gone to bed and has experienced difficulty falling asleep.
DRUG ABUSE AND DEPENDENCE: Controlled Substance Class: Schedule IV Abuse Two studies assessed the abuse liability of zaleplon at doses of 25. pulse. However. sweating. following abrupt discontinuation.and 12-month durations by examining the emergence of rebound insomnia following discontinuation of the drug. hyptonia. respiratory depression. insomnia. 28-. and other appropriate signs should be monitored and supportive measures and treatment given as needed. but these situations were often associated with additional CNS depressant overdose. while more serious cases may include symptoms of ataxia. other sedative/hypnotics have been associated with withdrawal symptoms such as mild dysphoria. etc. hypotension. LABORATORY TESTS: No specific laboratory tests are recommended SPECIAL POPULATIONS Pregnancy Pregnancy Category C There are no studies of zaleplon use in pregnant women and therefore the use is not recommended. Mild cases may result in drowsiness. 50. and 75 mg in subjects with known histories of sedative drug abuse and found that this medication has an abuse potential similar to benzodiazepine and benzodiazepine-like hypnotics. Treatment should include symptomatic and supportive measures in addition to immediate gastric lavage or intravenous fluids if appropriate. and rarely coma/death. . Individuals with a history of addiction to or abuse of drugs/alcohol are at risk of dependence and should be carefully monitored while receiving this medication. tremors. mental confusion. convulsions. vomiting. Tolerance No tolerance to zaleplon 10 and 20 mg was found for time to sleep onset over 4 weeks in two 28-night placebo-controlled studies and latency to persistent sleep in one 35night placebo-controlled study where tolerance was evaluated on nights 29 and 30. OVERDOSAGE: Overdose symptoms typically present as exaggerations of the pharmacologic effects of zaleplon and may range from drowsiness to coma. Loss of consciousness has been reported in zaleplon overdose. Pre-marketing studies did not show any evidence for withdrawal symptom following abrupt discontinuation of therapy. Respiration. Rare instances of fatal outcomes following zaleplon overdose has occurred. Dependence Potential for physical dependence and subsequent withdrawal symptoms from zaleplon was examined in controlled studies of 14-. and 35-night durations and in open-label studies of 6. blood pressure. lethargy.
a total of 628 patients were at least 65 years of ages. placebo-controlled.5 mg 10 mg 12. As small amounts of this medication from breast milk may result in potentially important concentrations in infants and because the effects of this medication on infants on nursing infants are not known.Nursing Mothers A study in lactating mothers showed clearance and half-life of zaleplon to be similar to that of young normal subjects. with the highest excretion occurring during feeding approximately 1 hour after Sonata administration. parallel-group clinical trials. A small amount of zaleplon was found to be excreted in breast milk. DOSAGE AND ADMINISTRATION: Agent Dose Maximu m dosage 20 mg Special Instructions Elderly: 5 mg with max of 10 mg Hepatic: Mild to moderate impairment – 5mg Severe impairment – not recommended Cimetidine: Initiate zaleplon at 5 mg daily Take at bedtime and avoid taking with food Elderly/debilitated /hepatically impaired patients: 5mg Take at bedtime and avoid taking with food Elderly/debilitated /hepatically impaired patients: 5mg Swallow whole and do not crush.5 mg Eszopiclone 2 mg 3 mg Ramelteon 8 mg 8 mg . Do not take with or immediately after a meal Elderly patients: 1 mg with max of 2 mg Hepatic: Mild to moderate impairment – no adjustment Severe impairment: 1 mg with max of 2 mg Take at bedtime and avoid taking with food Hepatic: Mild to moderate impairment – no adjustment Severe impairment – not recommended Take within 30 minutes of going to bed Do not take with or immediately after a high-fat meal Zaleplon 10 mg Zolpidem Zolpidem CR 10 mg 12. chew. divide. 14-night. treatment of elderly patients with zaleplon showed no adverse event with a frequency of at least 1% occurred at a significantly higher rate with either 5 or 10 mg doses compared to placebo. Elderly patients with insomnia responded to 5 mg with reduced sleep latency and thus 5 mg is the recommended dose in this population. it is not recommended for nursing mothers to take this medication. Pediatric Use Safety and efficacy of zaleplon has not be established in pediatric patients Geriatric Use In double-blind. Short-term.
0870/tablet 0. 20°C to 25°C (68°F to 77°F) Dispense in a light-resistant container as defined in the USP COST: Drug Zaleplon (Sonata®) Zaleplon (Sonata®) Zolpidem (Ambien®) Zolpidem (Ambien®) CONCLUSION: Zaleplon is indicated for and has been shown to be effective in the treatment of short-term insomnia • According to the prescribing information as well as data from clinical trials.0101/tablet 0. Due to the drug’s faster time to peak onset and shorter half-life.0670/tablet 0.0097/tablet Inpatient Cost 0. .0759/tablet 0. rebound insomnia and withdrawal effects compared to zolpidem • Dose 5 mg 10 mg 5 mg 10 mg Outpatient Cost 0. this drug has not been shown to increase total sleep time • This drug has shown no benefit over zolpidem in improving sleep maintenance or quality of sleep • Clinical trials have shown this drug to have significantly less residual effects.0914/tablet We do not recommend zaleplon (Sonata®) to be added to the formulary at this time as it has not shown to have benefit over zolpidem in sleep maintenance.PRODUCT AVAILABILITY: Zaleplon capsules are supplied as follows: 5 mg: opaque green cap and opaque pale green body with “5 mg” on the cap and “SONATA” on the body (NDC 60793-145-01) Bottles of 100 10 mg: opaque green cap and opaque light green body with “10 mg” on the cap and “SONATA” on the body (NDC 60793-146-01) Bottles of 100 STORAGE CONDITIONS: Store at controlled-room temperature. it may reduce sleep latency and residual effects.1823/tablet 0. Yet there is no evidence from clinical trials to show superiority to zolpidem other than causing less residual and rebound effects.3900/tablet 0.
4. Series F.L. Ambien (zolpidem tartrate) [package insert]. 10. a novel nonbenzodiazepine hypnotic. Gandon J-M.1(4):114-120. Elie R. Lunesta (eszopiclone) tablets [package insert]. Thompson C. 2003. 9. Mangano RM. 2005. Emilien G. Marlborough. Preference of insomniac patients between a single dose of zolpidem 10 mg versus zaleplon 10 mg. Fujimori M. Zaleplon improves sleep without producing rebound effects in outpatients with insomnia. Bristol. Moscovitch A. 2007. Ill: Takeda Pharmaceuticals America. 5. 3. Nonbenzodiazepine Agents for Insomnia. George CFP. for the Zaleplon Clinical Study Group. Prim Care Companion J Clin Psychiatry. Allain H. Inc. and the Zaleplon Clinical Study Group. Polard E. Farr I. 2004. J Clin Psychiatry. www. Kryger MH.UHC. Abstract C527. . 2006. NY: Sanofi-Synthelabo Inc. 8. Inc. Sleep. a novel nonbenzodiazepine hypnotic. Bentué-Ferrer D. Salinas E. UHC Drug Monographs.edu Sonata (zaleplon) capsules [package insert]. 2. Rüther E. New York. 6. 2000. effectively treats insomnia in elderly patients without causing rebound effects. Mangano R.22(suppl):S320. 2005. Sleep latency is shortened during 4 weeks of treatment with zaleplon. for the Zaleplon Clinical Study Group. 1999. Ancoli-Israel S. Rozerem (ramelteon) tablets [package insert].18(5):369374. Fry J. Safety and efficacy of zaleplon versus zolpidem in outpatients with chronic obstructive pulmonary disease (COPD) and insomnia [abstract]. Zaleplon. Int Clin Psychopharmacol. 1999. 1999.REFERENCES: 1. Fujimori M. MA: Sepracor Inc. 7. Hum Psychopharmacol Clin Exp. Scharf M. Lincolnshire.15(3):141152.60(8):536-544. Walsh JK. Le Breton S. TN: King Pharmaceuticals.
and phenobarbital Could not find any data on if zaleplon powder could be removed from capsule and administered through a feeding tube .Other Pertinent Information: • • Zolpidem and zaleplon both interact with CYP3A4 inducers such as rifampin. phenytoin. carmabazepine.