Zolpidem (Ambien): Drug Whys
A comprehensive examination of ambien uses, pharmacology, pharmacokinetics, administration routes and dosing
Article updated May 30, 2018
Generic Name: Zolpidem (multiple manufacturers)
Common Brand Name: Ambien (Sanofi – U.S.)
Popularity: 12th most commonly prescribed drug in Q1, 2016 (U.S.)
Ambien treatment Uses
For short-term treatment of insomnia (trouble sleeping). Zolpidem has also been used with some success for preoperative sedation, Parkinson related dystonias, restless leg syndrome, and a variety of other movement disorders. Studies have found long-term use of zolpidem for up to one year safe and effective, but current FDA (U.S. Food and Drug Administration) approval is limited to short-term use.
Zolpidem appears to offer significant advantages over benzodiazepines, the other drug class most commonly used for insomnia. This is due to zolpidem's lower incidence of adverse side effects including daytime sedation, amnesia, tolerance, drug dependence, and rebound insomnia after discontinuing the drug. Sleep physiology is adversely affected by benzodiazepines, primarily by suppressing REM sleep. Zolpidem produces a sleep pattern very comparable to normal sleep, which likely explains its superiority. While not all studies confirm these benefits, prescribing patterns would seem to indicate that both patients and prescribers consider zolpidem the current agent of choice for insomnia.
Sleep disturbances are often associated with medical or psychiatric disorders. They require careful evaluation before prescribing a sleep aid. Failure to improve following seven to 10 days of treatment with a prescription sleep aid (such as zolpidem) strongly suggests an underlying psychiatric or medical condition and warrants further investigation.
With regard to safety (as will be noted later), zolpidem use was associated in a near doubling of hip fracture risk in a large study of elderly patients (mean 82 years of age). While other agents including benzodiazepines, antipsychotics, and antidepressants also increased risk of hip fractures in the elderly, none had risks higher than zolpidem.
An agent similar to zolpidem entered the pharmaceutical market in 2005: eszopiclone (Lunesta™ manufactured by Sepracor – U.S.). Eszopiclone has the advantage of FDA approval for long-term use, but few other differences in clinical use compared to zolpidem with the exception of a higher incidence of two side effects: headache and an unpleasant taste that develops in the mouth following use. From a formulary policy perspective, patients and hospitals are best served by using whichever agent costs the least. Some patients will find that they tolerate zolpidem or eszopiclone with fewer side effects.
Ambien dosing and administration
The normal zolpidem dose for treatment of insomnia in adults is 10 milligrams immediate release or 12.5 milligrams extended release taken orally immediately before bedtime. Dosing should be individualized to patient response. Therapy should be limited to seven to 10 days. In reality, insomnia patients are often long-term users of zolpidem; few experience adverse effects. While the manufacturer recommends a maximum adult dose of 10 milligrams (immediate release), studies have found 10 to 20 milligrams effective for insomnia in healthy adults. There are no data on the effectiveness or safety of zolpidem in children under 18 years of age.
Zolpidem should not be taken with food; doing so decreases absorption and lowers the maximum concentration of the drug in the bloodstream (this includes all dosage forms including oral spray). Due to its rapid effects, zolpidem should be taken immediately before bedtime or when having trouble falling asleep. Patients should not take zolpidem unless they have 8 hours available to sleep.
Dose adjustments of zolpidem should be considered in patients with impaired liver function and in the elderly. A 5 milligram dose of immediate release or 6.25 milligram extended release dose is recommended for patients with cirrhosis, liver disease, and in the elderly to compensate for sizeable increases in the drug half-life. Dose adjustments are not usually recommended in patients with renal dysfunction. Zolpidem is not removed by hemodialysis. There have been some reports of dialysis patients requiring lower doses of zolpidem but specific circumstances when lower dosing might be necessary are still unclear. Close monitoring is recommended and, as mentioned previously, adjust all zolpidem doses to the individual patient.
Toxic doses of zolpidem have not been defined as yet however; profound coma has been reported with acute overdoses of 300 milligrams. As noted previously zolpidem is not removed from the body by hemodialysis. Flumazenil has been shown to decrease sedative-hypnotic effects of zolpidem but risk of seizures outweighs potential benefits. Treatment of overdoses should be supportive.
Zolpidem pharmacology, pharmacokinetics and Stability
Zolpidem is rapidly absorbed following oral administration; initial response is seen within 7 to 27 minutes and drug action lasts 6 to 8 hours. Peak concentrations appear in the bloodstream in 1.6 with immediate release zolpidem and 1.5 hours with extended release tablets. The liver is responsible for most metabolism of zolpidem, which explains the need for reduced doses in the presence of liver disease.
Nearly all of zolpidem (up to 96 percent) is excreted in the bile, urine, and feces. The kidneys eliminate less than 1 percent. There are no adequate studies on use of zolpidem during pregnancy although zolpidem does cross the placenta. Other sedative-hypnotic agents have resulted in withdrawal symptoms in newborns following maternal use during pregnancy. Zolpidem is excreted in breast milk in small, often in barely detectable quantities, and almost all within 3 hours after oral dosing. The risk to nursing infants is unknown, but presumed to be extremely small. While the manufacturer recommends against use of zolpidem by nursing mothers, the American Academy of Pediatrics rates zolpidem as a medication compatible with breastfeeding.
Zolpidem is chemically unrelated to other sedative-hypnotic agents and is thought to exert its effects in the body by binding to the same (GABA) receptor sites as benzodiazepines. More selective attachment of zolpidem may explain its lack of muscle relaxing and anticonvulsant properties seen with other sedative-hypnotic drugs, as well as preservation of deep sleep (stages 3 and 4) in humans.
Zolpidem comes in 5 and 10 milligram immediate release tablets and as 12.5 milligram extended release tablets and an oral spray (two sprays equals 10 milligrams). Zolpidem (brand name Ambien) 5 milligram tablets are capsule shaped, pink, film coated, with AMB 5 debossed on one side and 5401 on the other. Ambien 10 milligram tablets are also capsule shaped, white, film coated, with AMB 10 debossed on one side and 5421 on the other. Generic zolpidem comes in a wide variety of shapes, colors, and sizes. Zolpidem tablets should be stored at room temperature between 68-77 F.
Zolpidem cautions and warnings
Unusual behaviors have been reported in patients taking sedative-hypnotics including zolpidem. While extremely rare, these behaviors are extraordinarily troubling. They include “sleep driving” (operating a motor vehicle while not fully awake with no subsequent memory of the event), as well as other complex behaviors such as preparing and eating food, making phone calls, or having sex while not fully awake with no recollection afterward of the event.
These occur in both sedative-hypnotic-naïve as well as sedative-hypnotic-experienced people and, in the case of zolpidem, have an increased incidence when zolpidem is combined with alcohol or other central nervous system (CNS) depressing drugs or when zolpidem doses exceed maximum recommendations. As many of the important side effects of zolpidem are dose related, the smallest effective dose possible should be used, especially in elderly patients. Patients should be cautioned to take zolpidem immediately prior to bedtime, and should have at least 8 hours time to devote to sleep after taking zolpidem.
Because the drug has CNS depressant effects, patients should not engage in hazardous tasks or occupations requiring complete mental alertness after taking zolpidem (emergency responders take note). Alcohol and other CNS depressing drugs exacerbate CNS depressant effects of zolpidem. For the same reasons, caution should be exercised in prescribing zolpidem for patients with depression. In patients with primary depression, worsening of depressive symptoms can occur when taking sedative-hypnotics including suicidal thoughts and completed suicides. It is difficult to determine if there is a relationship between sedative-hypnotics and increased symptoms.
Important side effects of ambien
Daytime drowsiness, dizziness, headache, and GI symptoms (nausea, vomiting, and diarrhea) were the most frequent side effects reported with short-term use (up to 10 nights at doses up to 10 milligrams) of zolpidem. Dizziness and drugged feelings were most frequently reported with longer term use (28 to 35 nights at doses up to 10 milligrams). In post marketing studies, overall side effects have remained in the 1-2 percent frequency (meaning they are relatively rare). Rarely, severe anaphylactic reactions have been reported with zolpidem. Amnesia has also been (rarely) reported with zolpidem, most occurring within 1-2 hours of taking the drug. Zolpidem should be discontinued with the occurrence of “sleep driving” or amnesia as well as with any other complex behaviors previously described. Falls occur in 1-2 percent of patients who take zolpidem; virtually all of these patients are elderly (greater than 70 years old) and have received doses greater than 10 milligrams. The hip fractures mentioned earlier are probably related to these falls, which are clearly related to the high doses of zolpidem. Interestingly, a study on the respiratory effects of zolpidem showed no significant incidence of respiratory depression in healthy adults although reductions in lowest oxygen saturations were reported in one study of mild to moderate sleep apnea patients given 10 milligrams of zolpidem.
Zolpidem should be used with caution in patients with untreated sleep apnea (i.e., not using CPAP) or myasthenia gravis patients. Addiction and dependence are possible with any sedative-hypnotic agent but appear less frequent with zolpidem compared to benzodiazepines. Nonetheless, addiction or abuse should be a concern with zolpidem, especially with higher doses and long-term use. Patients should be advised that zolpidem can be habit forming with long-term use. Withdrawal symptoms have been reported following abrupt dose decreases or discontinuation of zolpidem.
Ten drugs are reported to interact with zolpidem of which two groups have good documentation. Combinations of zolpidem with antidepressants have resulted in increased incidences of hallucinations in patients. Both ketoconazole antibiotics and rifampin have demonstrated increased plasma levels of zolpidem suggesting a need for downward dose adjustment of the zolpidem when used in combination.
Average Costs – U.S.
• 5 mg and 10 mg tablets (generic)
Patient cost: $ 0.80 each (both strengths)
Large Hospital cost: $0.07 each (both strengths)
1. MICROMEDEXÒ Healthcare Series: Thomson Micromedex, Greenwood Village, Colorado (accessed November, 2009).
2. Albany Medical Center Pharmacy, Albany, New York.