FDA approved a REMS for zolpidem to ensure that the benefits of a drug outweigh the risks. The REMS may apply to one or more preparations of zolpidem and consists of the following: medication guide. See the FDA REMS page ([Web]) or the ASHP REMS Resource Center ([Web]).
Conventional tablets used for short-term management of insomnia characterized by difficulties with sleep initiation. Decreases sleep latency in patients with chronic or transient insomnia; no substantial evidence of diminished effectiveness during the end of each night’s use (early morning insomnia) despite short half-life.
Extended-release tablets used for management of insomnia characterized by difficulty with sleep onset or sleep maintenance.
Dosage and Administration
General
Use only when able to get 7–8 hours of sleep before being active again.
Reevaluate patient if zolpidem is to be used for more than 2–3 weeks. (See Adequate Patient Evaluation under Cautions.)
Avoid abrupt discontinuance after prolonged (e.g., longer than 1–2 weeks) therapy; consider gradual dosage reduction (e.g., over several nights) when discontinuing short-term therapy.
Administration
Oral Administration
Administer immediately before going to bed when ready to go to sleep.
Onset of sleep may be facilitated by taking the drug on an empty stomach. Do not administer extended-release tablets with or immediately after a meal. (See Food under Pharmacokinetics.)
Swallow extended-release tablets whole; do not divide, crush, or chew.
Dosage
Available as zolpidem tartrate; dosage is expressed in terms of the salt.
Individualize dosage; use smallest effective dose.
Maximum 10 mg daily as conventional tablets. Higher doses (e.g., 15 or 20 mg) occasionally have been used but may be associated with increased risk of adverse effects, including abuse potential.
Possible pharmacokinetic alterations. (see Elimination: Special Populations, under Pharmacokinetics.) Manufacturer recommends close monitoring but states that dosage reduction is not necessary; some clinicians recommend that dosage reduction be considered.
Geriatric or Debilitated Patients
Possible increased sensitivity to sedatives and hypnotics. Initially, 5 mg (as conventional tablets) or 6.25 mg (as extended-release tablets). (See Geriatric Use under Cautions.)
Cautions
Contraindications
Known hypersensitivity to zolpidem or any ingredient in the formulation.
Warnings/Precautions
Warnings
Adequate Patient Evaluation
Insomnia may be a manifestation of an underlying physical and/or psychiatric disorder; carefully evaluate patient before providing symptomatic treatment.
Failure of insomnia to remit after 7–10 days of treatment, worsening of insomnia, or emergence of new abnormal thinking or behavior may indicate the presence of an underlying psychiatric and/or medical condition that requires evaluation.
Adverse Psychiatric Events
Abnormal thinking and behavioral changes (e.g., aggressiveness, uncharacteristic extroversion, bizarre behavior, agitation, hallucinations, depersonalization, amnesia) may occur unpredictably. Possible worsening of depression (including suicidal thinking) with sedative or hypnotic use in patients with depression. Immediately evaluate any new behavioral sign or symptom.
Some adverse effects appear to be dose related; use the lowest effective dose.
Complex Sleep-related Behaviors
Complex behaviors such as sleep-driving (i.e., driving while not fully awake after ingesting a sedative and hypnotic drug, with no memory of the event), preparing and eating food, making phone calls, or having sex while not fully awake after taking a sedative and hypnotic drug, and usually with no memory of the event, reported.
May occur in sedative and hypnotic drug-naive or drug-experienced patients.
Increased risk with concomitant use of alcohol and other CNS depressants or use of the drug at dosages exceeding the maximum recommended dosage; however, may occur with the drug alone at therapeutic dosages.
Consider discontinuing drug in patients who report a sleep-driving episode because of the risk to the patient and community.
Withdrawal Effects
Rapid dosage reduction or abrupt discontinuance of sedatives or hypnotics has resulted in signs and symptoms of withdrawal.
Abuse Potential
Abuse potential similar to that of benzodiazepines and related hypnotics.
Patients with a history of drug or alcohol dependence or abuse are at risk of habituation or dependence; use only with careful surveillance in such patients.
CNS Effects
Rapid onset of CNS effects (sedation, impairment of psychomotor function, impairment of short-term memory); administer only immediately before going to bed.
Performance of activities requiring mental alertness or physical coordination may be impaired the day after ingestion. Some reports of decreased psychomotor and mental performance in adults and geriatric individuals; other studies found no evidence of residual daytime sedative effects. Risk of residual daytime sedation and impaired performance appears to be minimal at usual dosages.
Concurrent use of other CNS depressants may cause additive or potentiated CNS depression. (See Specific Drugs under Interactions.)
Sensitivity Reactions
Angioedema involving the tongue, glottis, or larynx reported rarely following initial or subsequent doses of sedative and hypnotic drugs, including zolpidem. Some patients experienced additional symptoms (e.g., dyspnea, closing of the throat, nausea and vomiting [suggestive of anaphylaxis]). Some individuals required medical treatment in an emergency department. Angioedema reported during postmarketing surveillance.
Airway obstruction may occur if angioedema involves the throat, glottis, or larynx and can be fatal.
Do not rechallenge with the drug if angioedema occurs.
Advise patients to immediately discontinue the drug and inform their clinician if signs of an allergic reaction (e.g., rash, hives, dyspnea, swelling of tongue or throat) occur.
General Precautions
Respiratory Effects
No respiratory depressant effects reported at hypnotic doses in healthy individuals or in patients with mild to moderate COPD; however, decreased oxygen saturation reported in patients with mild to moderate sleep apnea. Respiratory insufficiency reported, mostly in patients with preexisting respiratory impairment.
Use with caution in patients with compromised respiratory function.
Suicide
Use with caution in depressed patients. Potential for suicidal tendencies; overdosage more frequent in such patients. Prescribe and dispense drug in the smallest feasible quantity.
Concurrent Diseases
Limited experience in patients with concurrent systemic disease. Use with caution in patients with diseases affecting metabolism or hemodynamic response. Use zolpidem tartrate extended-release tablets with caution in patients with sleep apnea syndrome or myasthenia gravis.
Specific Populations
Pregnancy
Category C.
Lactation
Distributed into milk in small amounts; potential effects on nursing infants are not known. Use is not recommended.
Pediatric Use
Safety and efficacy of zolpidem tartrate conventional tablets not established in children. Dizziness, headache, and hallucinations reported.
Safety and efficacy of zolpidem tartrate extended-release tablets not established in children <18 years of age.
Geriatric Use
Pharmacokinetic changes in geriatric patients compared with younger adults. (See Absorption and also Elimination, under Pharmacokinetics.)
Potential increased sensitivity to sedatives and hypnotics. Adverse effects tend to be dose related, particularly in geriatric patients. Adverse effect profile in patients ≥65 years of age receiving 6.25-mg dose (as extended-release tablets) similar to that in younger adults receiving 12.5-mg dose.
Use low initial dose and monitor closely. (See Geriatric or Debilitated Patients under Dosage and Administration.)
Hepatic Impairment
Prolonged elimination; reduce initial dose and monitor closely. (See Hepatic Impairment under Dosage and Administration.)
Renal Impairment
Possible pharmacokinetic alterations. (See Elimination: Special Populations, under Pharmacokinetics.) Monitor closely. Some clinicians recommend dosage reduction (see Renal Impairment under Dosage and Administration.)
Common Adverse Effects
With short-term use at recommended dosages: drowsiness or somnolence, dizziness, headache, diarrhea.
Interactions
Metabolized principally by CYP3A4 and to a lesser extent by CYP1A2 and CYP2D6.
Pharmacodynamic interaction (effect on PT) unlikely
Pharmacokinetics
Absorption
Bioavailability
Conventional tablets: Rapidly absorbed following oral administration, with peak plasma concentrations attained in about 1.6 hours. Absolute bioavailability is about 70%.
Extended-release tablets: Exhibit biphasic absorption characteristics; rapid initial absorption following oral administration (similar to conventional tablets), but with extended plasma concentrations beyond 3 hours after administration. Peak plasma concentrations are attained in about 1.5 hours.
Food
Conventional tablets: Food decreases AUC by 15%, decreases peak plasma concentration by 25%, and prolongs time to peak plasma concentration by 60%.
Extended-release tablets: Food decreases AUC by 23%, decreases peak plasma concentration by 30%, and prolongs time to peak plasma concentration by about 2 hours (from 2 hours to 4 hours).
Special Populations
In geriatric patients receiving zolpidem tartrate as conventional tablets, peak plasma concentration and AUC are increased by 50 and 64%, respectively, compared with younger adults.
In patients with chronic hepatic impairment receiving zolpidem tartrate as conventional tablets, peak plasma concentration and AUC are 2 and 5 times higher, respectively, than in healthy individuals. Zolpidem tartrate extended-release tablets not studied to date in patients with hepatic impairment.
Distribution
Extent
Distributed into breast milk in small amounts. Not known whether zolpidem crosses the placenta.
Plasma Protein Binding
Approximately 92%.
Elimination
Metabolism
Metabolized in the liver via oxidation and hydroxylation, principally by CYP3A4 and to a lesser extent by CYP1A2 and CYP2D6. No active metabolites.
Elimination Route
Excreted principally in urine as inactive metabolites.
Half-life
Approximately 2.5 hours (conventional tablets) or 2.8 hours (extended-release tablets).
Special Populations
In geriatric patients receiving zolpidem tartrate as conventional tablets, half-life is increased by 32% compared with younger adults. Half-life is 2.9 hours in geriatric patients receiving zolpidem tartrate 6.25 mg as extended-release tablets.
In patients with cirrhosis receiving zolpidem tartrate as conventional tablets, half-life is about 9.9 hours. Extended-release tablets not studied to date in patients with hepatic impairment.
In nondialyzed patients with chronic renal disease and in patients undergoing periodic dialysis, slower elimination rates reported with IV zolpidem (not commercially available in the US). No substantial pharmacokinetic alterations reported with oral zolpidem in patients with end-stage renal failure undergoing hemodialysis. Extended-release tablets not studied to date in patients with renal impairment.
Not removed by hemodialysis.
Stability
Storage
Oral
Conventional Tablets
20–25°C.
Extended-release Tablets
15–25°C (may be exposed to temperatures up to 30°C).
Actions
Interacts with the CNS GABAA-receptor-chloride ionophore complex at benzodiazepine (BZ, ο) receptors.
Selectivity for the BZ1 receptor may account for the decreased muscle relaxant, anxiolytic, and anticonvulsant effects compared with benzodiazepines reported in animal studies, as well as the preservation of deep sleep (stages 3 and 4) reported in human studies.
Advice to Patients
Provide patient with a copy of manufacturer’s patient information.
Potential risk of complex sleep-related behaviors; importance of immediately informing clinician if sleep-driving events or other complex behaviors occur.
Importance of advising patients to immediately discontinue drug and inform clinician if signs of an allergic reaction (e.g., rash, hives, dyspnea, swelling of tongue or throat) occur.
Importance of administering immediately before retiring.
Importance of taking only when able to get a full night’s sleep (i.e., 7–8 hours) before being active again.
Importance of taking only as prescribed; do not increase dosage or duration of therapy unless otherwise instructed by a clinician.
Importance of not abruptly discontinuing therapy if drug has been used for more than 1–2 weeks; consult clinician about discontinuing use.
Potential for drug to impair mental alertness or physical coordination; use caution when operating machinery or performing hazardous tasks until effects on individual are known.
Importance of informing clinicians of existing or contemplated concomitant therapy, including prescriptions and OTC drugs, and of concomitant illnesses, particularly depression.
Importance of avoiding alcohol-containing beverages or products.
Importance of informing clinicians of any behavioral or mental changes, memory impairment, tolerance, or dependence/withdrawal symptoms.
Risk of rebound insomnia for 1 or 2 nights after discontinuance.
Importance of women informing their clinician if they are or plan to become pregnant or plan to breast-feed.
Importance of informing patients of other important precautionary information. (See Cautions.)
Preparations
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Subject to control under the Federal Controlled Substances Act of 1970 as a schedule IV (C-IV) drug.
This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 09/2009. For the most current and up-to-date pricing information, please visit www.drugstore.com. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.
Remember, keep this and all other medicines out of the reach of children,
never share your medicines with others, and use this medication only for the indication prescribed.
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