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Zaleplon (Systemic)

Primary: CN309

Note: Controlled substance classification—

Note: Controlled substance classification

U.S.—Schedule IV
Commonly used brand name(s): Sonata.

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).





Insomnia (treatment)—Zaleplon is indicated for the short-term treatment of insomnia{01}. Zaleplon decreases the time to sleep onset but has not been shown to increase total sleep time or decrease number of awakenings. Failure of insomnia to remit after 7 to 10 days of treatment may indicate the presence of a primary psychiatric or medical illness. Worsening of insomnia or the emergence of new abnormalities of thinking or behavior may be a consequence of an unrecognized psychiatric or physical disorder{01}.


Physicochemical characteristics:

Chemical group—
    Pyrazolopyrimidine; structurally unrelated to benzodiazepines, barbiturates, or other drugs with known hypnotic properties{01} .
Molecular weight—

    Practically insoluble in water; sparingly soluble in alcohol or propylene glycol {01}.

Partition coefficient
    Log partition coefficient is 1.23 in octanol/water over a pH range of 1 to 7.{01}

Mechanism of action/Effect:

Zaleplon interacts with the gamma-aminobutyric acid type A-benzodiazepine (GABA-BZ) receptor complex. Modulation of the GABA-BZ receptor chloride channel macromolecular complex appears to be responsible for the pharmacological properties of the benzodiazepines including sedative, anxiolytic, muscle relaxant, and anticonvulsant effects. Zaleplon binds selectively to the brain alpha subunit of the GABAA omega-1 receptor{01}.


Zaleplon absorption is rapid and almost complete. Due to significant presystemic metabolism, its absolute bioavailability is approximately 30%. Food may prolong the absorption{01}.


The volume of distribution of zaleplon is approximately 1.4 L/kg following intravenous administration. Substantial distribution into extravascular tissues occurs. The blood to plasma ratio for zaleplon is approximately 1, indicating uniform distribution throughout the blood with no extensive distribution into red blood cells. Small amounts of zaleplon are distributed into breast milk, with the highest concentrations occurring during a feeding approximately 1 hour post-administration{01}.

Protein binding:

Moderate (60%){01}.


Zaleplon is extensively metabolized, primarily by aldehyde oxidase and, to a lesser extent, by CYP3A4 All metabolites are inactive.{01}


Approximately 1 hour{01}

Onset of action:


Time to peak concentration:

Peak concentrations are attained within approximately 1 hour. Peaks may be delayed if zaleplon is taken with food{01}.


        71% of a single dose is eliminated in the urine; almost all is recovered as zaleplon metabolites and their glucuronides.{01} Less than 1% is excreted unchanged.{01}

        17% of a single dose is eliminated in the feces{01}.

Precautions to Consider


In mice receiving doses of 25, 50, 100, and 200 mg per kg of body weight (mg/kg) a day (6 to 49 times the maximum recommended human dose [MRHD] on a mg per square meter of body surface area [mg/m2] basis), there was a significant increase in the incidence of hepatocellular adenomas in females receiving the highest dose. No evidence of carcinogenic potential was seen in rats receiving 1, 10, and 20 mg/kg a day (0.5 to 10 times the MRHD on a mg/m 2 basis){01}.


When testing for chromosomal aberrations, in the in vitro Chinese hamster ovary cell assay, zaleplon was clastogenic in both the presence and absence of metabolic activation, causing structural and numerical aberrations.{01} In the in vitro human lymphocyte assay, zaleplon was clastogenic causing numerical but not structural aberrations{01}. In other in vitro studies including the Ames bacterial gene mutation assay and the Chinese hamster ovary HGPRT gene mutation assay, zaleplon was not mutagenic{01}. In two in vivo assays, the mouse bone marrow micronucleus assay and the rat bone marrow chromosomal aberration assay, zaleplon was not clastogenic{01}. Zaleplon did not cause DNA damage in the rat hepatocyte unscheduled DNA synthesis assay.{01}

In studies in rats, mortality and decreased fertility were associated with administration of zaleplon 100 mg/kg a day (49 times the MRHD on a mg/m2 basis) to males and females prior to and during mating. The impaired fertility was due to an effect on the female rat {01}.

Zaleplon has not been studied in pregnant women{01}.

No teratogenicity was seen in rat and rabbit studies. Female rats administered 100 mg of zaleplon per kg a day (49 times the MRHD on a mg/m 2 basis) produced offspring with reduced pre- and postnatal growth . This dose was also maternally toxic (clinical signs and decreased maternal body weight during gestation). Rats treated with doses of 7 mg/kg a day or greater during the latter part of gestation and throughout lactation produced a greater number of stillbirths, and offspring with increased postnatal mortality, and decreased growth and physical development. The no-effect dose on growth reduction and offspring development was five times the MRHD (10 mg/kg) and 0.5 times the MRHD (1mg/kg), respectively, for rat offspring. No adverse effects on embryofetal development were observed in rabbits{01}.

FDA Pregnancy Category C{01}.


A small amount of zaleplon is distributed into breast milk. The effect of zaleplon on the infant is unknown {01}.


Appropriate studies on the relationship of age to the effects of zaleplon have not been performed in the pediatric population. Safety and efficacy have not been established{01}.


In studies performed on 628 elderly patients, sleep latency improved with a reduced dose of 5 mg. The incidence of adverse events with a frequency of at least 1% was not significantly different between placebo and zaleplon at doses of either 5 mg or 10 mg during studies of a 14 day duration. The pharmacokinetics of zaleplon in the elderly, age 65 to 85 years, are not significantly different from those in younger patients. However, elderly patients appear to be more sensitive to the effects of hypnotics {01}.

Pharmacokinetics between men and women are not significantly different.{01}

The peak serum concentration of zaleplon was 37% higher in Japanese subjects. The effects of race on pharmacokinetic characteristics among other ethnic groups are not well-defined.{01}

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.

» Alcohol{01}, or
» Central nervous system (CNS) depression–producing medications, other (see Appendix II), especially
Thioridazine {01}    (concurrent use may cause additive CNS depressant effects such as decreased alertness and impaired psychomotor performance {01})

» Cimetidine    (concurrent use with an enzyme inhibitor of both aldehyde oxidase and CYP3A4, such as cimetidine, may increase peak concentrations and area under the time-concentration curve [AUC] of zaleplon; dosage reductions of zaleplon are needed{01})

» Enzyme inducers, hepatic, cytochrome P450 (see Appendix II),{01} especially
Rifampin    (concurrent use with CYP3A4 enzyme inducers may greatly decrease concentrations of zaleplon, rendering it ineffective{01})

Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).

Except under special circumstances, this medications should not be used when the following medical problems exist:
» Severe hepatic function impairment {01}    (zaleplon is metabolized primarily by the liver and undergoes significant presystemic metabolism)

Risk-benefit should be considered when the following medical problems exist
» Alcohol abuse (or history of) or
» Drug abuse or dependence (or history of)    (dependence on zaleplon may develop)

» Mental depression {01}    (potential for suicidal tendencies in depressed patients; likelihood of intentional overdose is greater in depressed patients {01})

» Hepatic function impairment, mild to moderate{01}    ( reduced metabolism may lead to toxicity; dosage reductions are necessary{01})

» Respiratory disease {01}    (possibility of depressed respiratory drive {01})

Sensitivity to zaleplon

Side/Adverse Effects
The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence less frequent
Abnormal vision (blurred or double vision)
depersonalization (not feeling like oneself)

Incidence rare
Epistaxis (nosebleed)
hallucinations (seeing, hearing, smelling, or feeling things that are not there)


Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
myalgia (muscle pain)

{01}Incidence less frequent
Abdominal pain
amnesia (memory loss)
arthritis ( joint stiffness and/or pain)
asthenia (unusual weakness or tiredness)
bronchitis (cough; shortness of breath; tightness in chest; troubled breathing; wheezing )
conjunctivitis (dry, itching, or burning eyes)
difficulty concentrating
dryness of mouth
dyspepsia (heartburn, indigestion, or acid stomach)
dysmenorrhea (menstrual pain )
eye pain
hyperacusis (sensitive hearing )
hypertonia (excess muscle tone )
mental depression
migraine ( severe headache)
paresthesia ( burning, prickling, or tingling sensation)
pruritus (itching)
skin rash
somnolence (drowsiness)
tremor (trembling or shaking)

{01}Incidence rare
Anorexia (loss of appetite)
back pain
chest pain
ear pain
hypesthesia (numbness)
malaise ( general feeling of discomfort or illness)
parosmia (sense of smell difficulty)
peripheral edema (swelling of fingers, hands, arms, legs, ankles, and feet; bloating or swelling of face; rapid weight gain )
photosensitivity (increased sensitivity of skin and eyes to sunlight; blisters; skin rash; redness; burning sensation ; severe sunburn)


Those indicating need for medical attention if they occur after medication is discontinued
Incidence rare
Abdominal and muscle cramps
dysphoria (sadness)
increased sweating
tremors (trembling or shaking)


For specific information on the agents used in the management of zaleplon overdose, see:   • Flumazenil (Systemic)monograph

For more information on the management of overdose or unintentional ingestion, contact a Poison Control Center (see Poison Control Center Listing).

Clinical effects of overdose
The following effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Ataxia, severe (clumsiness or unsteadiness)


drowsiness, severe

hypotension (dizziness or fainting)

hypotonia (weak muscle tone)

lethargy (unusual drowsiness, dullness, or feeling sluggish )

mental confusion

respiratory problems (troubled breathing)

Treatment of overdose
To decrease absorption—Perform gastric lavage as appropriate{01}.

Specific treatment—Flumazenil may be useful in reversing zaleplon's sedative and respiratory depressant effects{01}. See the package insert or Flumazenil (Systemic) monographfor specific dosing guidelines for the use of this product {01}.

Monitoring—Monitor respiratory, cardiac, and central nervous system status {01}.

Supportive care—Providing general supportive therapy as indicated{01}. Intravenous fluids should be administered as appropriate{01}. Patients in whom intentional overdose is confirmed or suspected should be referred for psychiatric consultation .

Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Zaleplon (Systemic).

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Hypersensitivity to zaleplon {01}

Breast-feeding—Small amount of zaleplon is distributed into breast milk; effect on infant is unknown{01}

Use in the elderly—— Elderly patients are usually more sensitive to central nervous system effects of zaleplon {01}
Other medications, especially alcohol, CNS depressants, cimetidine , and hepatic P450 enzyme inducers{01}
Other medical problems, especially alcohol or drug abuse (or history of), hepatic function impairment, mental depression, and respiratory disease{01}

Proper use of this medication
Not taking more medication than the amount prescribed, because of habit-forming potential {01}

Not increasing dose if medication becomes less effective over time; checking with physician {01}

» Being prepared to go to sleep immediately after taking medicine {01}

» Proper dosing
Skipping missed dose; not doubling doses {01}

» Proper storage

Precautions while using this medication
» Avoid use of alcohol or other central nervous system depressants during therapy {01}

Caution if clumsiness or unsteadiness, drowsiness, dizziness, visual disturbances or changes in behavior or thinking occur, especially in the elderly {01}

Checking with physician before discontinuing medication after more than 1 to 2 weeks of use; gradual dosage reduction may be necessary to avoid withdrawal symptoms {01}

Side/adverse effects
Signs of potential side effects, especially abnormal vision, anxiety, depersonalization, epistaxis, and hallucinations {01}

General Dosing Information
Geriatric and debilitated patients should receive a decreased initial dosage since they may be more sensitive to the central nervous system effects of zaleplon {01}.

Patients with mild to moderate hepatic impairment or low weight individuals should receive a decreased initial dosage since elimination of zaleplon may be prolonged, resulting in increased central nervous system side effects. Individual dosage adjustments should be made {01}.

The minimal effective dose should be used for the shortest period with re-evaluation of the patient if taken for more than 2 to 3 weeks {01}.

Worsening of insomnia or the emergence of new thinking or behavior abnormalities may be the consequence of an unrecognized psychiatric or physical disorder{01}.

Because of zaleplon's rapid onset of action, the patients should be ready for sleep when the dose is taken {01}.

To minimize the occurrence of anterograde amnesia and hangover effects, zaleplon should be taken only when the patient's schedule will allow for 4 or more hours of sleep {01}.

For the most rapid effect, zaleplon should be taken on an empty stomach {01}.

Following prolonged administration, zaleplon should be withdrawn gradually to lessen the possibility of precipitating withdrawal symptoms {01}.

Potentially suicidal patients, particularly those who use alcohol excessively, should not have access to large quantities of zaleplon {01}.

Oral Dosage Forms


Usual Adult Dose
Oral, 10 milligrams at bedtime{01}.

Note: Debilitated patients, or patients with hepatic function impairment or low body weight—Oral, initially 5 milligrams at bedtime, the dosage being adjusted as needed and tolerated {01}.

Usual adult prescribing limits
20 milligrams a day {01}.

Usual pediatric dose
Children up to 18 years of age
Safety and efficacy have not been established {01}.

Usual geriatric dose
Oral, initially 5 milligrams at bedtime, the dosage being adjusted as needed and tolerated {01}.

Strength(s) usually available

5 mg (Rx) [Sonata (microcrystalline cellulose ) (pregelatinized starch) ( silicon dioxide) (sodium lauryl sulfate) (magnesium stearate) (lactose) (gelatin) (titanium dioxide)]

10 mg (Rx) [Sonata (microcrystalline cellulose ) (pregelatinized starch) ( silicon dioxide) (sodium lauryl sulfate) (magnesium stearate) (lactose) (gelatin) (titanium dioxide)]

Not commercially available in Canada.

Packaging and storage:
Store at controlled room temperature between 20 and 25 ° C (68 and 77 ° F). Store in a light-resistant container.{01}

Auxiliary labeling:
   • Avoid alcoholic beverages.
   • May cause daytime drowsiness.

Note: Controlled substance in the U.S.

Developed: 12/02/1999

  1. Product Information: Sonata®, zaleplon. Wyeth Laboratories, Philadelphia, PA, USA. 8/1999.