Absorption

Zaleplon is rapidly and almost completely absorbed following oral administration. Peak plasma concentrations are attained within approximately 1 hour after oral administration. Although zaleplon is well absorbed, its absolute bioavailability is approximately 30% because it undergoes significant presystemic metabolism.

Distribution

Zaleplon is a lipophilic compound with a volume of distribution of approximately 1.4 L/kg following intravenous (IV) administration, indicating substantial distribution into extravascular tissues. The in vitro plasma protein binding is approximately 60%±15% and is independent of zaleplon concentration over the range of 10 ng/mL to 1000 ng/mL. This suggests that zaleplon disposition should not be sensitive to alterations in protein binding. The blood to plasma ratio for zaleplon is approximately 1, indicating that zaleplon is uniformly distributed throughout the blood with no extensive distribution into red blood cells.

Metabolism

After oral administration, zaleplon is extensively metabolized, with less than 1% of the dose excreted unchanged in urine. Zaleplon is primarily metabolized by aldehyde oxidase to form 5-oxo-zaleplon. Zaleplon is metabolized to a lesser extent by cytochrome P450 (CYP) 3A4 to form desethylzaleplon, which is quickly converted, presumably by aldehyde oxidase, to 5-oxo-desethylzaleplon. These oxidative metabolites are then converted to glucuronides and eliminated in urine. All of zaleplon's metabolites are pharmacologically inactive.

Elimination

After either oral or IV administration, zaleplon is rapidly eliminated with a mean t1/2 of approximately 1 hour. The oral-dose plasma clearance of zaleplon is about 3 L/h/kg and the IV zaleplon plasma clearance is approximately 1 L/h/kg. Assuming normal hepatic blood flow and negligible renal clearance of zaleplon, the estimated hepatic extraction ratio of zaleplon is approximately 0.7, indicating that zaleplon is subject to high first-pass metabolism.

After administration of a radiolabeled dose of zaleplon, 70% of the administered dose is recovered in urine within 48 hours (71% recovered within 6 days), almost all as zaleplon metabolites and their glucuronides. An additional 17% is recovered in feces within 6 days, most as 5-oxo-zaleplon.

Effect of Food

In healthy adults a high-fat/heavy meal prolonged the absorption of zaleplon compared to the fasted state, delaying tmax by approximately 2 hours and reducing Cmax by approximately 35%. Zaleplon AUC and elimination half-life were not significantly affected. These results suggest that the effects of zaleplon on sleep onset may be reduced if it is taken with or immediately after a high-fat/heavy meal.

Special Populations

Age: The pharmacokinetics of zaleplon have been investigated in three studies with elderly men and women ranging in age from 65 to 85 years. The pharmacokinetics of zaleplon in elderly subjects, including those over 75 years of age, are not significantly different from those in young healthy subjects.

Gender: There is no significant difference in the pharmacokinetics of zaleplon in men and women.

Race: The pharmacokinetics of zaleplon have been studied in Japanese subjects as representative of Asian populations. For this group, Cmax and AUC were increased 37% and 64%, respectively. This finding can likely be attributed to differences in body weight, or alternatively, may represent differences in enzyme activities resulting from differences in diet, environment, or other factors. The effects of race on pharmacokinetic characteristics in other ethnic groups have not been well characterized.

Hepatic impairment: Zaleplon is metabolized primarily by the liver and undergoes significant presystemic metabolism. Consequently, the oral clearance of zaleplon was reduced by 70% and 87% in compensated and decompensated cirrhotic patients, respectively, leading to marked increases in mean Cmax and AUC (up to 4-fold and 7-fold in compensated and decompensated patients, respectively), in comparison with healthy subjects. The dose of zaleplon should therefore be reduced in patients with mild to moderate hepatic impairment (see DOSAGE AND ADMINISTRATION). Zaleplon is not recommended for use in patients with severe hepatic impairment.

Renal impairment: Because renal excretion of unchanged zaleplon accounts for less than 1% of the administered dose, the pharmacokinetics of zaleplon are not altered in patients with renal insufficiency. No dose adjustment is necessary in patients with mild to moderate renal impairment. Zaleplon has not been adequately studied in patients with severe renal impairment.

Controlled Trials Supporting Effectiveness

Zaleplon (typically administered in doses of 5 mg, 10 mg, or 20 mg) has been studied in patients with chronic insomnia (n = 3,435) in 12 placebo- and active-drug-controlled trials. Three of the trials were in elderly patients (n = 1,019). It has also been studied in transient insomnia (n = 264). Because of its very short half-life, studies focused on decreasing sleep latency, with less attention to duration of sleep and number of awakenings, for which consistent differences from placebo were not demonstrated. Studies were also carried out to examine the time course of effects on memory and psychomotor function, and to examine withdrawal phenomena.

Transient Insomnia

Normal adults experiencing transient insomnia during the first night in a sleep laboratory were evaluated in a double-blind, parallel-group trial comparing the effects of two doses of zaleplon (5 mg and 10 mg) with placebo. Zaleplon 10 mg, but not 5 mg, was superior to placebo in decreasing latency to persistent sleep (LPS), a polysomnographic measure of time to onset of sleep.

Chronic Insomnia

Non-elderly patients:

Adult outpatients with chronic insomnia were evaluated in three double-blind, parallel-group outpatient studies, one of 2 weeks duration and two of 4 weeks duration, that compared the effects of zaleplon at doses of 5 mg (in two studies), 10 mg, and 20 mg with placebo on a subjective measure of time to sleep onset (TSO). Zaleplon 10 mg and 20 mg were consistently superior to placebo for TSO, generally for the full duration of all three studies. Although both doses were effective, the effect was greater and more consistent for the 20-mg dose. The 5-mg dose was less consistently effective than were the 10-mg and 20-mg doses. Sleep latency with zaleplon 10 mg and 20 mg was on the order of 10-20 minutes (15%-30%) less than with placebo in these studies.

Adult outpatients with chronic insomnia were evaluated in six double-blind, parallel-group sleep laboratory studies that varied in duration from a single night up to 35 nights. Overall, these studies demonstrated a superiority of zaleplon 10 mg and 20 mg over placebo in reducing LPS on the first 2 nights of treatment. At later time points in 5-, 14-, and 28-night studies, a reduction in LPS from baseline was observed for all treatment groups, including the placebo group, and thus, a significant difference between zaleplon and placebo was not seen beyond 2 nights. In a 35-night study, zaleplon 10 mg was significantly more effective than placebo in reducing LPS at the primary efficacy endpoint on nights 29 and 30.

Elderly patients:

Elderly outpatients with chronic insomnia were evaluated in two 2-week, double-blind, parallel-group outpatient studies that compared the effects of zaleplon 5 mg and 10 mg with placebo on a subjective measure of time to sleep onset (TSO). Zaleplon at both doses was superior to placebo on TSO, generally for the full duration of both studies, with an effect size generally similar to that seen in younger persons. The 10-mg dose tended to have a greater effect in reducing TSO.

Elderly outpatients with chronic insomnia were also evaluated in a 2-night sleep laboratory study involving doses of 5 mg and 10 mg. Both 5-mg and 10-mg doses of zaleplon were superior to placebo in reducing latency to persistent sleep (LPS).

Generally in these studies, there was a slight increase in sleep duration, compared to baseline, for all treatment groups, including placebo, and thus, a significant difference from placebo on sleep duration was not demonstrated.

Studies Pertinent to Safety Concerns for Sedative/Hypnotic Drugs

Memory Impairment

Studies involving the exposure of normal subjects to single fixed doses of zaleplon (10 mg or 20 mg) with structured assessments of short-term memory at fixed times after dosing (e.g., 1, 2, 3, 4, 5, 8, and 10 hours) generally revealed the expected impairment of short-term memory at 1 hour, the time of peak exposure to zaleplon, for both doses, with a tendency for the effect to be greater after 20 mg. Consistent with the rapid clearance of zaleplon, memory impairment was no longer present as early as 2 hours post dosing in one study, and in none of the studies after 3-4 hours. Nevertheless, spontaneous reporting of adverse events in larger premarketing clinical trials revealed a difference between zaleplon and placebo in the risk of next-day amnesia (3% vs 1%), and an apparent dose-dependency for this event (see ADVERSE REACTIONS).

Sedative/Psychomotor Effects

Studies involving the exposure of normal subjects to single fixed doses of zaleplon (10 mg or 20 mg) with structured assessments of sedation and psychomotor function (e.g., reaction time and subjective ratings of alertness) at fixed times after dosing (e.g., 1, 2, 3, 4, 5, 8, and 10 hours) generally revealed the expected sedation and impairment of psychomotor function at 1 hour, the time of peak exposure to zaleplon, for both doses. Consistent with the rapid clearance of zaleplon, impairment of psychomotor function was no longer present as early as 2 hours post dosing in one study, and in none of the studies after 3-4 hours. Spontaneous reporting of adverse events in larger premarketing clinical trials did not suggest a difference between zaleplon and placebo in the risk of next-day somnolence (see ADVERSE REACTIONS).

Withdrawal-Emergent Anxiety and Insomnia

During nightly use for an extended period, pharmacodynamic tolerance or adaptation to some effects of hypnotics may develop. If the drug has a short elimination half-life, it is possible that a relative deficiency of the drug or its active metabolites (i.e., in relationship to the receptor site) may occur at some point in the interval between each night's use. This sequence of events is believed to be responsible for two clinical findings reported to occur after several weeks of nightly use of other rapidly eliminated hypnotics: increased wakefulness during the last quarter of the night and the appearance of increased signs of daytime anxiety.

Zaleplon has a short half-life and no active metabolites. At the primary efficacy endpoint (nights 29 and 30) in a 35-night sleep laboratory study, polysomnographic recordings showed that wakefulness was not significantly longer with zaleplon than with placebo during the last quarter of the night. No increase in the signs of daytime anxiety was observed in clinical trials with zaleplon. In two sleep laboratory studies involving 14- and 28-nightly doses of zaleplon (5 mg and 10 mg in one study and 10 mg and 20 mg in the second) and structured assessments of daytime anxiety, no increases in daytime anxiety were detected. Similarly, in a pooled analysis (all the parallel-group, placebo-controlled studies) of spontaneously reported daytime anxiety, no difference was observed between zaleplon and placebo.

Rebound insomnia, defined as a dose-dependent temporary worsening in sleep parameters (latency, total sleep time, and number of awakenings) compared to baseline following discontinuation of treatment, is observed with short- and intermediate-acting hypnotics. Rebound insomnia following discontinuation of zaleplon relative to baseline was examined at both nights 1 and 2 following discontinuation in three sleep laboratory studies (14, 28, and 35 nights) and five outpatient studies utilizing patient diaries (14 and 28 nights). Overall, the data suggest that rebound insomnia may be dose dependent. At  20 mg, there appeared to be both objective (polysomnographic) and subjective (diary) evidence of rebound insomnia on the first night after discontinuation of treatment with zaleplon. At 5 mg and 10 mg, there was no objective and minimal subjective evidence of rebound insomnia on the first night after discontinuation of treatment with zaleplon. At all doses, the rebound effect appeared to resolve by the second night following withdrawal. In the 35-night study, there was a worsening in sleep on the first night off for both the 10-mg and 20-mg groups compared to placebo, but not to baseline. This discontinuation-emergent effect was mild, had the characteristics of the return of the symptoms of chronic insomnia, and appeared to resolve by the second night after zaleplon discontinuation.

Other Withdrawal-Emergent Phenomena

The potential for other withdrawal phenomena was also assessed in 14- to 28-night studies, including both the sleep laboratory studies and the outpatient studies, and in open-label studies of 6- and 12-month durations. The Benzodiazepine Withdrawal Symptom Questionnaire was used in several of these studies, both at baseline and then during days 1 and 2 following discontinuation. Withdrawal was operationally defined as the emergence of 3 or more new symptoms after discontinuation. Zaleplon was not distinguishable from placebo at doses of 5 mg, 10 mg, or 20 mg on this measure, nor was zaleplon distinguishable from placebo on spontaneously reported withdrawal-emergent adverse events. There were no instances of withdrawal delirium, withdrawal associated hallucinations, or any other manifestations of severe sedative/hypnotic withdrawal.

Timing of Drug Administration

Zaleplon should be taken immediately before bedtime or after the patient has gone to bed and has experienced difficulty falling asleep. As with all sedative/hypnotics, taking zaleplon while still up and about may result in short-term memory impairment, hallucinations, impaired coordination, dizziness, and lightheadedness.

Use in the Elderly and/or Debilitated Patients

Impaired motor and/or cognitive performance after repeated exposure or unusual sensitivity to sedative/hypnotic drugs is a concern in the treatment of elderly and/or debilitated patients. A dose of 5 mg is recommended for elderly patients to decrease the possibility of side effects (see DOSAGE AND ADMINISTRATION). Elderly and/or debilitated patients should be monitored closely.

Use in Patients with Concomitant Illness

Clinical experience with zaleplon in patients with concomitant systemic illness is limited. Zaleplon should be used with caution in patients with diseases or conditions that could affect metabolism or hemodynamic responses.

Although preliminary studies did not reveal respiratory depressant effects at hypnotic doses of zaleplon in normal subjects, caution should be observed if zaleplon is prescribed to patients with compromised respiratory function, because sedative/hypnotics have the capacity to depress respiratory drive. Controlled trials of acute administration of zaleplon 10 mg in patients with mild to moderate chronic obstructive pulmonary disease or moderate obstructive sleep apnea showed no evidence of alterations in blood gases or apnea/hypopnea index, respectively. However, patients with compromised respiration due to preexisting illness should be monitored carefully.

The dose of zaleplon should be reduced to 5 mg in patients with mild to moderate hepatic impairment (see DOSAGE AND ADMINISTRATION). It is not recommended for use in patients with severe hepatic impairment.

No dose adjustment is necessary in patients with mild to moderate renal impairment. Zaleplon has not been adequately studied in patients with severe renal impairment.

Use in Patients with Depression

In primarily depressed patients treated with sedative-hypnotics, worsening of depression, including suicidal thoughts and actions (including completed suicides), have been reported. As with other sedative/hypnotic drugs, zaleplon should be administered with caution to patients exhibiting signs or symptoms of depression. Suicidal tendencies may be present in such patients and protective measures may be required. Intentional overdosage is more common in this group of patients (see OVERDOSAGE); therefore, the least amount of drug that is feasible should be prescribed for the patient at any one time.

Allergic-Type Reactions FD&C Yellow No. 5

This product contains FD&C Yellow No. 5 (tartrazine) which may cause allergic-type reactions (including bronchial asthma) in certain susceptible persons. Although the overall incidence of FD&C Yellow No. 5 (tartrazine) sensitivity in the general population is low, it is frequently seen in patients who also have aspirin hypersensitivity.

CNS-Active Drugs

Drugs That Induce CYP3A4

Drugs That Inhibit CYP3A4

CYP3A4 is a minor metabolic pathway for the elimination of zaleplon because the sum of desethylzaleplon (formed via CYP3A4 in vitro) and its metabolites, 5-oxo-desethylzaleplon and 5-oxo-desethylzaleplon glucuronide, account for only 9% of the urinary recovery of a zaleplon dose. Coadministration of single, oral doses of zaleplon with erythromycin (10 mg and 800 mg respectively), a strong, selective CYP3A4 inhibitor, produced a 34% increase in zaleplon's maximal plasma concentrations and a 20% increase in the area under the plasma concentration-time curve. The magnitude of interaction with multiple doses of erythromycin is unknown. Other strong selective CYP3A4 inhibitors such as ketoconazole can also be expected to increase the exposure of zaleplon. A routine dosage adjustment of zaleplon is not considered necessary.

Drugs That Inhibit Aldehyde Oxidase

The aldehyde oxidase enzyme system is less well studied than the cytochrome P450 enzyme system.

Drugs That Inhibit Both Aldehyde Oxidase and CYP3A4

Drugs Highly Bound to Plasma Protein

Zaleplon is not highly bound to plasma proteins (fraction bound 60%±15%); therefore, the disposition of zaleplon is not expected to be sensitive to alterations in protein binding. In addition, administration of zaleplon to a patient taking another drug that is highly protein bound should not cause transient increase in free concentrations of the other drug.

Drugs with a Narrow Therapeutic Index

Drugs That Alter Renal Excretion

Carcinogenesis

Lifetime carcinogenicity studies of zaleplon were conducted in mice and rats. Mice received doses of 25 mg/kg/day, 50 mg/kg/day, 100 mg/kg/day, and 200 mg/kg/day in the diet for two years. These doses are equivalent to 6 to 49 times the maximum recommended human dose (MRHD) of 20 mg on a mg/m2 basis. There was a significant increase in the incidence of hepatocellular adenomas in female mice in the high dose group. Rats received doses of 1 mg/kg/day, 10 mg/kg/day, and 20 mg/kg/day in the diet for two years. These doses are equivalent to 0.5 to 10 times the maximum recommended human dose (MRHD) of 20 mg on a mg/m2 basis. Zaleplon was not carcinogenic in rats.

Mutagenesis

Zaleplon was clastogenic, both in the presence and absence of metabolic activation, causing structural and numerical aberrations (polyploidy and endoreduplication), when tested for chromosomal aberrations in the in vitro Chinese hamster ovary cell assay. In the in vitro human lymphocyte assay, zaleplon caused numerical, but not structural, aberrations only in the presence of metabolic activation at the highest concentrations tested. In other in vitro assays, zaleplon was not mutagenic in the Ames bacterial gene mutation assay or the Chinese hamster ovary HGPRT gene mutation assay. Zaleplon was not clastogenic in two in vivo assays, the mouse bone marrow micronucleus assay and the rat bone marrow chromosomal aberration assay, and did not cause DNA damage in the rat hepatocyte unscheduled DNA synthesis assay.

Impairment of Fertility

In a fertility and reproductive performance study in rats, mortality and decreased fertility were associated with administration of an oral dose of zaleplon of 100 mg/kg/day to males and females prior to and during mating. This dose is equivalent to 49 times the maximum recommended human dose (MRHD) of 20 mg on a mg/m2 basis. Follow-up studies indicated that impaired fertility was due to an effect on the female.

Adverse Events Associated With Discontinuation of Treatment

In premarketing placebo-controlled, parallel-group phase 2 and phase 3 clinical trials, 3.1% of 744 patients who received placebo and 3.7% of 2,149 patients who received zaleplon discontinued treatment because of an adverse clinical event. This difference was not statistically significant. No event that resulted in discontinuation occurred at a rate of ≥ 1%.

Adverse Events Occurring at an Incidence of 1% or More Among Zaleplon 20 mg-Treated Patients

Table 1 enumerates the incidence of treatment-emergent adverse events for a pool of three 28-night and one 35-night placebo-controlled studies of zaleplon at doses of 5 mg or 10 mg and 20 mg. The table includes only those events that occurred in 1% or more of patients treated with zaleplon 20 mg and that had a higher incidence in patients treated with zaleplon 20 mg than in placebo-treated patients.

The prescriber should be aware that these figures cannot be used to predict the incidence of adverse events in the course of usual medical practice where patient characteristics and other factors differ from those which prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses, and investigators. The cited figures, however, do provide the prescribing physician with some basis for estimating the relative contribution of drug and non-drug factors to the adverse event incidence rate in the population studied.

a Events for which the incidence for zaleplon 20 mg-treated patients was at least 1% and greater than the incidence among placebo-treated patients. Incidence greater than 1% has been rounded to the nearest whole number.

Abuse

Two studies assessed the abuse liability of zaleplon at doses of 25 mg, 50 mg, and 75 mg in subjects with known histories of sedative drug abuse. The results of these studies indicate that zaleplon has an abuse potential similar to benzodiazepine and benzodiazepine-like hypnotics.

Dependence

The potential for developing physical dependence on zaleplon and a subsequent withdrawal syndrome was assessed in controlled studies of 14-, 28-, and 35-night durations and in open-label studies of 6- and 12-month durations by examining for the emergence of rebound insomnia following drug discontinuation. Some patients (mostly those treated with 20 mg) experienced a mild rebound insomnia on the first night following withdrawal that appeared to be resolved by the second night. The use of the Benzodiazepine Withdrawal Symptom Questionnaire and examination of any other withdrawal-emergent events did not detect any other evidence for a withdrawal syndrome following abrupt discontinuation of zaleplon therapy in pre-marketing studies.

However, available data cannot provide a reliable estimate of the incidence of dependence during treatment at recommended doses of zaleplon. Other sedative/hypnotics have been associated with various signs and symptoms following abrupt discontinuation, ranging from mild dysphoria and insomnia to a withdrawal syndrome that may include abdominal and muscle cramps, vomiting, sweating, tremors, and convulsions. Seizures have been observed in two patients, one of which had a prior seizure, in clinical trials with zaleplon. Seizures and death have been seen following the withdrawal of zaleplon from animals at doses many times higher than those proposed for human use. Because individuals with a history of addiction to, or abuse of, drugs or alcohol are at risk of habituation and dependence, they should be under careful surveillance when receiving zaleplon or any other hypnotic.

Tolerance

Possible tolerance to the hypnotic effects of zaleplon 10 mg and 20 mg was assessed by evaluating time to sleep onset for zaleplon compared with placebo in two 28-night placebo-controlled studies and latency to persistent sleep in one 35-night placebo-controlled study where tolerance was evaluated on nights 29 and 30. No development of tolerance to zaleplon was observed for time to sleep onset over 4 weeks.

Hepatic insufficiency:

Patients with mild to moderate hepatic impairment should be treated with zaleplon capsules 5 mg because clearance is reduced in this population. Zaleplon capsules are not recommended for use in patients with severe hepatic impairment.

Renal insufficiency:

No dose adjustment is necessary in patients with mild to moderate renal impairment. Zaleplon capsules have not been adequately studied in patients with severe renal impairment.

An initial dose of 5 mg should be given to patients concomitantly taking cimetidine because zaleplon clearance is reduced in this population (see Drug Interactions under PRECAUTIONS).