zolpidem (Rx)

>10%

Dizziness (5-12%)

Headache (7-19%)

Drowsiness (6-15%)

1-10%

Allergy (4%)

Hallucinations (4%)

Myalgia (4%)

Sinusitis (4%)

Memory disorder (3%)

Visual disturbance (3%)

Pharyngitis (3%)

Lightheadedness (2%)

Palpitation (2%)

Rash (2%)

Constipation (2%)

Depression (2%)

Drowsiness (2%)

Asthenia (1%)

Diarrhea (1%)

Dry mouth (1%)

Flu-like symptoms (1%)

Postmarketing reports

Respiratory depression

Complex sleep behaviors

Sublingual tablet: Oral ulcers, blisters, and mucosal inflammation

Liver and biliary system: Acute hepatocellular, cholestatic or mixed liver injury with or without jaundice (i.e., bilirubin greater than 2x ULN, alkaline phosphatase greater than or equal to 2x ULN, transaminase greater than or equal to 5x ULN).

Contraindications

Contraindicated in patients with known hypersensitivity to zolpidem; observed reactions include anaphylaxis and angioedema

Patients who have experienced complex sleep behaviors after receiving therapy

Cautions

The risk of next-day psychomotor impairment, including impaired driving, is increased if taken with less than a full night of sleep remaining (7 to 8 hours); if a higher than the recommended dose is taken; if co-administered with other CNS depressants or alcohol; or if co-administered with other drugs that increase blood levels of zolpidem; patients should be warned against driving and other activities requiring complete mental alertness if drug taken in these circumstances

Co-administration with other CNS depressants (e.g., benzodiazepines, opioids, tricyclic antidepressants, alcohol) increases the risk of CNS depression; dosage adjustments of zolpidem and of other concomitant CNS depressants may be necessary when zolpidem is administered with such agents because of the potentially additive effects; the use of zolpidem with other sedative-hypnotics (including other zolpidem products) at bedtime or the middle of the night is not recommended

Vehicle drivers and machine operators should be warned that, there may be a possible risk of adverse reactions including drowsiness, prolonged reaction time, dizziness, sleepiness, blurred/double vision, reduced alertness and impaired driving the morning after therapy; to minimize risk, a full night of sleep (7-8 hours) recommended; this next-morning impairment is highest for the extended-release dosage form and is more prevalent in women because they eliminate more slowly than men

Can cause drowsiness and a decreased level of consciousness, which may lead to falls and consequently to severe injuries; severe injuries such as hip fractures and intracranial hemorrhage have been reported

Use caution in patients with history of drug dependence (increases risk of abuse)

Food increases time to attain peak plasma level and decreases peak plasma concentration

Need to evaluate for comorbid diagnoses; reevaluate if insomnia persists after 7-10 days of use

Severe anaphylactic/anaphylactoid reactions including angioedema and anaphylaxis reported; do not rechallenge if such reactions occur

Abnormal thinking, behavioral changes, complex behaviors: May include “sleep driving” and hallucinations; coadministration of alcohol and other CNS depressants appears to increase the risk of such behaviors

Do not use with alcohol

Use can impair respiratory drive, alertness, and motor coordination; if used in combination with other CNS depressants, dose reductions of 50% may be needed due to additive effects

Consider risk of respiratory depression before prescribing in patients with compromised regulatory functions

Worsening of depression or suicidal thinking may occur; prescribe the least amount feasible to avoid intentional overdose

Withdrawal symptoms may occur with rapid dose reduction or discontinuation

Use lower dose in elderly/debilitated patients due to impaired motor, cognitive performance and increased sensitivity

Use with caution and monitor closely in patients with hepatic impairment, mild to moderate COPD, impaired drug metabolism or hemodynamic responses, or mild to moderate sleep apnea

Use with caution in patients with myasthenia gravis

GABA agonists such as zolpidem tartrate have been associated with precipitation of hepatic encephalopathy in patients with hepatic insufficiency; patients with hepatic insufficiency do not clear zolpidem tartrate as rapidly as patients with normal hepatic function; avoid zolpidem use in patients with severe hepatic impairment as it may contribute to encephalopathy

Pregnancy

Neonates born to mothers using zolpidem late in the third trimester of pregnancy reported to experience symptoms of respiratory depression and sedation; published data on use of zolpidem during pregnancy have not reported clear association with zolpidem and major birth defects

There are limited postmarketing reports of severe to moderate cases of respiratory depression that occurred after birth in neonates whose mothers had taken zolpidem during pregnancy; these cases required artificial ventilation or intratracheal intubation; the majority of neonates recovered within hours to a few weeks after birth once treated Zolpidem has been shown to cross the placenta

Animal data

• Oral administration of zolpidem to pregnant rats and rabbits did not indicate a risk for adverse effects on fetal development at clinically relevant doses

Lactation

Limited data report presence of zolpidem in human milk; there are reports of excess sedation in infants exposed to zolpidem through breastmilk; there is no information on effects on milk production; consider developmental and health benefits of breastfeeding along with mother’s clinical need for therapy and any potential adverse effects on breastfed infant from therapy or from underlying maternal condition

Monitor, for excess sedation, infants exposed to drug through breastmilk, hypotonia, and respiratory depression; a lactating woman may consider interrupting breastfeeding and pumping and discarding breast milk during treatment and for 23 hours (approximately 5 elimination half-lives) after drug administration in order to minimize drug exposure to a breast fed infant

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.

Mechanism of Action

Imidazopyridine; modulates omega-1 type GABA receptor via selective antagonism, resulting in increased chloride conductance, neuronal hyperpolarization, inhibition of action potential, and a decrease in neuronal excitability that in turn produce sedative and hypnotic effects

Absorption

Bioavailability: 70%

Peak plasma time: 1.6 hr (immediate-release); 1.5 hr (extended-release); 0.9 hr (spray); 1.4 hr (sublingual Edluar); 0.6-1.3 hr (sublingual Intermezzo)

Peak plasma time delayed by food intake

Peak plasma concentration: (5 mg dose) 59 ng/mL; (10 mg) 121 ng/mL; (12.5 mg CR) 134 ng/mL

Distribution

Protein bound: 92.5%

Metabolism

Metabolized by CYP3A4 (60%), CYP2C9 (22%), CYP1A2 (14%), CYP2D6 (3%), CYP2C (3%)

Metabolized to inactive metabolites

Elimination

Half-life

• Immediate release: 2.5 hr (normal liver function); 9.9 hr (cirrhosis)
• Spray: 1.7-8.4 hr
• Sublingual: 1.4-6.7 hr

Excretion

• Urine (48-67%)
• Feces (29-42%)

Oral Administration

Extended-release tablet: Swallow whole; do not chew, crush, or split