Zolpidem
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Authored by:Dlbenson 18:16, 23 April 2007 (PDT) |
 |
imidazo(1,2-a)pyridine-3-acetamide
Brand/Trade Names of Drug
Ambien®, Ambien C.R.®
Generic Name of Drug
Zolpidem (zōl'pə-dĕm')
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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]
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]
Time Required for Therapeutic Response
Pharmacokinetics
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]
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.]
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]
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]
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]
Indications
FDA Approved Indications
Ambien
- Short-term treatment of transient insomnia (up to 1 month)
Ambien C.R.
- Treatment of insomnia [8] -Specifically treats insomnia characterized by difficulties with sleep onset and/or sleep maintenance
Non-FDA Approved Indications
Ambien
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
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)
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]
Contraindications/Precautions
Contraindications
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]
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.
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]
Drug-Drug Interactions
Drug-Food-Herb Interactions
Severity Level | Increased Effect/Toxicity | Decreased Effect | |
|---|---|---|---|
| 4 | Ethanol[2] St. John’s Wort[17] | None | |
| 3 | None | None | |
| 2 | Ethanol[2] St. John’s Wort[17] Valerian[2] Kava Kava[21] Pramiprexole[2] Diphenhydramine[2] | None | |
| 1 | None | None |
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]
| 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%) |
| 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%) |
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.
Product Information and Distribution
| 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 |
| 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 |
| 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 |
| 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 |
| 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 |
| 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 |
| 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 |
| 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 |
| 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 |
| 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
Pharmacogenomic information
No Zolpidem Pharmacogenomic Information Currently Exists
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.