Zaleplon

In case of overdose, call your local poison control center at 1-800-222-1222. If the victim has collapsed or is not breathing, call local emergency services at 911.

Symptoms of overdose may include:

• drowsiness
• confusion
• problems with coordination
• floppy muscles
• slow or difficult breathing
• coma (loss of consciousness for a period of time)

>10%

Headache (38%)

1-10%

Dizziness (7-9%)

Nausea (6-8%)

Abdominal pain (6%)

Weakness (5-7%)

Dysmenorrhea (3-4%)

Eye pain (3-4%)

Amnesia (2-4%)

Parasthesia (3%)

Tremor (2%)

<1%

Fever

Photosensitivity

Anorexia

Colitis

Periphipheral edema

Amnesia

Anxiety

Depersonalization

Hallucination

Hypesthesia

Vertigo

Epistaxis

Abnl vision

Ear pain

Hyperacusis

Parosmia

Postmarketing Reports

Anaphylactic/anaphylactoid reactions, including severe reactions

Nightmares

Pregnancy Category: C

Lactation: small amount secreted in breast milk, not recommended

Pregnancy Categories

A:Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B:May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C:Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D:Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X:Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA:Information not available.

Tell your doctor if you are pregnant or plan to become pregnant. It is not known if zaleplon will harm your unborn baby.

You should not use this medicine if you are allergic to zaleplon.

To make sure zaleplon is safe for you, tell your doctor if you have:

• liver or kidney disease;

• sleep apnea (breathing stops while you are asleep);

• lung disease (asthma, bronchitis, emphysema, COPD) or other breathing problems;

• a history of depression, mental illness, or suicidal thoughts; or

• a history of drug or alcohol addiction.

It is not known whether zaleplon will harm an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant while using this medication.

It is not known whether zaleplon passes into breast milk or if it could harm a nursing baby. You should not breast-feed while using this medicine.

The sedative effects of zaleplon may be stronger in older adults. Dizziness or severe drowsiness can cause falls or other accidents.

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

Overdose symptoms may include severe drowsiness, confusion, loss of coordination, limp muscles, weak or shallow breathing, fainting.

Pyrazolopyrimidine-derivative sedative and hypnotic; structurally unrelated to benzodiazepines and other sedatives and hypnotics.1 2 3 4 12 13 18

Administration

Oral Administration

Administer orally, generally without regard to meals.1

Avoid administration with a high-fat or heavy meal; may decrease rate of absorption and effect on sleep latency.1

Administer immediately before retiring (when ready to sleep) or after retiring when experiencing difficulty falling asleep.1

Use only when able to get ≥4 hours of sleep; amnesic episodes may result with less (e.g., overnight flight of <4 hours’ duration) sleep.1 17

Dosage

Adults

Individualize dosage.1

Adults <65 years of age: 10 mg.1 Although risk of certain adverse effects appears to be dose dependent, 20-mg doses have been adequately tolerated; may consider if unresponsive to a trial of lower dosage.1

Generally, limit use to 7–10 days; reevaluate patient if plan to use >2–3 weeks.a

Prescribing Limits

Adults

Doses >20 mg not adequately studied; not recommended by manufacturer.1

Special Populations

Hepatic Impairment

In patients with mild to moderate hepatic impairment, 5 mg;1 doses >10 mg not recommended.1 Not recommended in patients with severe hepatic impairment.1

Renal Impairment

No dosage adjustment necessary in patients with mild to moderate renal impairment.1 Not adequately studied in patients with severe renal impairment.1

Geriatric Patients

In adults ≥65 years of age, 5 mg may be sufficient; doses >10 mg not recommended.1

Debilitated or Low-weight Patients

In debilitated patients or low-weight patients <65 years of age, 5 mg may be sufficient; doses >10 mg not recommended.1

Patients Receiving Cimetidine

In patients receiving cimetidine concomitantly, initial dose of 5 mg recommended.1 (See Specific Drugs under Interactions.)

Zaleplon belongs to the group of medicines called central nervous system (CNS) depressants (medicines that make you drowsy or less alert). Zaleplon is used to treat insomnia (trouble sleeping). In general, when sleep medicines are used every night for a long time, they may lose their effectiveness. In most cases, sleep medicines should be used only for short periods of time, such as 1 or 2 days, and generally for no longer than 1 or 2 weeks.

zaleplon is available only with your doctor's prescription.

• It is used to treat sleep problems.

Pharmacodynamics and Mechanism of Action

While Zaleplon is a hypnotic agent with a chemical structure unrelated to benzodiazepines, barbiturates, or other drugs with known hypnotic properties, it interacts with the gamma-aminobutyric acid-benzodiazepine (GABA-BZ) receptor complex. Subunit modulation of the GABA-BZ receptor chloride channel macromolecular complex is hypothesized to be responsible for some of the pharmacological properties of benzodiazepines, which include sedative, anxiolytic, muscle relaxant, and anticonvulsive effects in animal models.

Other nonclinical studies have also shown that Zaleplon binds selectively to the brain omega-1 receptor situated on the alpha subunit of the GABAA /chloride ion channel receptor complex and potentiates t-butyl-bicyclophosphorothionate (TBPS) binding. Studies of binding of Zaleplon to recombinant GABAA receptors (α1β1γ2[omega-1] and α2β1γ2 [omega-2]) have shown that Zaleplon has a low affinity for these receptors, with preferential binding to the omega-1 receptor.

Pharmacokinetics

The pharmacokinetics of Zaleplon have been investigated in more than 500 healthy subjects (young and elderly), nursing mothers, and patients with hepatic disease or renal disease. In healthy subjects, the pharmacokinetic profile has been examined after single doses of up to 60 mg and once-daily administration at 15 mg and 30 mg for 10 days. Zaleplon was rapidly absorbed with a time to peak concentration (tmax) of approximately 1 hour and a terminal-phase elimination half-life (t1/2) of approximately 1 hour. Zaleplon does not accumulate with once-daily administration and its pharmacokinetics are dose proportional in the therapeutic range.

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.

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.

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.

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.

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.

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.

Drug-Drug Interactions

Because Zaleplon is primarily metabolized by aldehyde oxidase, and to a lesser extent by CYP3A4, inhibitors of these enzymes might be expected to decrease Zaleplon's clearance and inducers of these enzymes might be expected to increase its clearance. Zaleplon has been shown to have minimal effects on the kinetics of warfarin (both R- and S- forms), imipramine, ethanol, ibuprofen, diphenhydramine, thioridazine, and digoxin. However, the effects of Zaleplon on inhibition of enzymes involved in the metabolism of other drugs have not been studied. (See Drug Interactions under PRECAUTIONS.)

Clinical Trials

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.

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.

Store at 20°C to 25°C (68°F to 77°F) [see USP Controlled Room Temperature]. Dispense in a light-resistant container as defined in the USP.

Insomnia: Short-term treatment of insomnia.

Insomnia: Oral: Usual dosage 5 mg immediately before bedtime (maximum dose: 10 mg daily).

Avoid taking with or after a heavy, high-fat meal; reduces absorption.

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience headache, dizziness, abdominal pain, fatigue, or nausea. Have patient report immediately to prescriber signs of depression (suicidal ideation, anxiety, emotional instability, or confusion), confusion, hallucinations, memory impairment, behavioral changes, agitation, numbness or tingling, change in balance, or severe loss of strength and energy (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

-Mild to Moderate Hepatic Impairment: 5 mg orally immediately before bedtime or after going to bed and experiencing difficulty falling asleep.
-Severe Hepatic Impairment: Not recommended.