Zolpidem

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Authored by:Dlbenson 18:16, 23 April 2007 (PDT)



Zolpidem Quick Reference
Zolpidem
IUPAC Name
N,N,6-trimethyl-2-(4-methylphenyl)-

imidazo(1,2-a)pyridine-3-acetamide

Chemical Information
Empirical Formula C19H21N3O
Molecular Weight 764.88
General Drug Information
Classification Sedatives / Hypnotics/ Imidazopyridine Class
Schedule Legend- Schedule IV
How Supplied Oral Tablets: Immediate-Release: 5 mg, 10 mg; Controlled-release: 6.25 mg, 12.5 mg
Trade Names Ambien, Ambien C.R.
Pregnancy Category
  • B - Ambien
  • C - Ambien C.R.
Breast Feeding Use of Zolpidem in nursing mothers is NOT recommended; 0.004%-0.016% of the total dose is excreted into breast milk
Generic Availability Generic released for immediate-release tablets
Patent Expiration Date December 1, 2019 - Extended-release formulation
Administration Information
Route(s) Oral
Method(s) Oral: Take one dose immediately before bedtime on an empty stomach; Do not crush or split extended-release formulation
Pharmacokinetic Information
Absorption F = 70%
Cmax = 134 ng/mL (range 68.9 - 197 ng/mL)
tmax = 1.5 hours
Protein binding = 92.5 +/- 0.1%
Metabolism Hepatic metabolism to inactive metabolites; CYP450 Metabolism: 3A4(61%), 2C9(22%), 1A2(14%), 2D6 (<3%), 2C19 (<3%)
Excretion t1/2 = 2.8 hours
Renal

Contents

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Brand/Trade Names of Drug

Ambien®, Ambien C.R.®

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Generic Name of Drug

Zolpidem (zōl'pə-dĕm') Zolpidem Pronunciation Click Here

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Description

Zolpidem is a short-acting sedative agent in the imidazopyridine class that is approved for the short-term treatment of insomnia.[1] [2]Transient insomnia is known to affect between 25% and 35% of the population.[3] Full Text Here Medications in the imidazopyridine class act at gamma-aminobutyric acid (GABA) by binding to benzodiazepine type 1 receptor (BZ1; omega-1 receptor) sites.[1] [2] Although these agents work at BZ1 receptor sites, they are not considered to be part of the benzodiazepine class.[1] [2] Zolpidem is available as both regular-release and extended-release tablets.[1] [2] Regular-release zolpidem (Ambien) was approved by the FDA in 2003.[2] The patent for regular-release zolpidem (number 4382938) was held by Sanofi-Aventis and expired on April 21, 2007.[2] The FDA approved the extended-release version of zolpidem (Ambien C.R.) on September 2, 2005.[1] The extended-release version consists of two layers: one layer that releases zolpidem immediately to induce sleep and a second layer that slowly releases the drug in order to maintain sleep.[1]

Zolpidem has been shown to improve sleep without affecting daytime mental alertness.[4] A double-blind, randomized placebo comparison was conducted in 1995 showing that zolpidem is safe and effective for the treatment of transient insomnia.[5] Patients experienced decreased sleep latency and improved sleep maintenance in a multi-center, placebo controlled study conducted to determine the efficacy of zolpidem in treating insomnia.[6] In addition, patients receiving daily nightly doses of zolpidem did not develop tolerance to the agent.[6] An extended-release version of zolpidem was created that releases 60% of the total dose immediately, while 40% of the dose is released slowly throughout the night.[7] This formulation has been shown to have greater efficacy in providing decreased wake time after sleep onset.[7] The extended-release version of zolpidem has been found to have a similar tolerability profile to regular-release zolpidem.[8]


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Mechanism of action

The sedative properties of zolpidem are thought to be due to the modulation of α-1GABA(A) receptor subunits by the increased production of gamma-aminobutyric acid (GABA), an inhibitory neurotransmitter.[1] [2]

Gamma-aminobutyric acid-A (GABA(A)) macromolecular complexes are found on post-synaptic neurons and are typically composed of five subunits that surround a chloride channel (refer to diagram).[9] The α-1 subunit is one subunit found on the GABA(A) complex, and it is also known as the benzodiazepine receptor (BZ1).[9]

In vitro studies have determined that zolpidem selectively acts at BZ1.[2] Binding at the BZ1 subunit potentiates the production of GABA allowing for the preservation of deep sleep stages 3 and 4.[1] [2] The characteristic of selective binding to one type of subunit is unique when compared to the non-selective binding of the benzodiazepine class to multiple subunit sites.[2] The lack of anticonvulsant and anxiolytic activity by zolpidem is thought to be due to the selectivity of binding to one receptor subtype.[2]

Image:GABA2.JPG


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Time Required for Therapeutic Response

  • Initial: 30 minutes[2]
  • Maximum: 2 hours[2]

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Pharmacokinetics

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Absorption

Zolpidem (Ambien) is rapidly and extensively absorbed following oral administration, however the drug undergoes first-pass metabolism that permits only a 70% bioavailability (F).[1] Maximum plasma concentrations are reached approximately 1.6 hours (Tmax) post-dose for both 5mg and 10mg doses.[1] Zolpidem has an AUC of 955 ng*hr/mL after a 10mg dose.[1] Cmax has been measured to be 59 ng/mL (range: 20-113 ng/mL) after a 5mg dose and 121 ng/mL (range: 58-272 ng/mL) after a 10mg dose.[1] Food may increase the Tmax of a 10mg dose by approximately 60% to 2.2 hours.[1] The AUC and Cmax may be decreased by 15% and 20% if a 10mg dose is taken 20 minutes after a meal.[1]

Zolpidem extended-release (Ambien C.R.) has a Tmax of 1.5 hours, an AUC of 740 ng*hr/mL, and a Cmax of 134 ng/mL (range: 68.9-197 ng/mL) following a 12.5mg dose.[2] Food may increase the Tmax of a 12.5mg dose to 4 hours.[2] The AUC and Cmax may be decreased by 23% and 30% if a 12.5mg dose is taken 30 minutes after a meal.[1]

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Distribution

An 8mg intravenous zolpidem produces a mean volume of distribution (Vd) of 0.54 L/kg. Zolpidem is approximately 92% protein bound for all serum concentrations between 40 and 790 ng/mL.[10] [Distribution properties remain constant for both Ambien and Ambien C.R.]

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Metabolism

Zolpidem undergoes hepatic metabolism into three inactive metabolites via oxidation and hydroxylation.[1] [2] [11] Metabolism occurs via cytochrome P450 enzymes 3A4 (61%), 2C9 (22%), 1A2 (14%), and 2D6 (<3%) and 2C19 (<3%).[11] [12]

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Excretion

Zolpidem has a short terminal half-life (T1/2) that averages 2.6 hours (range: 1.4-4.5 hours) after a 5mg dose and 2.5 hours (range: 1.4-3.8 hours) after a 10mg dose. After a single dose of zolpidem, 48-67% is eliminated in the urine and [1] is eliminated in the feces. Zolpidem is excreted primarily as inactive metabolites.[1] Total clearance of zolpidem ranges from 0.24 to 0.27 mL/min/kg.[10]

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Special Population Pharmacokinetics

  • Renal insufficiency 
     Ambien
      *Study Group: CrCl = 6.5 +/-1.5 mL/min; 10mg dose
      *No differences in Cmax, Tmax, T1/2, AUC
      *No dosage adjustment necessary

     Ambien C.R.
      *Controlled-release formulation not studied in patients with renal insufficiency; data exists from immediate-release 
      formulation
  • Hepatic insufficiency 
     Ambien
      *Study Group: 20mg dose (immediate-release formulation)
      *Cmax: 499 ng/mL (50% increase) and AUC: 4203 ng*hr/mL (5-fold increase)
      *No change in Tmax
      *T1/2 = 9.9 hours (range: 1.6-2.4 hours)
      *Dose reduction necessary 

     Ambien C.R.
      *Controlled-release formulation not studied in patients with renal insufficiency; data exists from immediate-release
      formulation
  • Hemodialysis 
     Ambien
      *Hemodialysis increased protein binding significantly[13]
      *Zolpidem is not removed by hemodialysis[1]

     Ambien C.R.
      *Hemodialysis data does not exist independently for the controlled-release formulation
  • Geriatric 
    Ambien
     *Study Group: >70 years old; 20mg dose
     *Cmax increased 50% (384 ng/mL)
     *T1/2 increased 32% (2.9 hours)
     *AUC increased 64% (1592 ng*hr/mL)

    Ambien C.R.
     *Study Group: >=65 years old; 6.25mg dose
     *Cmax: 70.6 ng/mL (range: 35-161 ng/mL)
     *Tmax: 2.0 hours
     *T1/2: 2.9 hours (range: 1.59-5.50 hours)
     *AUC: 413 ng*hr/mL (range: 124-1190 ng*hr/mL)
  • Pediatric 
    Ambien
     *Zolpidem has not undergone safety and efficacy trials in patients under the age of 18

    Ambien C.R.
     *Zolpidem has not undergone safety and efficacy trials in patients under the age of 18
  • Gender 
    Ambien
     *There are no significant differences in pharmacokinetics between male and female patients[10]

    Ambien C.R.
     *There are no significant differences in pharmacokinetics between male and female patients[10]

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Indications

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FDA Approved Indications

Ambien

Ambien C.R.

  • Treatment of insomnia [8] -Specifically treats insomnia characterized by difficulties with sleep onset and/or sleep maintenance


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Non-FDA Approved Indications

Ambien


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Dosage

Ambien[2]

  • Short-term treatment of insomnia
    • Starting Dose: 10mg PO at bedtime; 5mg if using other CNS-depressant medications
    • Titration Schedule: Titration based on response; may increase by 5mg/day up to 10mg/day
    • Maintenance Dose: 5-10mg/day; Dosing based on response; treatment should not exceed 1 month
  • Maximum Dosage Limits
    • Adults: 10mg/day PO
    • Elderly: 10mg/day PO
    • Adolescents and children >=10 years: Safety has not been established in patients under age 18
    • Children < 10 years: Safety has not been established in patients under age 18
  • Dosage Adjustment
    • Renal insufficiency: No dosage adjustment necessary
    • Hepatic insufficiency: 5mg PO at bedtime, monitor closely for adverse events
    • Hemodialysis: No dosage adjustment necessary; however, monitor closely[13]
    • Geriatric: 5mg PO at bedtime
    • Pediatric: Safety has not been established in patients under age 18
    • Gender: No dosage adjustment necessary

Ambien C.R.[1]

  • Short-term treatment of insomnia
    • Starting Dose: 12.5mg PO at bedtime; 6.25mg if using other CNS-depressant medications
    • Titration Schedule: Titration based on response; may increase by 6.25mg/day up to 12.5mg/day
    • Maintenance Dose: Dosing based on response; treatment should not exceed 1 month
  • Maximum Dosage Limits
    • Adults: 12.5mg/day PO
    • Elderly: 12.5mg/day PO
    • Adolescents and children >=10 years: Safety has not been established in patients under age 18
    • Children < 10 years: Safety has not been established in patients under age 18
  • Dosage Adjustment
    • Renal insufficiency: No dosage adjustment necessary
    • Hepatic insufficiency: 6.25mg PO at bedtime, monitor closely for adverse events
    • Hemodialysis: No dosage adjustment necessary; however, monitor closely[13]
    • Geriatric: 6.25mg PO at bedtime
    • Pediatric: Safety has not been established in patients under age 18
    • Gender: No dosage adjustment necessary

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Administration

Ambien

  • Route: Oral
  • Method: Take one tablet by mouth on an empty stomach immediately before bedtime
  • Special considerations: Food may slow the absorption of zolpidem. Patients should be re-evaluated after 2-3 weeks of therapy (treatment should not exceed one month).

Ambien C.R.

  • Route: Oral
  • Method: Take one tablet by mouth on an empty stomach immediately before bedtime
  • Special considerations: Do not chew, crush, or swallow. Food may slow the absorption of zolpidem. Patients should be re-evaluated after 2-3 weeks of therapy (treatment should not exceed one month)


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Monitoring Parameters

Routine monitoring is not necessary; caution should be used in elderly patients and in patients with hepatic dysfunction – side effects may be more prominent in these patients.[1] [2]

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Contraindications/Precautions

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Contraindications

  • Hypersensitivity to drug, drug class, or components of the medication[1] [2]

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Precautions

  • Concomitant CNS Depressant Use[1] [2]
  • Alcohol/ Illegal Drug Use[1] [2]
  • Diagnosis of Depression, Psychiatric Disorder[1] [2]
  • Impaired Respiratory and/or Liver Function[1] [2]
  • Elderly or Debilitated Patients[1] [2]
  • Pregnancy / Breast-feeding[1] [2]


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Pregnancy indications

Pregnancy category:

  • Ambien – Pregnancy Category B[1] [2]
  • Zolpidem regular-release – Pregnancy Category B
  • Ambien C.R. – Pregnancy Category C[1] [2]

Teratogenicity: Fetal lethargy and ataxia have been demonstrated in pregnant rats receiving doses greater than or equal to 20mg/kg.[1] [2] Dose-related effects of incomplete ossification of rat skulls also occurred during these trials.[1] [2] There are no clearly defined studies demonstrating safety of zolpidem in pregnant women. Zolpidem should be used during pregnancy ONLY when the benefits outweigh the risks.

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Breast-feeding indications

Secretion into breast milk: Between 0.004-0.019% of the total zolpidem dose is secreted into breast milk.[1] [2] The effect of the drug on infants is unknown, and therefore the use of zolpidem during breast-feeding is not recommended. During clinical rat trials, breast milk secretion was inhibited.[2]

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Drug-Drug Interactions

Zolpidem Drug/Drug Interaction Chart
Severity Level Click here to see Severity Level Legend Increased Effect/Toxicity Decreased Effect
4 None Flumazenil[15] [2] Antagonizes the effects of zolpidem and can reverse the sedative/hypnotic effects seen with zolpidem
3 Anti-retroviral protease inhibitors PIs usually inhibit CYP3A4 and are expected to increase zolpidem concentrations, causing excessive sedation and possible respiratory depression. Chlorpromazine[2] Additive effects resulting in a loss of mental alertness and/or psychomotor function. Itraconazole[2]34% increase in zolpidem AUC may occur. May reduce zolpidem clearance. Voriconazole[16] Increased peak plasma concentrations of zolpidem by 1.23-fold and the AUC by 1.48-fold Ketoconazole[17] Reduces oral clearance of zolpidem by 41%, half-life is prolonged by about 26%, CNS activity or side effects of zolpidem may be increased. Fluoxetine[2] Zolpidem half-life decreases by 17% after multiple doses of fluoxetine. Sertraline[2] Zolpidem Cmax increases by ~43% and Tmax decreases by ~53% Delavirdine[2] Expected to increase zolpidem concentrations None
2 Barbiturates[2] Benzodiazepines[2] These drugs are CNS depressants and may have cumulative sedative effects when administered concurrently. Pramipexole[2] These drugs are CNS depressants and may have cumulative sedative effects when administered concurrently. Entacapone [2] CNS depressant drugs may have cumulative effects when administered concurrently. Anti-psychotics [2] CNS depressant drugs have cumulative effects when administered concurrently and they should be used cautiously with zolpidem when given in multiple doses. Anxiolytics[2] CNS depressant drugs have cumulative effects when administered concurrently and they should be used cautiously with zolpidem. Sedatives[2] CNS depressant drugs have cumulative effects when administered concurrently and they should be used cautiously with zolpidem. Hypnotics[2] CNS depressant drugs have cumulative effects when administered concurrently and they should be used cautiously with zolpidem. H1-blockers[2] CNS depressant drugs have cumulative effects when administered concurrently and they should be used cautiously with zolpidem. Tramadol[2] CNS depressant drugs have cumulative effects when administered concurrently and they should be used cautiously with zolpidem. Trazodone[2] CNS depressant drugs have cumulative effects when administered concurrently and they should be used cautiously with zolpidem. Opiate agonists/antagonists[2] CNS depressant drugs have cumulative effects when administered concurrently and they should be used cautiously with zolpidem. Buprenorphine[2] CNS depressant drugs have cumulative effects when administered concurrently and they should be used cautiously with zolpidem. Butorphanol[2] CNS depressant drugs have cumulative effects when administered concurrently and they should be used cautiously with zolpidem. Nalbuphine[2] CNS depressant drugs have cumulative effects when administered concurrently and they should be used cautiously with zolpidem. Pentazocine[2] CNS depressant drugs have cumulative effects when administered concurrently and they should be used cautiously with zolpidem. Haloperidol[2] May have additive CNS depressant effects with multiple dose use. Clozapine[2] CNS depressant drugs have cumulative effects when administered concurrently and they should be used cautiously with zolpidem. Molindone[2] CNS depressant drugs have cumulative effects when administered concurrently and they should be used cautiously with zolpidem. Olanazapine[2] CNS depressant drugs have cumulative effects when administered concurrently and they should be used cautiously with zolpidem. Pimozide[2] CNS depressant drugs have cumulative effects when administered concurrently and they should be used cautiously with zolpidem. Quetiapine[2] CNS depressant drugs have cumulative effects when administered concurrently and they should be used cautiously with zolpidem. Risperidone[2] CNS depressant drugs have cumulative effects when administered concurrently and they should be used cautiously with zolpidem. Ropinirole[2] CNS depressant drugs have cumulative effects when administered concurrently and they should be used cautiously with zolpidem. Tolcapone[2] CNS depressant drugs have cumulative effects when administered concurrently and they should be used cautiously with zolpidem. General anesthetics[2] CNS depressant drugs have cumulative effects when administered concurrently and they should be used cautiously with zolpidem. Pregabalin[2] CNS depressant drugs have cumulative effects when administered concurrently and they should be used cautiously with zolpidem. Azole antifungals[18] Inhibit the metabolism and clearance of zolpidem. SSRIs[17] [19] Cases of impaired concentration, aggravated depression, mania, disorientation, delusions, or hallucinations have rarely been reported. Desipramine[17] Rare cases of hallucinations have been reported. Bupropion[17] Rare cases of hallucinations have been reported. Duloxetine[17] [19] Cases of disorientation, delusions, or hallucinations have rarely been reported. Venlafaxine[17] [19] Cases of disorientation, delusions, or hallucinations have rarely been reported. Fluconazole[18] May reduce zolpidem clearance. Imatinib May potently inhibit cytochrome P450 3A4 and is expected to inhibit zolpidem CYP3A4 metabolism. Valproic acid[20] One case of sleep walking has been reported. Tricyclic Antidepressants [2] Potentially decrease alertness due to potentiated CNS effects.

Imipramine[2] Peak serum concentrations of imipramine may be reduced by 20%. However, decreased alertness may result. Rifamycins May increase the clearance of zolpidem by inducing hepatic metabolism. Rifabutin[2] May increase the clearance of zolpidem by inducing hepatic metabolism. Rifampin[2] Reduces zolpidem AUC by ~73%, Cmax by ~58%, and T1/2 by ~36%. Significant reduction in zolpidem efficacy may also result. Rifapentine[2] Increases the clearance of zolpidem by inducing hepatic metabolism. Nevirapine Induces CYP450 enzymes and may decrease the plasma concentrations.

1 Aprepitant Potentially increases serum concentrations of zolpidem by interfering with zolpidem metabolism by CYP3A4. Conivaptan Potentially increases serum concentrations of zolpidem by interfering with zolpidem metabolism by CYP3A4. Ranolazine May inhibit zolpidem CYP3A4. None


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Drug-Food-Herb Interactions

Zolpidem Drug/Food/Herb Interaction Chart
Severity Level Click here to see Severity Level Legend Increased Effect/Toxicity Decreased Effect
4 Ethanol[2] Additive effects may occur on psychomotor performance. St. John’s Wort[17] The combination has been shown to cause hallucinations and disorientation. None
3 None None
2 Ethanol[2] Additive effects may occur on psychomotor performance. St. John’s Wort[17] The combination has been shown to cause hallucinations and disorientation. Valerian[2] May increase CNS effects of zolpidem due to duplication in indication. Kava Kava[21] May increase CNS effects of zolpidem by disrupting GABAnergic action at the receptor site. Pramiprexole[2] CNS depressant drugs may have cumulative effects when administered concurrently and they should be used cautiously with zolpidem. Diphenhydramine[2] CNS depressant drugs may have cumulative effects when administered concurrently and they should be used cautiously with zolpidem. None
1 None None

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Adverse Reactions/Side Effects

Ambien: Clinical trials revealed that approximately 4% of patients receiving Ambien discontinued the medication due to an adverse event. The most common side effects included headache, dizziness, drowsiness, nausea, and vomiting.[2]

Ambien C.R.: During clinical trials, the discontinuation rate due to adverse events associated with zolpidem was very low (3.5%). The most common side effects associated with zolpidem during these trials were generally mild and included headache, dizziness, and drowsiness.[1]


Ambien Adverse Reactions Chart
Incidence Body System Adverse Reactions
> 10 % All Headache (19%)
2-10% CNS Drowsiness (8%), Dizziness (5%), Lethargy (3%), Drugged feeling (3%), Lightheadedness (2%), Depression (2%)
CV Palpitation (2%)
Dermatologic Rash (2%)
GI Nausea (6%), Dyspepsia (5%), Diarrhea (3%), Abdominal pain (2%), Constipation (2%)
GU Urinary Tract Infection (2%)
Neuromuscular & skeletal Myalgia (7%), Arthralgia (4%)
Respiratory Upper respiratory infection (5%), Sinusitis (4%), Pharyngitis (3%)
Misc Dry mouth (3%), Allergy (4%), Back pain (3%), Flu-like symptoms (2%)
< 2% All Chest pain (1%), Fatigue (1%), Abnormal dreams (1%), Amnesia (1%), Anxiety (1%), Nervousness (1%), Sleep disorder (1%), Anorexia (1%), Vomiting (1%), Infection (1%), Rhinitis (1%)


Ambien C.R. Adverse Reactions Chart
Incidence Body System Adverse Reactions
> 10 % All Headache (19%), Somnolence (15%), Dizziness (12%)
2-10% CNS Hallucinations (4%), Disorientation (3%), Memory Disorders (3%), Balance disorder (2%), Disturbances in attention (2%), Hypoesthesia (2%)
CV -----
Dermatologic -----
GI Nausea (7%), Constipation (2%)
GU -----
Neuromuscular & skeletal Back pain (4%), Myalgia (4%)
Respiratory -----
Misc Visual disturbance (3%), Eye redness (3%), Fatigue (3%), Influenza (3%), Blurred vision (2%), Vertigo (2%), Anxiety (2%), Depression (2%), Pychomotor retardation (2%)
< 2% All Gastroenteritis (1%), Labyrinthitis (1%), Appetite disorder (1%), Binge eating (1%), Depersonalization (1%), Disinhibition (1%), Euphoric mood (1%), Mood swings (1%), Stress symptoms (1%), Ataxia (1%), Paresthesia (1%), Altered visual depth perception (1%), Asthenopia (1%), Tinnitus (1%), Throat irritation (1%), Abdominal discomfort (1%), Abdominal tenderness (1%), Frequent bowel movements (1%), GERD (1%), Vomiting (1%), Rash (1%), Wrinkling skin (1%), Urticartia (1%), Neck pain (1%), Menorrhagia (1%), Asthenia (1%), Chest discomfort (1%), Increased blood pressure (1%), Increased body temperature (1%)


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Overdosage Measures

In the event of a zolpidem overdose, patients should receive immediate gastric lavage (if appropriate), supportive care, and continuous monitoring of vital signs. All sedating drugs should be withdrawn until the patient is stable. Flumazenil administration has also been shown to be a safe and effective method to reverse the central inhibitory effects and sedation caused by zolpidem during an overdose.[15] Additional medical interventions should be used if necessary.


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Product Information and Distribution

Ambien Immediate-Release Product Availability Information
Name Manufacturer Dosage Form Strength Quantity NDC Storage Markings
Ambien[2] Sanofi-Aventis Oral Tablets 5 mg 100 00024-5401-31 20-25°C (68-77°F) AMB 5 / 5401
500 00024-5401-50
10 mg 100 00024-5421-31 AMB 10 / 5421
500 00024-5421-50


Ambien Extended-Release Product Availability Information
Name Manufacturer Dosage Form Strength Quantity NDC Storage Markings
Ambien C.R.[1] Sanofi-Aventis Oral Tablets 6.25 mg 100 00024-5501-34 20-25°C (68-77°F) A~
500 00024-5501-50
100 00024-5501-31
3 x 10 Blister Pk 00024-5501-10
12.5 mg 100 00024-5521-34 A~
500 00024-5521-50
100 00024-5521-31
3 x 10 Blister Pk 00024-5521-10


Zolpidem Immediate-Release Product Availability Information
Name Manufacturer Dosage Form Strength Quantity NDC Storage Markings
Zolpidem Roxane Oral Tablets 5 mg 100 00054-0086-20 20-25°C (68-77°F) 54 371
100 00054-0086-25
500 00054-0086-29
10 mg 100 00054-0087-20 54 553
100 00054-0087-25
500 00054-0087-29


Zolpidem Immediate-Release Product Availability Information
Name Manufacturer Dosage Form Strength Quantity NDC Storage Markings
Zolpidem Teva Oral Tablets 5 mg 100 00093-0073-01 20-25°C (68-77°F) 93 / 73
10 mg 100 00093-0074-01 93 / 74


Zolpidem Immediate-Release Product Availability Information
Name Manufacturer Dosage Form Strength Quantity NDC Storage Markings
Zolpidem Mylan Oral Tablets 5 mg 100 00378-5305-01 20-25°C (68-77°F) M Z1
500 00378-5305-05
10 mg 100 00378-5310-01 M Z2
500 00378-5310-05


Zolpidem Immediate-Release Product Availability Information
Name Manufacturer Dosage Form Strength Quantity NDC Storage Markings
Zolpidem Watson Oral Tablets 5 mg 100 00591-3366-01 20-25°C (68-77°F) WPI / 3366
500 00591-3366-05
10 mg 100 00591-3367-01 WPI / 3367
500 00591-3367-05


Zolpidem Immediate-Release Product Availability Information
Name Manufacturer Dosage Form Strength Quantity NDC Storage Markings
Zolpidem Sandoz Oral Tablets 5 mg 100 00781-5317-01 20-25°C (68-77°F) ZLP / 5
1000 00781-5317-10
10 mg 100 00781-5318-01 ZLP / 10
1000 00781-5318-10


Zolpidem Immediate-Release Product Availability Information
Name Manufacturer Dosage Form Strength Quantity NDC Storage Markings
Zolpidem Mutual Pharmaceuticals Oral Tablets 5 mg 1000 53489-0600-10 20-25°C (68-77°F) MP 724
10 mg 1000 53489-0601-10 MP 725


Zolpidem Immediate-Release Product Availability Information
Name Manufacturer Dosage Form Strength Quantity NDC Storage Markings
Zolpidem Ranbaxy Oral Tablets 5 mg 100 63304-0159-01 20-25°C (68-77°F) RB 81
500 63304-0159-05
10 mg 100 63304-0160-01 RB 82
500 63304-0160-05


Zolpidem Immediate-Release Product Availability Information
Name Manufacturer Dosage Form Strength Quantity NDC Storage Markings
Zolpidem Apotex Oral Tablets 5 mg 100 60505-2604-01 20-25°C (68-77°F) APO / ZOL 5
1000 60505-2604-08
10 x 10 Unit Dose 60505-2604-00
10 mg 100 60505-2605-01 APO / 10
1000 60505-2605-08
10 x 10 Unit Dose 60505-2605-00
  • Manufacturers/Distributors

Ambien / Ambien C.R. Manufactured by: Sanofi-Aventis, Bridgewater, New Jersey

Zolpidem Manufactured by:

  • Roxane Laboratories, Columbus, Ohio
  • Teva Pharmaceuticals U.S.A., North Wales, Pennsylvania
  • Mylan Pharmaceuticals Inc., Canonsburg, Pennsylvania
  • Watson Pharmaceuticals Inc., Brewster, New York
  • Sandoz Pharmaceuticals, Princeton, New Jersey
  • Mutual Pharmaceuticals Inc., Philadelphia, Pennsylvania
  • Ranbaxy Pharmaceuticals Inc., Princeton, New Jersey
  • Apotex Corp., Weston, Florida


  • Inactive ingredients

Ambien: hydroxypropyl methylcellulose, lactose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, sodium starch glycolate, and titanium dioxide; the 5-mg tablet also contains FD&C Red No. 40, iron oxide colorant, and polysorbate 80

Ambien C.R.: Colloidal silicon dioxide, FD&C Blue #2, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol, potassium bitartrate, sodium starch glycolate, titanium dioxide, and yellow ferric oxide

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Pharmacogenomic information

No Zolpidem Pharmacogenomic Information Currently Exists

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Patient Information

  • General Information[2]

Ambien / Ambien C.R. is a medication intended to help you fall asleep and stay asleep.

Ambien / Ambien C.R. is only intended to be used for up to 1 month, if needed. However, this medication has been prescribed for durations longer than 1 month. Talk to you doctor or pharmacist for guidance on the appropriate length of time you should remain on this medication.

Until you know how Ambien / Ambien C.R. affects you, use caution when driving and/or operating heavy machinery.

  • Administration

Take Ambien / Ambien C.R. with a drink of water directly before going to bed. This medication has been known to cause memory loss if taken greater than a half-hour prior to bed.

Ensure that you have a full 8 hours to sleep prior to taking Ambien / Ambien C.R. This medication may cause extreme drowsiness and functional impairment if you take the medication less than 8 hours prior to waking.

Do not crush, chew, or split Ambien C.R.

Always follow the instructions specifically given to you with your prescription for Ambien / Ambien C.R. Do not attempt to change the dose of your medication without first asking your doctor or pharmacist.

  • Drug-drug/ Drug-food interactions

Always ask you doctor or pharmacist before taking any other medication with Ambien / Ambien C.R. Some medications tend to increase the sedative effects of the medication.

Unless directed by your physician, OTC products such as Nyquil, Kava Kava, St. John’s Wort, Valerian, or diphenhydramine-containing products (Benadryl, Tylenol P.M., Advil P.M., etc.) should be avoided while using Ambien.

Alcohol should NEVER be consumed while taking Ambien / Ambien C.R. (or any other sleep aid). The side effects of Ambien / Ambien C.R. may be increased by alcohol, leading to increased drowsiness and/or respiratory depression.

  • Side Effects

The most common side effects with Ambien / Ambien C.R. are sleepiness, dizziness, and headache.

  • Side effects that should be reported to a physician

Contact your physician immediately if you develop a rash, swelling, or difficulty breathing. These may be signs and symptoms of a serious allergic reaction.

Report any cases of sleep-eating, sleep-driving, thoughts of suicide, worsening depression, or strange behavior to your physician as soon as possible.

  • Pregnancy and breast feeding precautions

If you are pregnant, trying to get pregnant, or breast feeding, discuss this with your doctor prior to taking Ambien / Ambien C.R. (See Pregnancy Indications)


Special Precautions: Ambien / Ambien C.R. may cause any of the following side effects:

  • Memory problems / memory loss
  • Tolerance
  • Dependence (“addiction”)
  • Withdrawal effects (rare, but may last for 1-2 days)
  • Changes in behavior (including aggressive/strange behavior, confusion, agitation, hallucinations, worsening depression, or suicidal thoughts)

These side effects are often rare, but there is no clear method to predict the occurrence of these events in any particular patient population. Therefore, caution must be taken by all patients that receive Ambien / Ambien C.R. (or any other sleep aid).

Sleep-driving and Sleep-eating have rarely been reported. The FDA announced a requirement for the administration of MedGuides to patients with each sedative/hypnotic prescription and prescription refill. This form is not yet available.

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References

  1. ↑ 1.00 1.01 1.02 1.03 1.04 1.05 1.06 1.07 1.08 1.09 1.10 1.11 1.12 1.13 1.14 1.15 1.16 1.17 1.18 1.19 1.20 1.21 1.22 1.23 1.24 1.25 1.26 1.27 1.28 1.29 1.30 1.31 1.32 1.33 Sanofi-Aventis. Ambien CR (zolpidem extended-release tablets) Package Insert. Bridewater, N.J., 2007 March
  2. ↑ 2.00 2.01 2.02 2.03 2.04 2.05 2.06 2.07 2.08 2.09 2.10 2.11 2.12 2.13 2.14 2.15 2.16 2.17 2.18 2.19 2.20 2.21 2.22 2.23 2.24 2.25 2.26 2.27 2.28 2.29 2.30 2.31 2.32 2.33 2.34 2.35 2.36 2.37 2.38 2.39 2.40 2.41 2.42 2.43 2.44 2.45 2.46 2.47 2.48 2.49 2.50 2.51 2.52 2.53 2.54 2.55 2.56 2.57 2.58 2.59 2.60 2.61 2.62 2.63 2.64 2.65 2.66 2.67 2.68 2.69 2.70 2.71 2.72 2.73 2.74 2.75 2.76 Sanofi-Aventis. Ambien (zolpidem) Package Insert. New York, N.Y., 2004 March.
  3. ↑ Benca RM. Diagnosis and Treatment of Chronic Insomnia: A Review. Vol 56; 2005:332-343. Full Text Here
  4. ↑ Brunner P, Dijk, D., Münch, M., Borbély, A. Effect of zolpidem on sleep and sleep EEG spectra in healthy young men Psychopharmacology. May 1991;104(1):1-5.
  5. ↑ Roth T, Roehrs T, Vogel G, Roth T, Roehrs T, Vogel G. Zolpidem in the treatment of transient insomnia: a double-blind, randomized comparison with placebo. Sleep. May 1995;18(4):246-251.
  6. ↑ 6.0 6.1 Scharf MB, Roth T, Vogel GW, et al. A multicenter, placebo-controlled study evaluating zolpidem in the treatment of chronic insomnia. Journal of Clinical Psychiatry. May 1994;55(5):192-199.
  7. ↑ 7.0 7.1 Owen RT, Owen RT. Extended-release zolpidem: efficacy and tolerability profile. Drugs of Today. Nov 2006;42(11):721-727.
  8. ↑ 8.0 8.1 Moen MD, Plosker GL, Moen MD, Plosker GL. Zolpidem extended-release. CNS Drugs. 2006;20(5):419-426; discussion 427-418.
  9. ↑ 9.0 9.1 Siegel G.J., Agranoff B.W., Fisher S.K., Albers R.W., and Uhler M.D. 1999. Basic Neurochemistry: Molecular, Cellular and Medical Aspects, Sixth Edition. GABA Receptor Physiology and Pharmacology. American Society for Neurochemistry. Lippincott Williams and Wilkins.
  10. ↑ 10.0 10.1 10.2 10.3 Salva, P., Costa, J. Clinical pharmacokinetics and pharmacodynamics of zolpidem. Therapeutic implications. Clinical Pharmacokinetics. Sep 1995;29(3):142-153.
  11. ↑ 11.0 11.1 Klupsch FH, R. Humbert, L. Imbenotte, M. Henichart, J. Lhermitte, M. Major Metabolites of Zolpidem: Expeditious Synthesis and Mass Spectra. CHEMICAL & PHARMACEUTICAL BULLETIN. 2006;54(9):1318-1321.Full Text Here
  12. ↑ Von Moltke LL, Greenblatt DJ, Granda BW, et al. Zolpidem metabolism in vitro: responsible cytochromes, chemical inhibitors, and in vivo correlations. British Journal of Clinical Pharmacology. Jul 1999;48(1):89-97.
  13. ↑ 13.0 13.1 13.2 Pacifici GM, Viani A, Rizzo G, et al. Plasma protein binding of zolpidem in liver and renal insufficiency. International Journal of Clinical Pharmacology, Therapy, & Toxicology. Sep 1988;26(9):439-443.
  14. ↑ Hajak G, Cluydts R, Declerck A, et al. Continuous versus non-nightly use of zolpidem in chronic insomnia: results of a large-scale, double-blind, randomized, outpatient study.[erratum appears in Int Clin Psychopharmacol 2002 Jul;17(4):206]. International Clinical Psychopharmacology. Jan 2002;17(1):9-17.
  15. ↑ 15.0 15.1 [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7955804&dopt=Abstract Patat A, Naef MM, van Gessel E, et al. Flumazenil antagonizes the central effects of zolpidem, an imidazopyridine hypnotic. Clinical Pharmacology & Therapeutics. Oct 1994;56(4):430-436.]
  16. ↑ Saari TI, Laine K, Leino K, et al Effect of voriconazole on the pharmacokinetics and pharmacodynamics of zolpidem in healthy subjects. Br J Clin Pharmacol 2007;63:116—20.
  17. ↑ 17.0 17.1 17.2 17.3 17.4 17.5 17.6 17.7 Elko CJ, Burgess JL, Robertson WO. Zolpidem-associated hallucinations and serotonin reuptake inhibition: a possible interaction. J Toxicol Clin Toxicol 1998;36:195—203.
  18. ↑ 18.0 18.1 Greenblatt DJ, von Moltke LL, Harmatz JS, et al. Kinetic and dynamic interaction study of zolpidem with ketoconazole, itraconazole, and fluconazole. Clin Pharmacol Ther 1998;64:661—71.
  19. ↑ 19.0 19.1 19.2 Richelson E. Pharmacokinetic Drug Interactions of New Antidepressants: A Review of the Effects on the Metabolism of Other Drugs. Vol 72; 1997:835-847.
  20. ↑ Sattar SP, Ramaswamy S, Bhatia SC, et al. Somnambulism due to probable interaction of valproic acid and zolpidem. Ann Pharmacother. 2003;37:1429—33
  21. ↑ Sheree Cairney PMARCACJCBJC. Saccade and cognitive impairment associated with kava intoxication. Vol 18; 2003:525-533. Link Here
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PUBMED References

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Efficacy Trial Articles

1. Doghramji, P. Insomnia: zolpidem extended-release for the treatment of sleep induction and sleep maintenance symptoms. Medscape General Medicine. 9(1):11, 2007 January.

2. Dockhorn RJ. Dockhorn DW. Zolpidem in the treatment of short-term insomnia: a randomized, double-blind, placebo-controlled clinical trial. [Clinical Trial. Journal Article. Randomized Controlled Trial. Research Support, Non-U.S. Gov't) Clinical Neuropharmacology. 19(4):333-40, 1996 Aug.

3. Walsh JK. Roth T. Randazzo A. Erman M. Jamieson A. Scharf M. Schweitzer PK. Ware JC. Eight weeks of non-nightly use of zolpidem for primary insomnia. [Clinical Trial. Journal Article. Randomized Controlled Trial. Research Support, Non-U.S. Gov't) Sleep. 23(8):1087-96, 2000 Dec 15.

4. Roth T. Roehrs T. Vogel G. Zolpidem in the treatment of transient insomnia: a double-blind, randomized comparison with placebo. (Clinical Trial. Journal Article. Randomized Controlled Trial) Sleep. 18(4):246-51, 1995 May.

5. Roth T. Soubrane C. Titeux L. Walsh JK. Zoladult Study Group. Efficacy and safety of zolpidem-MR: a double-blind, placebo-controlled study in adults with primary insomnia. (Journal Article. Multicenter Study. Randomized Controlled Trial) Sleep Medicine. 7(5):397-406, 2006 Aug.

6. Asnis GM. Chakraburtty A. DuBoff EA. Krystal A. Londborg PD. Rosenberg R. Roth-Schechter B. Scharf MB. Walsh JK. Zolpidem for persistent insomnia in SSRI-treated depressed patients. (Clinical Trial. Journal Article. Multicenter Study. Randomized Controlled Trial. Research Support, Non-U.S. Gov't) Journal of Clinical Psychiatry. 60(10):668-76, 1999 Oct.

7. Herrmann WM. Kubicki ST. Boden S. Eich FX. Attali P. Coquelin JP. Pilot controlled double-blind study of the hypnotic effects of zolpidem in patients with chronic 'learned' insomnia: psychometric and polysomnographic evaluation. (Clinical Trial. Comparative Study. Journal Article. Randomized Controlled Trial) Journal of International Medical Research. 21(6):306-22, 1993 Nov-Dec.


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Therapeutic Class Comparison Trial Articles

1. Terzano MG. Rossi M. Palomba V. Smerieri A. Parrino L. New drugs for insomnia: comparative tolerability of zopiclone, zolpidem and zaleplon. (Comparative Study. Journal Article. Review) Drug Safety. 26(4):261-82, 2003.

2. Drover DR. Comparative pharmacokinetics and pharmacodynamics of short-acting hypnosedatives: zaleplon, zolpidem and zopiclone. (Comparative Study. Journal Article. Review) Clinical Pharmacokinetics. 43(4):227-38, 2004.

3. Sanger DJ. Morel E. Perrault G. Comparison of the pharmacological profiles of the hypnotic drugs, zaleplon and zolpidem. (Comparative Study. Journal Article) European Journal of Pharmacology. 313(1-2):35-42, 1996 Oct 10.

4. Greenblatt DJ. Harmatz JS. von Moltke LL. Ehrenberg BL. Harrel L. Corbett K. Counihan M. Graf JA. Darwish M. Mertzanis P. Martin PT. Cevallos WH. Shader RI. Comparative kinetics and dynamics of zaleplon, zolpidem, and placebo. (Clinical Trial. Comparative Study. Journal Article. Randomized Controlled Trial. Research Support, Non-U.S. Gov't. Research Support, U.S. Gov't, P.H.S.) Clinical Pharmacology & Therapeutics. 64(5):553-61, 1998 Nov.

5. Troy SM. Lucki I. Unruh MA. Cevallos WH. Leister CA. Martin PT. Furlan PM. Mangano R. Comparison of the effects of zaleplon, zolpidem, and triazolam on memory, learning, and psychomotor performance. (Clinical Trial. Comparative Study. Journal Article. Randomized Controlled Trial. Research Support, Non-U.S. Gov't) Journal of Clinical Psychopharmacology. 20(3):328-37, 2000 Jun.

6. Verster JC. Volkerts ER. Schreuder AH. Eijken EJ. van Heuckelum JH. Veldhuijzen DS. Verbaten MN. Paty I. Darwish M. Danjou P. Patat A. Residual effects of middle-of-the-night administration of zaleplon and zolpidem on driving ability, memory functions, and psychomotor performance. (Clinical Trial. Comparative Study. Controlled Clinical Trial. Journal Article. Research Support, Non-U.S. Gov't) Journal of Clinical Psychopharmacology. 22(6):576-83, 2002 Dec.


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Pharmacokinetics Articles

1. Salva P. Costa J. Clinical pharmacokinetics and pharmacodynamics of zolpidem. Therapeutic implications. (Comparative Study. Journal Article. Review) Clinical Pharmacokinetics. 29(3):142-53, 1995 Sep.

2. Langtry HD. Benfield P. Zolpidem. A review of its pharmacodynamic and pharmacokinetic properties and therapeutic potential. (Clinical Trial. Journal Article. Review) Drugs. 40(2):291-313, 1990 Aug.


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Drug Interaction Articles

1. Greenblatt DJ. von Moltke LL. Harmatz JS. Mertzanis P. Graf JA. Durol AL. Counihan M. Roth-Schechter B. Shader RI. Kinetic and dynamic interaction study of zolpidem with ketoconazole, itraconazole, and fluconazole. (Clinical Trial. Journal Article. Randomized Controlled Trial. Research Support, Non-U.S. Gov't. Research Support, U.S. Gov't, P.H.S.) Clinical Pharmacology & Therapeutics. 64(6):661-71, 1998 Dec.

2. Luurila H. Kivisto KT. Neuvonen PJ. Effect of itraconazole on the pharmacokinetics and pharmacodynamics of zolpidem. (Clinical Trial. Journal Article. Randomized Controlled Trial. Research Support, Non-U.S. Gov't) European Journal of Clinical Pharmacology. 54(2):163-6, 1998 Apr.

3. Villikka K. Kivisto KT. Luurila H. Neuvonen PJ. Rifampin reduces plasma concentrations and effects of zolpidem. (Clinical Trial. Comparative Study. Journal Article. Randomized Controlled Trial. Research Support, Non-U.S. Gov't) Clinical Pharmacology & Therapeutics. 62(6):629-34, 1997 Dec.

4. Greenblatt DJ. von Moltke LL. Harmatz JS. Durol AL. Daily JP. Graf JA. Mertzanis P. Hoffman JL. Shader RI. Differential impairment of triazolam and zolpidem clearance by ritonavir. (Clinical Trial. Journal Article. Multicenter Study. Randomized Controlled Trial. Research Support, Non-U.S. Gov't. Research Support, U.S. Gov't, P.H.S.) Journal of Acquired Immune Deficiency Syndromes: JAIDS. 24(2):129-36, 2000 Jun 1.

5. Sattar SP, Ramaswamy S, Bhatia SC, et al. Somnambulism due to probable interaction of valproic acid and zolpidem. Ann Pharmacother. 2003;37:1429—33

6. Elko CJ, Burgess JL, Robertson WO. Zolpidem-associated hallucinations and serotonin reuptake inhibition: a possible interaction. J Toxicol Clin Toxicol 1998;36:195—203.

7. Saari TI, Laine K, Leino K, et al Effect of voriconazole on the pharmacokinetics and pharmacodynamics of zolpidem in healthy subjects. Br J Clin Pharmacol 2007;63:116—20.

8. Greenblatt DJ, von Moltke LL, Harmatz JS, et al. Kinetic and dynamic interaction study of zolpidem with ketoconazole, itraconazole, and fluconazole. Clin Pharmacol Ther 1998;64:661—71.


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External Links

  • Manufacturers/Distributors

Sanofi-Aventis

  • Clinical treatment guidelines

NIH Insomnia Treatment Overview in Elderly Patients; NIH State-of-the-Science Conference Statement on Manifestations and Management of Chronic Insomnia in Adults

  • Patient information pages

Ambien patient information

  • Healthcare professional information pages

Ambien healthcare professional information; Ambien C.R. Package Insert

  • Other resources

American Sleep Association; National Sleep Foundation; National Institute of Health - Insomnia Overview

  • News Reports

New York Times Article on New FDA Warnings for Sleep Aids; San Diego Union-Tribune Article on Sleep-Driving Associated with Ambien Use


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