Class: Anxiolytics, Sedatives, and Hypnotics; Miscellaneous
VA Class: CN309
Chemical Name: N-[3-(3-cyanopyrazolo[1,5-α]pyrimidin-7-yl)phenyl]-N-ethyl-acetamide
Molecular Formula: C₁₇H₁₅N₅O
CAS Number: 151319-34-5
Brands: Sonata

Introduction

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

Uses for Zaleplon

Insomnia

Short-term management of insomnia.^{1 2 12 13 14 15 16 18 19}

Decreases sleep latency with repeated use for periods up to 30 days in duration.^{1 2 12 13 14 15 16 18 19}

Most useful for sleep initiation disorders;^{3 12} does not substantially increase total sleep time or decrease the number of awakenings.^{1 3 18}

Zaleplon Dosage and Administration

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

Insomnia

Oral

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

Insomnia

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.)

Cautions for Zaleplon

Contraindications

• Hypersensitivity to zaleplon or any ingredient in the formulation.^a

Warnings/Precautions

Warnings

Adequate Patient Evaluation

Insomnia may be a manifestation of an underlying physical and/or psychiatric disorder; carefully evaluate patient before providing symptomatic treatment.¹

Failure of insomnia to remit after 7–10 days of treatment, worsening of insomnia, or emergence of new abnormal thinking or behavior may indicate the presence of an underlying psychiatric and/or medical condition.¹

Adverse Psychiatric Events

Abnormal thinking and behavioral changes (e.g. aggressiveness, uncharacteristic extroversion, bizarre behavior, agitation, hallucinations, depersonalization, amnesia) may occur unpredictably.¹ Immediately evaluate any new behavioral sign or symptom.¹

Complex Sleep-related Behaviors

Potential risk of complex sleep-related behaviors such as sleep-driving (i.e., driving while not fully awake after ingesting a sedative-hypnotic drug, with no memory of the event), making phone calls, or preparing and eating food, while asleep.²⁵

Withdrawal Effects

Rapid dosage reduction or abrupt discontinuance of sedatives or hypnotics has resulted in signs or symptoms of withdrawal.¹

Rebound insomnia (1 day in duration) observed, principally in patients receiving 20-mg dose.¹ At least 2 cases of seizure (1 with seizure history) reported.¹

Abuse Potential

Abuse potential of high doses (2.5–7.5 times recommended hypnotic dose) similar to that of benzodiazepines and related hypnotics.^{1 4 10 12 20}

Patients with a history of drug or alcohol dependence or abuse are at risk of habituation or dependence; use only with careful surveillance in such patients.¹

CNS Effects

Rapid onset of CNS effects (short-term memory impairment, hallucinations, impaired coordination, dizziness, lightheadedness); administer only immediately before going to bed or after unsuccessfully attempting to sleep.¹

Peformance of activities requiring mental alertness or physical coordination (e.g., operating machinery, driving a motor vehicle) may be impaired the day after ingestion.¹

Concurrent use of other CNS depressants may cause additive or potentiated CNS depression.¹ (See Specific Drugs under Interactions.)

Sensitivity Reactions

Potential risk of anaphylaxis and angioedema; may occur as early as the first dose of the drug.²⁵

Tartrazine

Preparations contain tartrazine (FD&C; yellow No. 5).¹ Tartrazine may cause allergic reactions including bronchial asthma in susceptible individuals.¹ Although the incidence of tartrazine sensitivity is low, it frequently occurs in patients who are sensitive to aspirin.¹

General Precautions

Respiratory Effects

Possible depressed respiration with sedative-hypnotics.¹ No respiratory depressant effects reported at hypnotic doses of zaleplon in healthy individuals or in patients with mild to moderate COPD or moderate obstructive sleep apnea.¹

Caution is advised in patients with impaired respiratory function.¹

Concomitant Disease

Limited experience in patients with concomitant systemic disease.¹ Use with caution in patients with diseases affecting metabolism or hemodynamic response.¹

Suicide

Use with caution in depressed patients.¹ Potential for suicidal tendencies; overdosage more frequent in such patients.¹ Prescribe and dispense drug in the smallest feasible quantity.¹ Do not prescribe more than 30-day supply.^a

Specific Populations

Pregnancy

Category C.¹

Lactation

Distributed into milk.^{1 11} Use not recommended.¹

Pediatric Use

Safety and efficacy not established in children <18 years of age.^{1 20}

Geriatric Use

Possibility exists of greater sensitivity to pharmacologic and adverse effects of sedatives and hypnotics in patients ≥65 years of age;¹ reduce initial and maximum dose.^{1 19} (See Geriatric Patients under Dosage and Administration.)

Hepatic Impairment

Reduce dosage for mild to moderate hepatic impairment.¹ Use not recommended in patients with severe hepatic impairment.¹ (See Hepatic Impairment under Dosage and Administration.)

Debilitated Patients

Potential increased sensitivity to sedatives and hypnotics or impaired motor performance after repeated exposure.¹ Reduce dosage and monitor closely.¹ (See Debilitated or Low-weight Patients under Dosage and Administration.)

Common Adverse Effects

Headache, asthenia, dizziness, nausea, abdominal pain, somnolence.¹

Interactions for Zaleplon

Metabolized principally by aldehyde oxidase, and to a lesser extent by CYP3A4; metabolites are inactive.^a

Drugs Affecting Hepatic Microsomal Enzymes

Inducers of CYP3A4: potential pharmacokinetic interaction (decreased plasma zaleplon concentrations); may result in decreased efficacy of zaleplon.¹

Potent, selective inhibitors of CYP3A4: potential pharmacokinetic interaction (increased plasma zaleplon concentrations); routine dosage adjustment not considered necessary.^a

Protein Bound Drugs

Pharmacokinetic interaction unlikely.^a

Specific Drugs

Drug	Interaction	Comments
Carbamazepine	Possible increased clearance and decreased efficacy of zaleplon (CYP3A4 induction by carbamazepine) a	Consider alternate, non-CYP3A4 substrate hypnotic in patients receiving carbamazepinea
Cimetidine	Increased (85%) peak plasma concentrations and AUC of zaleplon (CYP3A4 and aldehyde oxidase inhibition by cimetidine)1 22 a	Reduce initial zaleplon dose to 5 mg 1 22
CNS depressants (e.g., alcohol, anesthetics, anticonvulsants, antihistamines, narcotic analgesics)	Possible additive CNS effects1 22
Digoxin	Pharmacokinetic interaction unlikely1 22
Diphenhydramine	Pharmacokinetic (aldehyde oxidase inhibition) interaction unlikely; possible additive CNS depressant effects1 22
Erythromycin	Increased (34%) plasma zaleplon concentrations (CYP3A4 inhibition by erythromycin)a	No routine dosage adjustment of zaleplon considered necessarya
Ibuprofen	Pharmacokinetic interaction unlikely1 22
Imipramine	Additive CNS effects; pharmacokinetic interaction unlikelya
Ketoconazole	Increased plasma zaleplon concentrations expected (CYP3A4 inhibition by ketoconazole) a	No routine dosage adjustment of zaleplon considered necessarya
Paroxetine	Pharmacokinetic interaction unlikely; concomitant use (paroxetine 20 mg and zaleplon 20 mg daily for 7 days) did not alter psychomotor performancea
Phenobarbital	Possible increased clearance and decreased efficacy of zaleplon (CYP3A4 induction by phenobarbital)a	Consider alternate, non-CYP3A4 substrate hypnotic in patients receiving phenobarbitala
Phenytoin	Possible increased clearance and decreased efficacy of zaleplon (CYP3A4 induction by phenytoin)a	Consider alternate, non-CYP3A4 substrate hypnotic in patients receiving phenytoina
Promethazine	Pharmacokinetic interaction unlikely; possible additive CNS effectsa
Rifampin	Decreased (80%) peak plasma concentrations and AUC of zaleplon; may result in decreased zaleplon efficacy (CYP3A4 induction by rifampin)a	Consider alternate, non-CYP3A4 substrate hypnotic in patients receiving rifampina
Thioridazine	Additive CNS effects; pharmacokinetic interaction unlikelya
Venlafaxine	Pharmacokinetic interaction unlikely; concomitant use of multiple doses (extended-release venlafaxine 75 or 150 mg and zaleplon 10 mg) did not alter psychomotor performancea
Warfarin	Pharmacokinetic or pharmacodynamic (prothrombin time) interactions unlikely1

Zaleplon Pharmacokinetics

Absorption

Bioavailability

Rapidly and almost completely absorbed after oral administration, with peak plasma concentrations attained in approximately 1 hour.^a Absolute oral bioavailability is about 30%.^a

Food

High-fat or heavy meal decreases peak plasma concentration by 35% and prolongs time to peak plasma concentration by 2 hours; effect on sleep onset may be decreased.^a

Special Populations

In Japanese patients, peak plasma concentrations and AUC were increased 37 and 64%, respectively; may be attributed to differences in body weight or enzyme activity resulting from differences in diet, environment, or other factors.^a

Distribution

Extent

Extensively distributed into extravascular tissues.^a

Plasma Protein Binding

60% (Range: 45–75%) .^a

Elimination

Metabolism

Extensively metabolized, principally by aldehyde oxidase and to a lesser extent by CYP3A4.^a All metabolites are inactive.^a

Elimination Route

Principally in urine (70%) as metabolites within 48 hours; also excreted in feces (17%), mainly as 5-oxo-zaleplon.^a

Half-life

About 1 hour.^a

Special Populations

In patients with cirrhosis, oral clearance is decreased by 70–87%.^a (See Hepatic Impairment under Dosage and Administration.)

Stability

Storage

Oral

Capsules

Tight, light-resistant containers at 20–25°C.^a

Actions

• Interacts with the CNS GABA_A-receptor-chloride ionophore complex at benzodiazepine (BZ) omega-1 (BZ₁, ο₁) receptors.^{1 2 3 5 6 7 12 13 18}

• Pharmacologically and pharmacokinetically similar to zolpidem.^{1 2 3 5 6 7 12 13 18}

Advice to Patients

• Importance of administering immediately before retiring, or after attempting to fall asleep, and only when able to get ≥4 hours of sleep before it is necessary to be active again.^{1 17}

• Importance of avoiding administration with or immediately after a high-fat meal.¹

• Importance of taking only as prescribed; do not increase the dose or duration of therapy unless otherwise instructed by a clinician.¹

• Potential to impair mental alertness or physical coordination; use caution when driving, operating machinery or performing other hazardous tasks during therapy.^{1 12 17}

• Importance of avoidance of alcohol during therapy.^{1 22}

• Importance of identifying and reporting to clinicians any potential adverse effects, such as memory impairment, dependence/withdrawal symptoms after multiple dosing, behavioral abnormalities, or tolerance potential.¹

• Advise patient of possible rebound insomnia for 1 or 2 nights after discontinuance.¹

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as concomitant illnesses, particularly depression.^{1 22}

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.¹

• Importance of informing patients of other important precautionary information.^{1 a} (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Subject to control under the Federal Controlled Substances Act of 1970 as a schedule IV (C-IV) drug.^{1 4}

Zaleplon

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Oral	Capsules	5 mg	Sonata (C-IV; with tartrazine)	Monarch, (also promoted by King)
		10 mg	Sonata (C-IV; with tartrazine)	Monarch, (also promoted by King)