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Zolpidem chemical structure
| CAS number |
| ATC code |
| PubChem |
| DrugBank |
|Molecular weight||307.395 g/mol|
|Bioavailability||70% (oral) 92% bound in plasma|
|Metabolism||Hepatic - CYP3A4|
|Elimination half-life||2 to 2.6 hours|
|Excretion|| 56% renal|
|Legal status||Class C / POM (UK)|
|Routes of administration||Oral|
Zolpidem is a prescription medication used for the short-term treatment of insomnia, as well as some brain disorders. It is a short-acting nonbenzodiazepine hypnotic that potentiates gamma-aminobutyric acid (GABA), an inhibitory neurotransmitter, by binding to gamma-aminobutyric acid (GABAA) receptors at the same location as benzodiazepines. It works quickly (usually within 15 minutes) and has a short half-life (2–3 hours). Trade names of zolpidem include Adormix, Ambien, Ambien CR, Edluar, Damixan, Ivedal, Nytamel, Stilnoct, Stilnox, Sucedal, Zoldem, Zolnod and Zolpihexal.
Its hypnotic effects are similar to those of the benzodiazepine class of drugs, but it is molecularly distinct from the classical benzodiazepine molecule and is classified as an imidazopyridine. Flumazenil, a benzodiazepine receptor antagonist, which is used for benzodiazepine overdose, can also reverse zolpidem's sedative/hypnotic and memory impairing effects.
As an anticonvulsant and muscle relaxant, the beneficial effects start to emerge at 10 and 20 times the dose required for sedation, respectively. For that reason, it has never been approved for either muscle relaxation or seizure prevention. Such drastically increased doses are more inclined to induce one or more negative side-effects, including hallucinations and/or amnesia. (See below.)
The patent 4382938 in the United States on zolpidem was held by the French pharmaceutical corporation Sanofi-Aventis. On April 23, 2007 the U.S. FDA approved 13 generic versions of zolpidem tartrate. Zolpidem is available from several generic manufacturers in the UK, as a generic from Sandoz in South Africa, as well as from other manufacturers such as Ratiopharm.
Recently, zolpidem has been cited in various medical reports mainly in the United Kingdom as waking persistent vegetative state (PVS) patients, and dramatically improving the conditions of people with brain injuries.
Zolpidem is approved for the short-term (usually two to six weeks) treatment of insomnia, and it has been studied for nightly use up to six months in a single-blind trial published in 1991, an open-label study lasting 180 days published in 1992 (with continued efficacy in patients who had kept taking it as of 180 days after the end of the trial), and in an open-label trial lasting 179 days published in 1993.
Zolpidem is also used off-label to treat restless leg syndrome, and, as is the case with many prescription sedative/hypnotic drugs, it is sometimes used by stimulant users to "come down" after the use of stimulants such as amphetamines (including methamphetamine), cocaine, and MDMA (ecstasy).
Recently, the drug has been reported anecdotally to have positive effects for patients in persistent vegetative state. Results from phase IIa trials are expected in June 2007. The trials are being conducted by Regen Therapeutics of the UK, who have a patent pending on this new use for Zolpidem.
Mechanism of actionEdit
Zolpidem due to its selective binding has very weak anxiolytic, myorelaxant and anticonvulsant properties but very strong hypnotic properties. Zolpidem binds with high affinity to the α1 containing GABAA receptors, about 10-fold lower affinity for those containing the α2, α3-GABAA receptor subunits, and with no appreciable affinity for α5 subunit containing receptors. Omega1 type GABAA receptors are the α1 containing GABAA receptors and Omega2 GABAA receptors are the α2, α3, α4, α5 and α6 containing GABAA receptors. Omega1 GABAA receptors are primarily found in the brain whereas omega2 receptors are primarily found in the spine. Thus zolpidem has a preferential binding for the GABAA-benzodiazepine receptor complex in the brain but a low affinity for the GABAA-benzodiazepine receptor complex in the spine.
Like the vast majority of benzodiazepine-like molecules, zolpidem has no affinity for α4 and α6 subunit-containing receptors. Zolpidem positively modulates GABAA receptors, probably by increasing the GABAa receptor complexes apparent affinity for GABA, without affecting desensitization or peak current. Zolpidem increases slow wave sleep and caused no effect on stage 2 sleep in laboratory tests.
A meta-analysis of the randomised controlled clinical trials that compared benzodiazepines against Z drugs has shown that there are few consistent differences between zolpidem and benzodiazepines in terms of sleep onset latency, total sleep duration, number of awakenings, quality of sleep, adverse events, tolerance, rebound insomnia, and daytime alertness.
Zolpidem has recently been very strongly related to certain instances of patients in a minimally conscious coma state being brought to a fully conscious state. While it was initially given to these supposed permanent coma patients to put them to sleep, it actually brought them to a fully conscious state in which they were capable of communicating and interacting for the first time in years. CT scans have shown that the use of the drug actually does dramatically increase the activity in the frontal lobe of the brain in some patients in a minimally conscious state. Large-scale studies are currently being done to see whether it has the same universal effect on all or most patients in a minimally conscious state. It may be that zolpidem's ability to stimulate the brain, particularly in the semi-comatose, may be related to one of its side-effects, which sometimes causes sleepwalking and other activity while asleep, that appears to observers to be fully conscious activity.
Tolerance, dependence and withdrawalEdit
A review medical publication found that long term use of zolpidem is associated with drug tolerance, drug dependence, rebound insomnia and CNS related adverse effects. It was recommended that zolpidem is used for short periods of time using the lowest effective dose. Non-pharmacological treatment options however, were found to have sustained improvements in sleep quality. Animal studies of the tolerance inducing properties have shown that in rodents zolpidem has less tolerance producing potential than benzodiazepines but in primates the tolerance producing potential of zolpidem was the same as that of benzodiazepines. Tolerance can develop in some people to the effects of zolpidem in just a few weeks. Abrupt withdrawal of zolpidem may cause delerium, seizures or other severe effects, especially if used for prolonged periods and at high dosages. When drug tolerance and physical dependence to zolpidem has developed, treatment usually entails a gradual dose reduction over a period of months in order to minimise withdrawal symptoms which can resemble those seen during benzodiazepine withdrawal. Failing that, an alternative method which may be necessary for some patients is a switch to a benzodiazepine equivalent dose of a longer acting benzodiazepine drug such as diazepam or chlordiazepoxide followed by a gradual reduction in dosage of the long acting benzodiazepine. Sometimes for difficult to treat patients an inpatient flumazenil rapid detoxification program can be used to detox from a zolpidem drug dependence or addiction. However, it should be noted that this treatment approach closely parallels that of the highly controversial rapid opiate detoxification therapy, which critics claim lacks long-term efficacy and can actually be detrimental to a patient's long-term recovery. Additionally, there have been many questions raised about the ethics as well as safety of rapid detox following a number of deaths resulting from the procedure.
Alcohol has cross tolerance with GABAa receptor positive modulators such as the benzodiazepines and the nonbenzodiazepine drugs. For this reason alcoholics or recovering alcoholics may be at increased risk of physical dependency on zolpidem. Also, alcoholics and drug abusers may be at increased risk of abusing and or becoming psychologically dependent on zolpidem. Zolpidem should be avoided in those with a history of Alcoholism, drug misuse, or in those with history of physical dependency or psychological dependency on sedative-hypnotic drugs.
Side-effects at any dose may include:
- Anterograde amnesia
- Hallucinations, through all physical senses, of varying intensity
- Altered thought patterns
- Ataxia or poor motor coordination, difficulty maintaining balance
- Euphoria and/or dysphoria
- Increased appetite
- Decreased libido
- Impaired judgment and reasoning
- Uninhibited extroversion in social or interpersonal settings
- Increased impulsivity
- When stopped, rebound insomnia may occur
- Headaches, in some people
A clinical trial found that after administration of zolpidem trial subjects tended to feel weak, fatigued and developed an antagonistic mood.
Some users take zolpidem recreationally for some of these side-effects, notably sedation, hallucinations and euphoria. However, the abuse of zolpidem may be less common than benzodiazepine abuse. Zolpidem can become addictive if taken for extended periods of time, due to drug tolerance and physical dependence or the euphoria it can sometimes produce. As with most addictive drugs, a tolerance in the zolpidem user develops and increases all the more quickly the longer the user has been regularly taking it. Under the influence of the drug, it is common for one to take more zolpidem than is necessary, due to either forgetting that one has already taken a pill (elderly users are particularly at risk here) or knowingly taking more than the prescribed dosage. The recent release of Ambien CR (zolpidem tartrate extended release) in the United States renewed interest in the drug among recreational drug users.
Some users have reported unexplained sleepwalking while using zolpidem, and a few have reported driving, binge eating, sleep talking, and performing other daily tasks while sleeping. The sleepwalker can sometimes perform these tasks as normally as they might if they were awake. They can sometimes carry on complex conversations and respond appropriately to questions or statements so much so that the observer may believe the sleepwalker to be awake. This is similar to, but unlike, typical sleep talking, which can usually be identified easily and is characterised by incoherent speech that often has no relevance to the situation or that is so disorganised as to be completely unintelligible. These effects make a strong suggestion to schizophasia, one of many symptoms commonly seen in individuals suffering from schizophrenia. A person under the influence of this medication may seem fully aware of their environment even though they are still asleep. This can bring about concerns for the safety of the sleepwalker and others. These side-effects may be related to the mechanism that also causes zolpidem to produce its hypnotic properties.
Driving while under the drug's influence is generally considered several orders of magnitude more dangerous than the average drunk driver, due to the diminished motor controls and delusions that may affect the user. It is unclear whether the drug is responsible for the behavior, but a class-action lawsuit was filed against Sanofi-Aventis in March 2006 on behalf of those that reported symptoms. Residual 'hangover' effects such as sleepiness, impaired psychomotor and cognitive after nighttime administration may persist into the next day which may impair the ability of users to drive safely, increase risks of falls and hip fractures.
More recently, the Sydney Morning Herald in Australia reported on March 4, 2007 that a man who fell 30 meters to his death from a high-rise unit balcony may have been sleepwalking under the influence of Stilnox. The coverage prompted over 40 readers to contact the newspaper with their own accounts of Stilnox-related automatism, and the drug is now under review by the Adverse Drug Reactions Advisory Committee.
The elderly are more sensitive to the effects of hypnotics including zolpidem. Zolpidem causes an increased risk of falls and may induce cognitive adverse effects.
Use of zolpidem may impair driving skills with a resultant increased risk of road traffic accidents. This adverse effect is not unique to zolpidem but also occurs with other hypnotic drugs. Caution should be exercised by motor vehicle drivers.
Notable drug interactions with the pharmacokinetics of zolpidem include the following drugs chlorpromazine, cimetidine, fluconazole, imipramine, itraconazole, ketoconazole, rifampicin, ritonavir. Interactions with carbamazepine and phenytoin can be expected based on their metabolic pathways but have not yet been studied.
An extensive review of the medical literature regarding the management of insomnia and the elderly found that there is considerable evidence of the effectiveness and durability of non-drug treatments for insomnia in adults of all ages and that these interventions are underutilized. Compared with the benzodiazepines, the nonbenzodiazepine (including zolpidem) sedative-hypnotics appeared to offer few, if any, significant clinical advantages in efficacy or tolerability in elderly persons. It was found that newer agents with novel mechanisms of action and improved safety profiles, such as the melatonin agonists, hold promise for the management of chronic insomnia in elderly people. Long-term use of sedative-hypnotics for insomnia lacks an evidence base and has traditionally been discouraged for reasons that include concerns about such potential adverse drug effects as cognitive impairment (anterograde amnesia), daytime sedation, motor incoordination, and increased risk of motor vehicle accidents and falls. In addition, the effectiveness and safety of long-term use of these agents remain to be determined. It was concluded that more research is needed to evaluate the long-term effects of treatment and the most appropriate management strategy for elderly persons with chronic insomnia.
Recreational use and abuseEdit
Zolpidem is a drug with the potential for misuse. Two types of drug misuse can occur either recreational misuse is where the drug is taken to achieve a high or when the drug is continued long term against medical advice. The transition from medicinal use to high dose addiction, drug dependence and recreational misuse of zolpidem can occur when the drug is used without the doctor's recommendation to continue using it, physiological drug tolerance leading to escalation to high doses (more than the usual 5 mg or 10 mg), when consumed other than orally (snorting or injecting), or when taken for purposes other than as a sleep aid. Abuse is more prevalent in those that have been dependent on other drugs in the past but tolerance and drug dependence and drug abuse can still sometimes occur in those without a history of drug dependence. Chronic high dose abusers are more likely to have a severe physical dependence on the drug which may cause severe withdrawal symptoms including seizures if abrupt withdrawal from zolpidem occurs. Zolpidem effects can increase and intensify if mixed with other substances like alcohol and cannabis.
In the U.S., recreational use of this drug is becoming more common in young people. Recreational users claim that "fighting" the effects of the drug by forcing themselves to stay awake will sometimes cause vivid visuals and a body high (see side-effects below).[How to reference and link to summary or text] Thus, some users report decreased anxiety, and even mild euphoria, as well as perceptual changes, visual distortions, and light-based hallucinations.
With regular use at high dosage, there can be a risk of a severe physical dependence on zolpidem, with cases being reported in the medical literature of epileptic seizures forming part of the withdrawal syndrome. One case involved a woman detoxing off a high dose of zolpidem experiencing a generalized seizure. The clinical withdrawal and dependence effects were reported to be similar to the benzodiazepine withdrawal syndrome in this case report.
Zolpidem and other sedative hypnotic drugs are detected frequently in cases of people suspected of driving under the influence of drugs. Other drugs including the benzodiazepines and zopiclone are also found in high numbers of suspected drugged drivers. Many drivers have blood levels far exceeding the therapeutic dose range suggesting a high degree of excessive-use potential for benzodiazepines, zolpidem and zopiclone.
As Ambien's patent expired April 21, 2007, new generic versions were approved, which do not have the "protective cover" present on the Sanofi name-brand Ambien they once previously had to prevent users from crushing, snorting, or injecting the drugs.
Overdose of zolpidem may present with excessive sedation, pin-point pupils, depressed respiratory function, which may progress to coma and possibly death. Zolpidem combined with alcohol, opiates or other CNS depressants may be even more likely to lead to fatal overdoses. Zolpidem overdosage can be treated with the benzodiazepine receptor antagonist flumazenil, which displaces zolpidem from its binding site the benzodiazepine receptor and therefore rapidly reverses the effects of zolpidem.
- ↑ Lemmer B (2007). The sleep-wake cycle and sleeping pills. Physiol. Behav. 90 (2-3): 285–93.
- ↑ Ambien.com (2004). AMBIEN Prescribing Information. Information About a Short-term Treatment for Insomnia - Ambien.com Home Page for Health-care Professionals. Sanofi-Synthelabo Inc. New York, NY 10016. URL accessed on 2005-06-27.
- ↑ STILNOX (zolpidem tartrate) PRODUCT INFORMATION Sanofi-Synthelabo Australia Pty Limited. April 15, 2004
- ↑ sanofi-aventis : Drugs and Products - CNS - Stilnox/Ambien/Myslee. URL accessed on 2006-11-22.
- ↑ Benzodiazepine Names.
- ↑ Patat A, Naef MM, van Gessel E, Forster A, Dubruc C, Rosenzweig P (October 1994). Flumazenil antagonizes the central effects of zolpidem, an imidazopyridine hypnotic. Clin Pharmacol Ther 56 (4): 430–6.
- ↑ Wesensten NJ, Balkin TJ, Davis HQ, Belenky GL (September 1995). Reversal of triazolam- and zolpidem-induced memory impairment by flumazenil. Psychopharmacology (Berl) 121 (2): 242–9.
- ↑ Depoortere H, Zivkovic B, Lloyd KG, Sanger DJ, Perrault G, Langer SZ, Bartholini G (1986). Zolpidem, a novel nonbenzodiazepine hypnotic. I. Neuropharmacological and behavioral effects. J. Pharmacol. Exp. Ther. 237 (2): 649–58.
- ↑ 9.0 9.1 Clauss RP, Güldenpfennig WM, Nel HW, Sathekge MM, Venkannagari RR (2000). Extraordinary arousal from semi-comatose state on zolpidem. A case report. S. Afr. Med. J. 90 (1): 68–72.
- ↑ includeonly>"Pill 'reverses' vegetative state", BBC, 2006-05-23. Retrieved on 2006-11-20.
- ↑ includeonly>Pidd, Helen. "Reborn", the Guardian, 2006-09-12. Retrieved on 2006-11-20.
- ↑ includeonly>"Judge rejects right-to-die plea by family", The Guardian, 2006-11-20. Retrieved on 2006-11-20.
- ↑ includeonly>Childs, Dan. "Could a Sleeping Pill 'Wake Up' Coma Patients?", ABC News, 2007-03-13. Retrieved on 2007-03-14.
- ↑ Schlich D, L'Heritier C, Coquelin JP, Attali P, Kryrein HJ (1991). Long-term treatment of insomnia with zolpidem: a multicentre general practitioner study of 107 patients. J. Int. Med. Res. 19 (3): 271–9.
- ↑ Maarek L, Cramer P, Attali P, Coquelin JP, Morselli PL (1992). The safety and efficacy of zolpidem in insomniac patients: a long-term open study in general practice. J. Int. Med. Res. 20 (2): 162–70.
- ↑ Kummer J, Guendel L, Linden J, Eich FX, Attali P, Coquelin JP, Kyrein HJ (1993). Long-term polysomnographic study of the efficacy and safety of zolpidem in elderly psychiatric in-patients with insomnia. J. Int. Med. Res. 21 (4): 171–84.
- ↑ Evidente VG, Caviness JN, Adler CH (2003). Case studies in movement disorders. Seminars in neurology 23 (3): 277–84.
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- ↑ Pharmalicensing.com, retrieved 20 June 2007.
- ↑ Christine Brefel-Courbon et al (2007). Clinical and Imaging Evidence of Zolpidem Effect in Hypoxic Encephalopathy Annals of Neurology, March 15 2007. Medscape summary Retrieved 2007-06-12.
- ↑ Salvà P, Costa J (September 1995). Clinical pharmacokinetics and pharmacodynamics of zolpidem. Therapeutic implications. Clin Pharmacokinet 29 (3): 142–53.
- ↑ Pritchett DB, Seeburg PH (1990). Gamma-aminobutyric acidA receptor alpha 5-subunit creates novel type II benzodiazepine receptor pharmacology. J. Neurochem. 54 (5): 1802–4.
- ↑ Rowlett JK, Woolverton WL (November 1996). Assessment of benzodiazepine receptor heterogeneity in vivo: apparent pA2 and pKB analyses from behavioral studies. Psychopharmacology (Berl.) 128 (1): 1–16.
- ↑ Wafford KA, Thompson SA, Thomas D, Sikela J, Wilcox AS, Whiting PJ (1996). Functional characterization of human gamma-aminobutyric acidA receptors containing the alpha 4 subunit. Mol. Pharmacol. 50 (3): 670–8.
- ↑ Perrais D, Ropert N (1999). Effect of zolpidem on miniature IPSCs and occupancy of postsynaptic GABAA receptors in central synapses. J. Neurosci. 19 (2): 578–88.
- ↑ Noguchi H, Kitazumi K, Mori M, Shiba T (2004). Electroencephalographic properties of zaleplon, a non-benzodiazepine sedative/hypnotic, in rats. J. Pharmacol. Sci. 94 (3): 246–51.
- ↑ Dündar Y, Dodd S, Strobl J, Boland A, Dickson R, Walley T (2004). Comparative efficacy of newer hypnotic drugs for the short-term management of insomnia: a systematic review and meta-analysis. Human psychopharmacology 19 (5): 305–22.
- ↑ Dziedzic, Jessica (2007). "Minimally Conscious Patient Makes Strides Following Deep Brain Stimulation". Neurology Reviews.
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- ↑ Petroski RE, Pomeroy JE, Das R, et al (April 2006). Indiplon is a high-affinity positive allosteric modulator with selectivity for alpha1 subunit-containing GABAA receptors. J. Pharmacol. Exp. Ther. 317 (1): 369–77.
- ↑ Harter C, Piffl-Boniolo E, Rave-Schwank M (November 1999). [Development of drug withdrawal delirium after dependence on zolpidem and zoplicone]. Psychiatr Prax 26 (6): 309.
- ↑ (February 2001) Hypnotic dependence: zolpidem and zopiclone too. Prescrire Int 10 (51): 15.
- ↑ Sethi PK, Khandelwal DC (February 2005). Zolpidem at supratherapeutic doses can cause drug abuse, dependence and withdrawal seizure. J Assoc Physicians India 53: 139–40.
- ↑ Quaglio G, Lugoboni F, Fornasiero A, Lechi A, Gerra G, Mezzelani P (September 2005). Dependence on zolpidem: two case reports of detoxification with flumazenil infusion. Int Clin Psychopharmacol 20 (5): 285–7.
- ↑ includeonly>Dyer, Clare. "Addict died after rapid opiate detoxification", BMJ Publishing Group, 1998-01-17. Retrieved on 2009-02-22.
- ↑ includeonly>Leeder, Jessica. "Coroner probes `rapid detox' death: Addict succumbed during procedure. Second fatality linked to clinics.", Toronto Star, 2006-03-10. Retrieved on 2009-02-22.
- ↑ Yasui M, Kato A, Kanemasa T, Murata S, Nishitomi K, Koike K, Tai N, Shinohara S, Tokomura M, Horiuchi M, Abe K (2005). [Pharmacological profiles of benzodiazepinergic hypnotics and correlations with receptor subtypes]. Nihon Shinkei Seishin Yakurigaku Zasshi = Japanese Journal of Psychopharmacology 25 (3): 143–51.
- ↑ Uchiumi M, Isawa S, Suzuki M, Murasaki M (August 2000). The effects of zolpidem and zopiclone on daytime sleepiness and psychomotor performance. Nihon Shinkei Seishin Yakurigaku Zasshi 20 (3): 123–30.
- ↑ Dolder CR, Nelson MH (2008). Hypnosedative-induced complex behaviours : incidence, mechanisms and management. CNS Drugs 22 (12): 1021–36.
- ↑ Perchance To ... Eat? - Newsweek Health - MSNBC.com
- ↑ Vermeeren A (2004). Residual effects of hypnotics: epidemiology and clinical implications. CNS drugs 18 (5): 297–328.
- ↑ includeonly>Gilmore, Heath. "Sleeping pill safety under federal review", the Sydney Morning Herald, 2007-03-11. Retrieved on 2007-03-11.
- ↑ Antai-Otong D (August 2006). The art of prescribing. Risks and benefits of non-benzodiazepine receptor agonists in the treatment of acute primary insomnia in older adults. Perspect Psychiatr Care 42 (3): 196–200.
- ↑ Gustavsen I, Bramness JG, Skurtveit S, Engeland A, Neutel I, Mørland J (December 2008). Road traffic accident risk related to prescriptions of the hypnotics zopiclone, zolpidem, flunitrazepam and nitrazepam. Sleep Med. 9 (8): 818–22.
- ↑ Wang JS, DeVane CL (2003). Pharmacokinetics and drug interactions of the sedative hypnotics. Psychopharmacol Bull 37 (1): 10–29.
- ↑ Bain KT (June 2006). Management of chronic insomnia in elderly persons. Am J Geriatr Pharmacother 4 (2): 168–92.
- ↑ Griffiths RR, Johnson MW (2005). Relative abuse liability of hypnotic drugs: a conceptual framework and algorithm for differentiating among compounds. J Clin Psychiatry 66 Suppl 9: 31–41.
- ↑ Barrero-Hernández FJ, Ruiz-Veguilla M, López-López MI, Casado-Torres A (2002). [Epileptic seizures as a sign of abstinence from chronic consumption of zolpidem]. Rev Neurol 34 (3): 253–6.
- ↑ http://www.ksl.com/index.php?nid=248&sid=588181 Ambien Abuse on Rise Among Teens
- ↑ Cubała WJ, Landowski J (2007). Seizure following sudden zolpidem withdrawal. Prog. Neuropsychopharmacol. Biol. Psychiatry 31 (2): 539–40.
- ↑ Jones AW, Holmgren A, Kugelberg FC (2007). Concentrations of scheduled prescription drugs in blood of impaired drivers: considerations for interpreting the results. Therapeutic drug monitoring 29 (2): 248–60.
- ↑ Lheureux P, Debailleul G, De Witte O, Askenasi R (1990). Zolpidem intoxication mimicking narcotic overdose: response to flumazenil. Human & experimental toxicology 9 (2): 105–7.
- Ambien CR official website
- Erowid Zolpidem (Ambien) Vault
- Ambien CIV (zolpidem tartrate) at the NIH DailyMed website
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