Zolpidem (Systemic)

VA CLASSIFICATION
Primary: CN309

Note: Controlled substance classification—

Note: Controlled substance classification


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

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

^†Not commercially available in Canada.

Category:


Sedative-hypnotic—

Indications

Accepted

Insomnia (treatment)—Zolpidem is indicated for short-term treatment of insomnia ^{{01} {03}}. A decrease in sleep latency and increase in the duration of sleep for up to 5 weeks have been demonstrated in controlled clinical studies with zolpidem. ^{40}Failure of insomnia to remit after 7 to 10 days of treatment may indicate the presence of a primary psychiatric or medical illness ^{01}. Worsening of insomnia or the emergence of new abnormalities of thinking or behavior may be the consequence of an unrecognized psychiatric or physical disorder ^{{01} {03}}.


Pharmacology/Pharmacokinetics

Physicochemical characteristics:

Chemical group—
    Imidazopyridine ^{{01} {02} {03} {08} {09} {10} {11} {12}} sedative hypnotic ^{{01} {02} {03} {04}} structurally unrelated to benzodiazepines ^{{01} {02} {03}}, barbiturates ^{01}, or other available sedative-hypnotics ^{01}.
Molecular weight—
    764.9 ^{{01} {04}}

pKa—
    6.16 ^{10}

Mechanism of action/Effect:

Zolpidem is a potent ^{10} agonist ^{10} with high intrinsic activity ^{10} at the omega (ω) 1 subtype ^{{01} {02} {03} {28}} (also called the benzodiazepine 1 [BZ ₁] subtype) ^{{01} {02} {03}} of the gamma-aminobutyric acid type A (GABA _A) ^{01} receptor-chloride ionophore complex ^{{01} {02} {03} {28}}. The omega 1 GABA _A receptor is thought to be located primarily in the cerebellum ^{{01} {02} {03}}, sensory-motor cortex ^{{01} {09} {29} {30}}, substantia nigra ^{{01} {02}}, inferior colliculus ^{{01} {02}}, olfactory bulb ^{01}, ventral thalamic complex ^{01}, pons ^{01}, and globus pallidus ^{01} in the central nervous system (CNS). The receptor complex resides on neuronal membranes ^{38} and functions in the gating of the chloride channel ^{37}. Activation of the GABA _A receptor results in the opening of the chloride channel ^{{02} {37}}, allowing the flow of chloride ions through the neuronal membrane and into the neuron ^{{26} {37}}. This results in hyperpolarization ^{{26} {38}}, which inhibits firing of that neuron ^{38}.

In contrast to the benzodiazepines, which bind non-selectively to the omega 1, omega 2, and omega 3 GABA _A receptors ^{{01} {02}}, zolpidem possesses relative selectivity for the omega 1 GABA _A receptor. This preference for the omega 1 GABA _A receptor ^{{01} {02} {03} {28}} may account for zolpidem's relative lack of anticonvulsant ^{{01} {02} {03} {08} {29} {30} {31}}, myorelaxant ^{{01} {02} {03} {08} {29} {30} {31}}, and anxiolytic ^{{02} {03} {08}} effects at therapeutic doses, and for the general preservation of sleep architecture ^{{01} {03} {08} {16} {24} {31} {33} {36}} seen with zolpidem use.

Absorption:

Rapid ^{{01} {02} {03} {08} {10} {16}} and complete ^{{08} {10}}, although first-pass metabolism ^{{02} {03} {10}} results in 70% bioavailability ^{{01} {02} {08} {10}}. Food may decrease the rate and extent of absorption ^{{01} {02} {03} {10}}.

Distribution:

The volume of distribution (Vol _D) of zolpidem in healthy volunteers was 0.54 L per kg (L/kg) following an 8 mg intravenous dose ^{{02} {03}}. Zolpidem is distributed into breast milk; amounts ranging from 0.004 to 0.019% ^{{01} {02} {20}} of a 20-mg oral dose were present in milk samples taken 3 hours following administration ^{{02} {20}}.

Protein binding:

Very high (92%) ^{{01} {03} {10} {18}}.

Biotransformation:

Hepatic ^{08}, resulting in 3 major ^{{02} {03} {10}} and several minor ^{10} metabolites, all of which are inactive ^{{01} {02} {10}}.

Half-life:


Elimination:

2.6 hours (range, 1.4 to 4.5 hours) ^{{01} {02} {03} {08} {10} {20} {30}} . The elimination half-life of zolpidem is prolonged in the elderly ^{{01} {02} {03} {08} {10}} and in patients with impaired hepatic ^{{01} {02} {03} {08} {10}} or renal ^{{02} {03} {10}} function.


Onset of action:

Rapid ^{{01} {16} {39}}.

Time to peak concentration:

30 minutes to 2 hours ^{{01} {02} {03} {08} {10}} ; may be longer if zolpidem is taken with food ^{{01} {03}}

Peak serum concentration:

Mean peak plasma concentration (C _{m a x}) following oral administration of 5 mg of zolpidem to healthy volunteers was 59 nanograms per mL (nanograms/mL) (0.077 micromoles per L [micromoles/L]), with a range of 29 to 113 nanograms/mL (0.038 to 0.148 micromoles/L); C _{m a x} following administration of 10 mg of zolpidem was 121 nanograms/mL (0.158 micromoles/L) with a range of 58 to 272 nanograms/mL (0.076 to 0.356 micromoles/L) ^{01}.

Elimination:


Renal ^{{01} {08} {10}}—
        48 to 67% of a single dose is eliminated in the urine ^{10}. Unchanged zolpidem is present in trace amounts in urine and feces ^{{02} {03} {10}}.



Fecal ^{10}—
        29 to 42% of a single dose is eliminated in the feces ^{10}. Unchanged zolpidem is present in trace amounts in urine and feces ^{{02} {03} {10}}.



In dialysis—
        Not hemodialyzable ^{{01} {02}}.



Precautions to Consider

Carcinogenicity/Tumorigenicity

No evidence of carcinogenic potential was observed in mice administered zolpidem in doses of 4, 18, and 80 mg per kg of body weight (mg/kg) per day (26 to 520 times the recommended human dose of 10 mg per day on a mg/kg basis) for 2 years ^{01}. In rats administered zolpidem in doses of 4, 18, and 80 mg/kg per day (43 to 876 times the recommended human dose on a mg/kg basis) for 2 years, the incidences of lipoma and liposarcoma were comparable to those seen in historical controls ^{01}.

Mutagenicity

Zolpidem showed no evidence of mutagenicity based on unscheduled DNA synthesis in rat hepatocytes in vitro , the Ames test, or the micronucleus test in mice. Zolpidem showed no evidence of genotoxicity in mouse lymphoma cells in vitro ; and caused no chromosomal aberrations in cultured human lymphocytes. ^{{01} {03}}

Pregnancy/Reproduction
Fertility—
In rats given daily oral doses of 4 to 100 mg/kg of zolpidem base (5 to 130 times the recommended human dose in mg per square meter of body surface area [mg/m ²]), neither male nor female fertility was affected ^{01}. However, female rats receiving 100 mg/kg of zolpidem base per day displayed irregular estrus cycles and prolonged precoital intervals ^{01}. The significance to humans is not known ^{01}.

Pregnancy—
Zolpidem has not been studied in pregnant women ^{01}.

No frank teratogenicity was seen in rat and rabbit studies ^{{01} {03}}. Rats administered 20 and 100 mg/kg of zolpidem base (25 to 125 times the recommended human dose in mg/m ²) showed maternal lethargy and ataxia as well as a dose-related trend toward incomplete ossification of fetal skull bones, which was believed to be secondary to delayed maturation ^{01}. Rabbits administered 16 mg/kg of zolpidem base (28 times the recommended human dose in mg/m ²) showed an increase in postimplantation fetal loss and underossification of fetal sternebrae ^{01}. These effects were believed to be secondary to decreased maternal weight gain ^{01}.

FDA Pregnancy Category B ^{01}.

Postpartum —
Studies of children whose mothers received zolpidem during pregnancy have not been conducted ^{01}. However, flaccidity and withdrawal symptoms have been reported in neonates born to mothers receiving other sedative-hypnotics during pregnancy ^{01}.

Breast-feeding

One study in 5 nursing mothers showed <0.02% of a single oral dose of zolpidem was distributed into breast milk ^{{01} {20}}. The effect of zolpidem on the infant is not known ^{01}.

In rats, zolpidem doses greater than 4 mg/kg (6 times the recommended human dose in mg/m ²) inhibited milk secretion ^{01}.

Pediatrics

Appropriate studies on the relationship of age to the effects of zolpidem have not been performed in children up to 18 years of age ^{01}. Safety and efficacy have not been established ^{01}.


Geriatrics


Studies have shown zolpidem to have an increased half-life ^{{01} {02} {03} {10}}, peak plasma concentration ^{{01} {02} {03}}, and area under the plasma concentration time curve ^{{01} {02} {03}} in geriatric patients. Elderly patients may be more likely to experience confusion or falls while taking zolpidem ^{{02} {03}}. A reduced starting dosage ^{{01} {02} {03}} and careful monitoring ^{01} are recommended. In addition, geriatric patients are more likely to have age-related renal function impairment, which may require dosage reductions ^{{02} {03} {10}}.

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}{03} or
» CNS depression–producing medications^{01} , other (See Appendix II )    (concurrent use may increase the CNS depressant effects of either these medications or zolpidem ^{{01} {03}}; caution is recommended, and dosage of one or both agents should be reduced ^{01})


Chlorpromazine    (concurrent use may prolong elimination half-life of chlorpromazine ^{{02} {03} {35}})


Imipramine    (concurrent use may increase drowsiness ^{01} and incidence of anterograde amnesia ^{{02} {03}}, and decrease peak concentrations of imipramine ^{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).


Risk-benefit should be considered when the following medical problems exist
» Alcohol intoxication, acute, with depressed vital signs    (additive CNS depression may occur ^{{01} {03}})


Alcohol or drug abuse or dependence, history of^{01}{03}    (predisposition to habituation and dependence may exist)


Hepatic function impairment    (zolpidem elimination may be prolonged ^{{01} {02} {03}} due to biphasic elimination with prolonged terminal half-life ^{10})


Mental depression^{01}    (condition may be exacerbated)


Pulmonary disease, severe chronic obstructive^{{01}{22}{23}{32}}    (ventilatory failure may be exacerbated)


Renal function impairment    (zolpidem elimination may be prolonged ^{{02} {03} {10}})


» Sensitivity to zolpidem
» Sleep apnea, established or suspected    (condition may be exacerbated ^{{02} {03} {18} {25}})




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
    
Ataxia^{{01}{02}{03}{14}{16}{27}} (clumsiness or unsteadiness)
    
confusion^{{01}{02}{03}{11}{16}{34}} —higher incidence in the elderly^{02}{03}
    
mental depression^{{01}{02}{03}{16}}

Incidence rare
    
Allergic reaction or rash^{01}
    
anaphylaxis^{01} (fast heartbeat; swelling of face; wheezing or difficulty in breathing)
    
falling^{01}{02}{03} —higher incidence in the elderly^{02}{03}
    
hypotension^{01}{02}{29} (dizziness, lightheadedness, or fainting)
    
paradoxical reactions, including agitation^{01}{14} (unusual excitement or nervousness), or irritability^{16}
hallucinations^{{01}{06}{07}{12}{13}} (seeing, hearing, or feeling things that are not there), or insomnia^{01} (trouble in sleeping)



Those indicating need for medical attention only if they continue or are bothersome
Incidence less frequent
    
Abnormal dreams, including nightmares^{{01}{02}{03}{11}{13}{14}}
    
anterograde amnesia^{{01}{02}{11}{21}{34}} (memory problems)
    
daytime drowsiness^{{01}{02}{03}{11}{13}{14}{16}{27}}
    
dizziness^{{01}{02}{03}{13}{29}}
lightheadedness^{01}{04}{16}
or vertigo^{{01}{11}{29}{34}}
    
drugged feelings^{{01}{11}{13}{16}}
    
dryness of mouth^{{01}{02}{16}{19}}
    
gastrointestinal effects, including abdominal or gastric pain^{02}{29}
diarrhea^{01}
nausea^{{01}{03}{11}{12}{13}{16}{19}{21}{29}}
or vomiting^{{01}{02}{12}{16}{21}}
    
headache^{{01}{02}{03}{12}{16}{19}{29}}
    
malaise^{{01}{02}{11}{34}} (general feeling of discomfort or illness)
    
vision abnormalities, including diplopia^{{01}{02}{11}{14}{21}} (double vision)



Those indicating possible withdrawal and/or the need for medical attention if they occur after medication is discontinued, usually within 48 hours
    
Abdominal or stomach cramps or discomfort^{01}
    
agitation^{15} , nervousness, or feelings of panic^{01}
    
flushing^{01}
    
lightheadedness^{01}
    
muscle cramps^{01}
    
nausea^{01}
    
psychotic exacerbation^{15} (worsening of mental or emotional problems)
    
seizures^{01}
    
sweating^{01}
    
tremors^{01}
    
uncontrolled crying^{01}
    
unusual tiredness or weakness^{01}
    
or vomiting^{01}




Overdose
For specific information on the agents used in the management of zolpidem overdose, see:
   • Charcoal, Activated (Oral-Local) monograph; and/or
   • 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^{02}{17} (clumsiness or unsteadiness)
    
cardiovascular compromise^{01} (slow heartbeat)
    
diplopia (double vision), or disturbed vision^{02}{17}
    
dizziness, severe^{02}{17}
    
drowsiness, severe^{01}{02}
    
nausea, severe^{02}{17}{39}
    
respiratory problems^{01}{05} (troubled breathing)
    
unconsciousness^{01}{05}
    
vomiting, severe^{02}{17}{39}


Treatment of overdose
Treatment is essentially symptomatic and supportive, possibly including:


To decrease absorption:
Inducing emesis ^{02} or performing gastric lavage ^{{01} {02}} as appropriate.



To enhance elimination:
Administering activated charcoal ^{{02} {05}} to increase clearance and decrease absorption of zolpidem.

Zolpidem is not dialyzable ^{{01} {02}}.



Specific treatment:
Withholding sedating drugs even if excitation occurs ^{01}.

Flumazenil may be useful in reversing zolpidem's sedative and respiratory depressant effects ^{{03} {05}}.



Monitoring:
Monitoring respiratory, cardiac, and CNS status ^{{01} {05}}.



Supportive care:
Providing general supportive therapy as indicated ^{{01} {05}}. Patients in whom intentional overdose is known or suspected should be referred for psychiatric consultation.



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

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

Before using this medication
»   Conditions affecting use, especially:
Sensitivity to zolpidem





Breast-feeding—Small amounts of zolpidem are distributed into breast milk; effect on infant is not known





Use in the elderly—Elderly patients are usually more sensitive to CNS effects of zolpidem
Other medications, especially other CNS depression–producing medications
Other medical problems, especially acute alcohol intoxication or sleep apnea

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

» Not increasing dose if medication becomes less effective over time; checking with physician

Being prepared to go to sleep immediately after taking medicine ^{{03} {39}}

» Proper dosing
Missed dose—Skipping missed dose; not doubling doses

» Proper storage

Precautions while using this medication
» Avoiding use of alcohol or other CNS depressants during therapy

» Caution if clumsiness or unsteadiness, drowsiness, dizziness, or visual disturbances occur, especially in the elderly

» Changes in behavior or thinking such as more outgoing or aggressive behavior than normal; loss of personal identity; confusion; strange behavior; agitation; hallucinations; worsening of depression; or suicidal thoughts. ^{01}

Amnesia; avoid by only taking zolpidem when able to get a full night's sleep (7 to 8 hours) before the need to be active again.^{40}

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


Side/adverse effects
Signs of potential side effects, especially ataxia, confusion, mental depression, allergic reaction or rash, anaphylaxis, falling, hypotension, or paradoxical reactions


General Dosing Information
Geriatric ^{{01} {02} {03} {10}} or debilitated ^{01} patients, or patients with hepatic ^{{01} {08} {10}} or renal ^{{02} {03} {10}} function impairment should receive decreased initial dosage since elimination of zolpidem may be prolonged, resulting in increased CNS ^{16} and gastrointestinal ^{{02} {03} {17} {39}} side effects.

Optimal dosage of zolpidem varies with patient response ^{01}. Individual dosage adjustments should be made ^{{01} {03}}. The minimal effective dose should be used ^{{01} {02}} for the shortest period ^{02}, with the need for continuing therapy with zolpidem reviewed regularly ^{01}.

Because of zolpidem's rapid onset of action ^{{01} {16} {39}}, the patient should be ready for sleep when the dose is taken ^{{01} {39}}.

To minimize the occurrence of anterograde amnesia ^{{01} {03}} and hang-over effects ^{03}, zolpidem should be taken only when the patient's schedule will allow for a full night's sleep ^{{01} {03}} (7 to 8 hours) ^{01}.

For the most rapid effect, zolpidem should be taken on an empty stomach ^{{01} {03} {18}}.

Following prolonged administration, zolpidem 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 zolpidem ^{01}.


Oral Dosage Forms

ZOLPIDEM TARTRATE TABLETS

Usual adult dose
Hypnotic
Oral, 10 mg at bedtime ^{{01} {04} {09}}.


Note: Debilitated patients ^{01} or patients with hepatic ^{{01} {02} {03}} or renal ^{18} function impairment—Oral, initially 5 mg at bedtime, the dosage being adjusted as needed and tolerated.


Usual adult prescribing limits
Up to 10 mg a day. ^{40}

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


Usual geriatric dose
Hypnotic
Oral, initially 5 mg at bedtime, the dosage being adjusted as needed and tolerated ^{{01} {14}}.


Usual geriatric prescribing limits
Up to 10 mg a day ^{{02} {18}}.

Strength(s) usually available
U.S.—


5 mg (Rx) [Ambien (hydroxypropyl methylcellulose) (lactose) (magnesium stearate) (microcrystalline cellulose) (polyethylene glycol) (sodium starch glycolate) (titanium dioxide) (FD&C Red No. 40) (iron oxide colorant) ( and polysorbate 80)^{01}]


10 mg (Rx) [Ambien (hydroxypropyl methylcellulose) (lactose) (magnesium stearate) (microcrystalline cellulose) (polyethylene glycol) (sodium starch glycolate) (titanium dioxide)^{01}]

Canada—
Not commercially available.

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Store in a well-closed container.

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

Note: Controlled substance in the U.S. ^{01}

Revised: 01/20/2000

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40. Product Information: Ambien®, zolpidem tartrate. G.D. Searle & Co., Chicago, IL, USA, 1/31/97.