Zolpidem Tartrate

(British Approved Name Modified, US Adopted Name, rINNM)

What Is Zolpidem Tartrate?

Zolpidem tartrate is a medication that is commonly prescribed for the short-term treatment of insomnia. It belongs to a class of drugs known as sedative-hypnotics, and it works by affecting the central nervous system to produce a calming effect. Zolpidem is typically used to help people fall asleep more quickly and stay asleep throughout the night.
It should be taken only under the supervision of a healthcare professional, as it can have side effects and may interact with other medications. Common brand names for zolpidem include Ambien, Ambien CR, Edluar, and Intermezzo.
Zolpidem is generally recommended for short-term use, typically no more than a few weeks, to avoid the development of dependence or tolerance. Prolonged use or misuse of zolpidem can lead to dependence, and abrupt discontinuation may result in withdrawal symptoms.
As with any medication, following your healthcare provider’s instructions and informing them of any other medications or health conditions you may have to ensure the safe and effective use of zolpidem is crucial.

Pharmacokinetics

Zolpidem is rapidly absorbed from the gastrointestinal tract after oral doses, reaching peak plasma concentrations within 3 hours. Zolpidem undergoes first-pass metabolism, and an absolute bioavailability of about 70% has been reported. Zolpidem has an elimination half-life of about 2.5 hours and is about 92% bound to plasma proteins. It is metabolized primarily by the cytochrome P450 isoenzyme CYP3A4. The inactive metabolites of zolpidem are excreted in the urine and feces. Zolpidem is distributed in breast milk.

Uses and Administration

Zolpidem tartrate is an imidazopyridine that is reported to have similar sedative properties to benzodiazepines (see Diazepam) but minimal anxiolytic, muscle relaxant, and anticonvulsant properties. It has a rapid onset and short duration of action and is used as a hypnotic in the short-term management of insomnia. The usual oral dose is 10 mg, taken before going to bed. In elderly or debilitated patients, treatment should be limited to 5 mg at night. Doses should also be reduced in patients with hepatic impairment. A modified-release formulation of zolpidem tartrate is also available.

Administration in Hepatic Impairment

In patients with hepatic impairment, treatment with immediate-release formulations of zolpidem tartrate should be started with a dose of 5 mg at night. If necessary, the dose may be increased to 10 mg for patients under 65 years. UK-licensed product information contra-indicates the use of zolpidem in patients with severe impairment.

Catatonia

Anecdotal reports suggest that the zolpidem challenge test is also proposed for catatonia screening.

Insomnia

Zolpidem is an imidazopyridine with strong sedative effects but only minor anxiolytic, muscle relaxant, or anticonvulsant properties. Some degree of amnesia has been reported. Zolpidem appears to act by binding to the benzodiazepine receptor component of the GABA receptor complex. It has, however, a selective affinity for the subtype of benzodiazepine receptors prevalent in the cerebellum (BZ1 – or ω1-receptors) as opposed to those more commonly found in the spinal cord (BZ2- or ω2-re-ceptors) or in the peripheral tissues (BZ3- or ω3-receptors). Zolpidem has a rapid onset and short duration of hypnotic action and, at usual doses, decreases the time to sleep onset and increases the duration of sleep with little apparent effect on sleep stages. Reviews agree that clinical studies have shown that zolpidem has hypnotic activity superior to placebo and is generally similar to comparative benzodiazepines. Although it does not appear to produce rebound insomnia to any great extent, there appears to be little evidence that zolpidem offers any advantage over short-acting benzodiazepines regarding residual effects the next day or its potential to induce tolerance, withdrawal symptoms, or dependence.

Parkinsonism

Although preliminary findings in 10 patients suggested that zolpidem might improve symptoms of Parkinson’s disease, concern has been expressed over the risk of falls associated with zolpidem-induced drowsiness and the severe consequences for these patients. Benefit has also been reported in treating antipsychotic-induced parkinsonism in one patient with symptoms of repetitive, persistent gross tremors of the hands.

Permanent Vegetative State

Zolpidem in a single dose of 10 mg has produced temporary arousal in 3 patients in a permanent vegetative state. The effects lasted for about 4 hours.

Adverse Effects, Treatment, and Precautions

As for Diazepam.

Treatment of overdose is mainly supportive. Activated charcoal may be given orally within one hour of ingesting 100 mg of zolpidem or more to adults or more than 5 mg to children. Alternatively, gastric lavage may be considered in adults if they present within 1 hour of a potentially life-threatening overdose. Flumazenil may be considered in cases of severe CNS depression (see also Overdosage).

Abuse

Zolpidem abuse has been reported, including a paradoxical stimulant effect when taking large doses of zolpidem. Tolerance may also develop. Intravenous abuse has also been reported. See also under Dependence and Withdrawal.

Breastfeeding

No adverse effects have been seen in breastfed infants whose mothers were receiving zolpidem, and the American Academy of Pediatrics considers that it is usually compatible with breastfeeding.

In 5 women given a 20-mg dose of zolpidem, the amount of drug excreted in breast milk after 3 hours ranged between 0.76 and 3.88 micrograms, representing 0.004 to 0.019% of the dose. No detectable (below 0.5 nanograms/mL) zolpidem was found in subsequent milk samples.

Effects on the Liver

Hepatitis developed in two cases in a 53-year-old woman after using zolpidem for insomnia.

Effects on Mental Function

Psychotic reactions, which may not subsequently be recalled, have been reported in patients taking therapeutic doses of zolpidem. Somnambulism has also been reported with zolpidem. Other complex sleep-related behaviors, such as eating or driving while asleep, have been reported with zaleplon, zolpidem, and zopiclone. Such behavior is more likely to occur when these drugs are taken with alcohol or other CNS depressants or in doses exceeding the recommended maximum. It is not clear if there are differences in risk with individual drugs; however, as a precautionary measure, the FDA requested labeling changes that highlight these adverse effects to all hypnotics marketed in the USA.

Hypersensitivity

Rare cases of angioedema involving the tongue, glottis, or larynx have been reported after the first or subsequent doses of hypnotics such as eszopiclone, zaleplon, zolpidem, and zopiclone; additional symptoms suggestive of anaphylaxis have also developed in some patients.

Overdosage

A retrospective analysis of 344 cases of acute overdosage with zolpidem reported to the Paris Poison Center and the manufacturers Synthelabo has been published. The ingested dose, where known, ranged from 10 to 1400 mg, and the most common adverse effect was drowsiness (in 89 patients). Other adverse effects probably associated with the overdosage included coma in 4 patients and vomiting in 7. Recovery was usually rapid when overdosage involved only zolpidem. It was recommended that patients who had ingested more than 100 mg of zolpidem should undergo gastric lavage and should be monitored for at least 12 hours (see also above). Although it has been shown that flumazenil can effectively antagonize the CNS effects of zolpidem, the authors of this analysis found that, in general, it was not required.

Dependence and Withdrawal

As for Diazepam.

Withdrawal Symptoms

A 37-year-old man, who increased his dose from 10 mg to 130 mg daily over two months, had a generalized tonic-clonic seizure after zolpidem was abruptly stopped. The patient recovered after being started on a benzodiazepine dosage tapering program. Symptoms attributed to daytime abstinence after excessive night-time doses have been reported in 2 patients, including anxiety, tremors, sweating, nausea, gastric and abdominal pain, swallowing difficulties, tachycardia, and tachypnoea. The patients had increased their doses because of developing tolerance to the hypnotic effect but had begun to experience muscle cramps and myoclonic jerks.

Interactions

As for Diazepam.

Antidepressants

A 16-year-old girl taking paroxetine 20 mg daily for three days began to hallucinate and became disorientated one hour after taking zolpidem 10 mg at night. The delirium cleared spontaneously 4 hours later without treatment. When questioned, at least one of the author’s patients receiving this combination reported transient visual hallucinations. Other isolated cases of visual hallucinations have been reported in patients taking zolpidem with antidepressants, including bupropion, desipramine, fluoxetine, sertraline, and venlafaxine.

Antiepileptics

A 47-year-old man with a history of bipolar disorder, who was receiving citalopram and zolpidem, had episodes of somnambulism after being given valproic acid to treat manic symptoms. The episodes stopped on withdrawal of valproic acid and returned on rechallenge. An interaction between zolpidem and valproic acid was suspected (but somnambulism has also been associated with zolpidem alone; see Effects on Mental Function).

For the suggestion that carbamazepine and phenytoin may interact with zolpidem, see Rifampicin section.

Antifungals

Using ketoconazole with zolpidem has increased plasma concentrations and moderately enhanced the sedative effect of zolpidem. Using zolpidem with fluconazole or itraconazole has resulted in minor, non-significant changes in the pharmacokinetics and sedative effects of zolpidem.

Antivirals

HIV-protease inhibitors, such as ritonavir, may increase plasma concentrations of zolpidem with a risk of extreme sedation and respiratory depression. Use together is possible if the patient is provided with careful monitoring for excessive sedative effects.

Rifampicin

Rifampicin reduced the hypnotic effect of zolpidem in a study of 8 healthy female subjects. The area under the curve for zolpidem was reduced by 73% after rifampicin and the peak plasma concentration by 58%. The elimination half-life of zolpidem was reduced from 2.5 to 1.6 hours. Similar effects could be expected with other potent inducers of the cytochrome P450 isoenzyme CYP3A4, such as carbamazepine and phenytoin.

Drug Nomenclature

INNs in main languages (French, Latin, Russian, and Spanish):

Synonyms: SL-80.0750 (zolpidem); SL-80.0750-23N; Tsolpideemitartraatti; Zolpidem Hemitartrate; Zolpidem, tartrato de; Zolpidem-tartarát; Zolpidemi Tartras; Zolpidemo tartratas; Zolpidemtartrat

BAN: Zolpidem Tartrate [BANM]

USAN: Zolpidem Tartrate

INN: Zolpidem Tartrate [rINNM (en)]

INN: Tartrato de zolpidem [rINNM (es)]

INN: Zolpidem, Tartrate de [rINNM (fr)]

INN: Zolpidemi Tartras [rINNM (la)]

INN: Золпидема Тартрат [rINNM (ru)]

Chemical name: N,N-Dimethyl-2-(6-methyl-2-p-tolylimidazo[1,2-a]pyridin-3-yl)acetamide hemitartrate

Molecular formula: (C19H21N3O)2,C4H6O6 =764.9

CAS: 82626-48-0 (zolpidem); 99294-93-6 (zolpidem tartrate)

ATC code: N05CF02

Note. The following terms have been used as ‘street names’ (see p.vi) or slang names for various forms of zolpidem tartrate: Sleepeasy; Tic-Tacs.

Pharmacopoeias. In Europe.

European Pharmacopoeia, 6th ed. (Zolpidem Tartrate). A white or almost white hygroscopic crystalline powder. Slightly soluble in water, practically insoluble in dichloromethane, sparingly soluble in methyl alcohol. Store in airtight containers. Protect from light.

Proprietary Preparations

Argentina: Balidorm Dormilan Durnit Nocte Somit Sumenan Zolodorm

Australia: Dormizol Somidem Stildem Stilnox Zolpibell

Austria: Ivadal Mondeal Zoldem Zolpidohexal

Belgium: Stilnoct

Brazil: Lioram Stilnox

Chile: Adormix Damixan Dormilam Dormosol Somnil Somnipron Somno Sucedal

Czech Republic: Eanox Hypnogen Stilnoct Stilnox Zolpimerck Zolpinox Zolsana Zonadin

Denmark: Eanox Nimadorm Stilnoct Zonoct

Finland: Somnor Stella Stilnoct

France: Stilnox

Germany: Bikalm Stilnox Zodormdura Zoldem Zolpi-Lich Zolpi-Q Zolpinox

Greece: Alespan Hypnoforin Stilnox

Hong Kong: Stilnox Stilpidem

Hungary: Ambien Hypnogen Pidezol Sanval Stilnox

India: Ambiz Sove Zleep Zoldem

Indonesia: Stilnox Zolmia

Ireland: Nytamel Stilnoct Zoldem Zolnod

Israel: Stilnox Zodorm

Italy: Niotal Nottem Stilnox

Japan: Myslee

Malaysia: Sobrium Somidem Stilnox

Mexico: Nocte Stilnox

The Netherlands: Stilnoct Zolpidol

Norway: Stilnoct

Philippines: Stilnox Ziohex

Poland: Hypnogen Nasen Polsen Sanval Stilnox Xenix Zolpic Zolpi

Germany: Zolsana Zoratio

Portugal: Cymerion Stilnox

Russia: Hypnogen Nitrest Sanval Snovitel

South Africa: Ivedal Noxidem Stilnox Zolnoxs Zolpihexal

Singapore: Stilnox

Spain: Dalparan Stilnox

Sweden: Stilnoct

Switzerland: Sedovalin Stilnox Zoldorm Zolpi-Med

Thailand: Stilnox

UK: Stilnoct

USA: Ambien Tovalt

Venezuela: Atrimon Stilnox Zolpidex