Zolpidem is a GABA A receptor positive modulator presumed to exert its therapeutic effects in the short-term treatment of insomnia through binding to the benzodiazepine site of α1 subunit containing GABA A receptors, increasing the frequency of chloride channel opening resulting in the inhibition of neuronal excitation.
Zolpidem binds to GABA A receptors with greater affinity for α1subunit relative to α2 and α3 subunit containing receptors. Zolpidem has no appreciable binding affinity for α5 subunit containing GABA A receptors. This binding profile may explain the relative absence of myorelaxant effects in animal studies. Zolpidem has no appreciable binding affinity for dopaminergic D2, serotonergic 5HT2, adrenergic, histaminergic or muscarinic receptors.
The pharmacokinetic profile of zolpidem tartrate tablets is characterized by rapid absorption from the gastrointestinal tract and a short elimination half-life (T 1/2 ) in healthy subjects.
In a single-dose crossover study in 45 healthy subjects administered 5 and 10 mg zolpidem tartrate tablets, the mean peak concentrations (C max ) were 59 (range: 29 to 113) and 121 (range: 58 to 272) ng/mL, respectively, occurring at a mean time (T max ) of 1.6 hours for both. The mean zolpidem tartrate tablets elimination half-life was 2.6 (range: 1.4 to 4.5) and 2.5 (range: 1.4 to 3.8) hours, for the 5 and 10 mg tablets, respectively. Zolpidem tartrate tablets are converted to inactive metabolites that are eliminated primarily by renal excretion. Zolpidem tartrate tablets demonstrated linear kinetics in the dose range of 5 to 20 mg. Total protein binding was found to be 92.5 ± 0.1% and remained constant, independent of concentration between 40 and 790 ng/mL. Zolpidem did not accumulate in young adults following nightly dosing with 20 mg zolpidem tartrate tablets for 2 weeks.
A food-effect study in 30 healthy male subjects compared the pharmacokinetics of zolpidem tartrate tablets 10 mg when administered while fasting or 20 minutes after a meal. Results demonstrated that with food, mean AUC and C max were decreased by 15% and 25%, respectively, while mean T max was prolonged by 60% (from 1.4 to 2.2 hr). The half-life remained unchanged. These results suggest that, for faster sleep onset, zolpidem tartrate tablets should not be administered with or immediately after a meal.
In the elderly, the dose for zolpidem tartrate tablets should be 5 mg [see Warnings and Precautions ( 5), Dosage and Administration ( 2)]. This recommendation is based on several studies in which the mean C max , T 1/2 , and AUC were significantly increased when compared to results in young adults. In one study of eight elderly subjects (>70 years), the means for C max , T 1/2 , and AUC significantly increased by 50% (255 vs. 384 ng/mL), 32% (2.2 vs. 2.9 hr), and 64% (955 vs. 1,562 ng·hr/mL), respectively, as compared to younger adults (20 to 40 years) following a single 20 mg oral dose. Zolpidem tartrate tablets did not accumulate in elderly subjects following nightly oral dosing of 10 mg for 1 week.
The pharmacokinetics of zolpidem tartrate tablets in eight patients with chronic hepatic insufficiency was compared to results in healthy subjects. Following a single 20 mg oral zolpidem tartrate dose, mean C max and AUC were found to be two times (250 vs. 499 ng/mL) and five times (788 vs. 4,203 ng·hr/mL) higher, respectively, in hepatically compromised patients. T max did not change. The mean half-life in cirrhotic patients of 9.9 hr (range: 4.1 to 25.8 hr) was greater than that observed in normal subjects of 2.2 hr (range: 1.6 to 2.4 hr) [see Dosage and Administration ( 2.2), Warnings and Precautions ( 5.8), Use in Specific Populations ( 8.7)].
The pharmacokinetics of zolpidem tartrate was studied in 11 patients with end-stage renal failure (mean Cl Cr = 6.5 ± 1.5 mL/min) undergoing hemodialysis three times a week, who were dosed with zolpidem tartrate 10 mg orally each day for 14 or 21 days. No statistically significant differences were observed for C max , T max , half-life, and AUC between the first and last day of drug administration when baseline concentration adjustments were made. Zolpidem was not hemodialyzable. No accumulation of unchanged drug appeared after 14 or 21 days. Zolpidem pharmacokinetics were not significantly different in renally impaired patients. No dosage adjustment is necessary in patients with compromised renal function.
Coadministration of zolpidem with other CNS depressants increases the risk of CNS depression [see Warnings and Precautions ( 5.2)]. Zolpidem tartrate was evaluated in healthy volunteers in single-dose interaction studies for several CNS drugs. Imipramine in combination with zolpidem produced no pharmacokinetic interaction other than a 20% decrease in peak levels of imipramine, but there was an additive effect of decreased alertness. Similarly, chlorpromazine in combination with zolpidem produced no pharmacokinetic interaction, but there was an additive effect of decreased alertness and psychomotor performance.
A study involving haloperidol and zolpidem revealed no effect of haloperidol on the pharmacokinetics or pharmacodynamics of zolpidem. The lack of a drug interaction following single-dose administration does not predict the absence of an effect following chronic administration.
An additive adverse effect on psychomotor performance between alcohol and oral zolpidem was demonstrated [see Warnings and Precautions ( 5.2)].
Following five consecutive nightly doses at bedtime of oral zolpidem tartrate 10 mg in the presence of sertraline 50 mg (17 consecutive daily doses, at 7:00 am, in healthy female volunteers), zolpidem C max was significantly higher (43%) and T max was significantly decreased (-53%). Pharmacokinetics of sertraline and N-desmethylsertraline were unaffected by zolpidem.
A single-dose interaction study with zolpidem tartrate 10 mg and fluoxetine 20 mg at steady-state levels in male volunteers did not demonstrate any clinically significant pharmacokinetic or pharmacodynamic interactions. When multiple doses of zolpidem and fluoxetine were given at steady state and the concentrations evaluated in healthy females, an increase in the zolpidem half-life (17%) was observed. There was no evidence of an additive effect in psychomotor performance.
Drugs that affect drug metabolism via cytochrome P450
Some compounds known to inhibit CYP3A may increase exposure to zolpidem. The effect of inhibitors of other P450 enzymes on the pharmacokinetics of zolpidem is unknown.
A single-dose interaction study with zolpidem tartrate 10 mg and itraconazole 200 mg at steady-state levels in male volunteers resulted in a 34% increase in AUC 0-∞ of zolpidem tartrate. There were no pharmacodynamic effects of zolpidem detected on subjective drowsiness, postural sway, or psychomotor performance.
A single-dose interaction study with zolpidem tartrate 10 mg and rifampin 600 mg at steady-state levels in female subjects showed significant reductions of the AUC (-73%), C max (-58%), and T 1/2 (-36 %) of zolpidem together with significant reductions in the pharmacodynamic effects of zolpidem tartrate. Rifampin, a CYP3A4 inducer, significantly reduced the exposure to and the pharmacodynamic effects of zolpidem [see Drug Interactions ( 7.2)].
Similarly, St. John’s wort, a CYP3A4 inducer, may also decrease the blood levels of zolpidem.
A single-dose interaction study with zolpidem tartrate 5 mg and ketoconazole, a potent CYP3A4 inhibitor, given as 200 mg twice daily for 2 days increased C max of zolpidem (30%) and the total AUC of zolpidem (70%) compared to zolpidem alone and prolonged the elimination half-life (30 %) along with an increase in the pharmacodynamic effects of zolpidem [see Drug Interactions ( 7.2)].
Additionally, fluvoxamine (a strong inhibitor of CYP1A2 and a weak inhibitor of CYP3A4 and CYP2C9) and ciprofloxacin (a strong inhibitor of CYP1A2 and a moderate inhibitor of CYP3A4) are also likely to inhibit zolpidem’s metabolic pathways, potentially leading to an increase in zolpidem exposure.
Other drugs with no interactions with zolpidem
A study involving cimetidine/zolpidem tartrate and ranitidine/zolpidem tartrate combinations revealed no effect of either drug on the pharmacokinetics or pharmacodynamics of zolpidem.
Zolpidem tartrate had no effect on digoxin pharmacokinetics and did not affect prothrombin time when given with warfarin in healthy subjects.
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