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Special Alerts
Sublinox™: Complex Sleep Behaviors Associated with Use
December 2011
Meda Valeant Pharma Canada Inc, in collaboration with Health Canada, has notified Canadian healthcare professionals regarding reports on the international market of complex sleep behaviors in patients treated with zolpidem (Canadian brand name: Sublinox™). Cases of complex sleep behaviors are rare, but possibly dangerous, and involve patients rising from bed not fully awake and performing activities such as driving a car or leaving the house. Patients have no recall of these activities the next morning. These behaviors have been associated with zolpidem use in other countries where zolpidem has been marketed; Sublinox™ sublingual zolpidem formulation has recently been introduced in Canada. Patients with a prior personal or family history of sleepwalking, taking other CNS-active drugs or alcohol, or taking higher than normal zolpidem doses may be at greater risk for complex sleep behaviors, although cases have occurred in patients using zolpidem as recommended. Patients should be instructed to take zolpidem only at bedtime when a full night's sleep is anticipated. Zolpidem should only be used for short-term insomnia treatment. Patients experiencing complex sleep behaviors should discontinue zolpidem therapy immediately. If sleep disorders persist after 7-10 days, additional medical and/or psychiatric evaluations may be indicated.
Further information may be found on Health Canada's website at http://hc-sc.gc.ca/dhp-mps/medeff/advisories-avis/prof/_2011/sublinox_hpc-cps-eng.php
Pronunciation
(zole PI dem)
Generic Available (U.S.)
Yes: Excludes oral spray, sublingual tablet
Index Terms
Controlled Substance
C-IV
Medication Guide
An FDA-approved patient medication guide, which is available with the product information and as follows, must be dispensed with this medication:
Ambien®: http://www.fda.gov/downloads/Drugs/DrugSafety/ucm085906.pdf
Ambien CR®: http://www.fda.gov/downloads/Drugs/DrugSafety/ucm085908.pdf
Edluar™: http://www.fda.gov/downloads/Drugs/DrugSafety/UCM135937.pdf
Zolpidem: http://www.fda.gov/downloads/Drugs/DrugSafety/ucm089833.pdf
Zolpimist®: http://www.fda.gov/downloads/Drugs/DrugSafety/UCM143465.pdf
REMS Components
Edluar™: Released from REMS requirement 8/10/2011
Zolpimist®: Released from REMS requirement 9/28/2011
Brand Names: U.S.
Brand Names: Canada
Pharmacologic Category
Pharmacologic Category Synonyms
Use: Labeled Indications
Ambien®, Edluar™, Zolpimist®: Short-term treatment of insomnia (with difficulty of sleep onset)
Ambien CR®: Treatment of insomnia (with difficulty of sleep onset and/or sleep maintenance)
Sublinox™ (Canadian availability; not available in U.S.): Short-term treatment of insomnia (with difficulty of sleep onset, frequent awakenings, and/or early awakenings)
Pregnancy Risk Factor
C
Pregnancy Considerations
Teratogenic effects were not observed in animal studies. Adverse effects were noted in animal reproduction studies at doses 20-100 times the maximum recommended human dose. Severe neonatal respiratory depression has been reported when zolpidem was used at the end of pregnancy, especially when used concurrently with other CNS depressants. Studies of prenatal exposure to zolpidem have not been conducted in children. Children born of mothers taking sedative/hypnotics may be at risk for withdrawal; neonatal flaccidity has been reported in infants following maternal use of sedative/hypnotics during pregnancy. Use during pregnancy only if the benefits justify the risk to the fetus.
Lactation
Enters breast milk/use caution (AAP rates “compatible”; AAP 2001 update pending)
Contraindications
Hypersensitivity to zolpidem or any component of the formulation
Canadian labeling: Additional contraindications (not in U.S. labeling): Significant obstructive sleep apnea syndrome and acute and/or severe impairment of respiratory function; myasthenia gravis; severe hepatic impairment; personal or family history of sleepwalking
Warnings/Precautions
Concerns related to adverse effects:
• Abnormal thinking/behavioral changes: Hypnotics/sedatives have been associated with abnormal thinking and behavior changes including decreased inhibition, aggression, bizarre behavior, agitation, hallucinations, and depersonalization. These changes may occur unpredictably and may indicate previously unrecognized psychiatric disorders; evaluate appropriately.
• CNS depression: May cause CNS depression impairing physical and mental capabilities; patients must be cautioned about performing tasks which require mental alertness (operating machinery or driving). Zolpidem should only be administered when the patient is able to stay in bed a full night (7-8 hours) before being active again.
• Hypersensitivity reactions: Postmarketing studies have indicated that the use of hypnotic/sedative agents for sleep has been associated with hypersensitivity reactions including anaphylaxis as well as angioedema.
• Sleep-related activities: An increased risk for hazardous sleep-related activities such as sleep-driving; cooking and eating food, and making phone calls while asleep have also been noted; amnesia may also occur. Discontinue treatment in patients who report any sleep-related episodes. Canadian labeling recommends avoiding use in patients with disorders (eg, restless legs syndrome, periodic limb movement disorder, sleep apnea) that may disrupt sleep and cause frequent awakenings, potentially increasing the risk of complex sleep-related behaviors.
Disease-related concerns:
• Depression: Use with caution in patients with depression; worsening of depression, including suicide or suicidal ideation has been reported with the use of hypnotics. Intentional overdose may be an issue in this population. The minimum dose that will effectively treat the individual patient should be used. Prescriptions should be written for the smallest quantity consistent with good patient care.
• Drug abuse: Use with caution in patients with a history of drug dependence.
• Hepatic impairment: Use with caution in patients with hepatic impairment; dose adjustment recommended. Canadian labeling contraindicates use in severe hepatic impairment.
• Myasthenia gravis: Use with caution in patients with myasthenia gravis. Canadian labeling contraindicates use in myasthenia gravis.
• Respiratory disease: Use with caution in patients with respiratory compromise, COPD, or sleep apnea. Canadian labeling contraindicates use in significant obstructive sleep apnea syndrome and acute and/or severe impairment of respiratory function.
Concurrent drug therapy issues:
• CNS depressants/psychoactive medications: Use with caution in patients receiving other CNS depressants or psychoactive medication; effects with other sedative drugs or ethanol may be potentiated, including risk of sleep-related behaviors. Concomitant use with alcohol is not recommended per Canadian labeling.
Special populations:
• Elderly: Use with caution in the elderly; dose adjustment recommended. Closely monitor elderly or debilitated patients for impaired cognitive or motor performance.
• Pediatrics: When studied for the unapproved use of insomnia associated with ADHD in children, a higher incidence (~7%) of hallucinations was reported. In addition, sleep latency did not decrease compared to placebo. Zolpidem is not FDA- or Health Canada-approved for use in pediatric patients.
Other warnings/precautions:
• Appropriate use: Symptomatic treatment of insomnia should be initiated only after careful evaluation of potential causes of sleep disturbance. Failure of sleep disturbance to resolve after 7-10 days may indicate psychiatric and/or medical illness.
• Rapid onset: Because of the rapid onset of action, administer immediately prior to bedtime or after the patient has gone to bed and is having difficulty falling asleep.
• Withdrawal: Abrupt discontinuance may lead to withdrawal symptoms.
Adverse Reactions
Actual frequency may be dosage form, dose, and/or age dependent
>10%: Central nervous system: Headache (7% to 19%), somnolence (6% to 15%), dizziness (1% to 12%)
1% to 10%:
Cardiovascular: Blood pressure increased, chest discomfort/pain, palpitation
Central nervous system: Abnormal dreams, anxiety, apathy, amnesia, ataxia, attention disturbance, body temperature increased, burning sensation, confusion, depersonalization, depression, disinhibition, disorientation, drowsiness, drugged feeling, euphoria, fatigue, fever, hallucinations, hypoesthesia, insomnia, lethargy, lightheadedness, memory disorder, mood swings, sleep disorder, stress
Dermatologic: Rash, urticaria, wrinkling
Endocrine & metabolic: Menorrhagia
Gastrointestinal: Abdominal discomfort, abdominal pain, abdominal tenderness, appetite disorder, constipation, diarrhea, dyspepsia, flatulence, gastroenteritis, gastroesophageal reflux, hiccup, nausea, vomiting, xerostomia
Genitourinary: Urinary tract infection, vulvovaginal dryness
Neuromuscular & skeletal: Arthralgia, back pain, balance disorder, involuntary muscle contractions, myalgia, neck pain, paresthesia, psychomotor retardation, tremor, weakness
Ocular: Asthenopia, blurred vision, depth perception altered, diplopia, red eye, visual disturbance
Otic: Labyrinthitis, tinnitus, vertigo
Renal: Dysuria
Respiratory: Pharyngitis, sinusitis, throat irritation, upper respiratory tract infection
Miscellaneous: Allergy, binge eating, flu-like syndrome
<1% (Limited to important or life-threatening): Agitation, anemia, anorexia, arthritis, bronchitis, cerebrovascular disorder, cognition decreased, concentrating difficulty, constipation, cough, cystitis, diaphoresis, dysarthria, dysphagia, dyspnea, edema, emotional lability, eye irritation, falling, hepatic function abnormalities, hyperglycemia, hyper-/hypotension, illusion, leg cramps, leukopenia, lymphadenopathy, menstrual disorder, migraine, nervousness, pallor, paresthesia of the tongue (sublingual tablets), postural hypotension, pruritus, renal failure (acute), rhinitis, scleritis, somnambulism (sleepwalking), speech disorder, stupor, sublingual erythema (sublingual tablets), syncope, tachycardia, taste perversion, thirst, thrombosis, urinary incontinence, vaginitis
Postmarketing and/or case reports: Anaphylaxis, angioedema, complex sleep-related behavior (sleep-driving, cooking or eating food, making phone calls)
Metabolism/Transport Effects
Substrate of CYP1A2 (minor), CYP2C19 (minor), CYP2C9 (minor), CYP2D6 (minor), CYP3A4 (major); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential
Drug Interactions
Alcohol (Ethyl): CNS Depressants may enhance the CNS depressant effect of Alcohol (Ethyl). Risk C: Monitor therapy
Antifungal Agents (Azole Derivatives, Systemic): May increase the serum concentration of Zolpidem. Management: Consider using a lower starting dose of zolpidem in patients receiving systemic azole antifungals. Monitor patients closely for increased magnitude and/or duration of zolpidem effects when using this combination. Risk D: Consider therapy modification
CarBAMazepine: Zolpidem may enhance the CNS depressant effect of CarBAMazepine. CarBAMazepine may decrease the serum concentration of Zolpidem. Risk C: Monitor therapy
CNS Depressants: May enhance the adverse/toxic effect of other CNS Depressants. Exceptions: Levocabastine (Nasal). Risk C: Monitor therapy
Conivaptan: May increase the serum concentration of CYP3A4 Substrates. Risk X: Avoid combination
CYP3A4 Inducers (Strong): May increase the metabolism of CYP3A4 Substrates. Risk C: Monitor therapy
CYP3A4 Inhibitors (Moderate): May decrease the metabolism of CYP3A4 Substrates. Risk C: Monitor therapy
CYP3A4 Inhibitors (Strong): May decrease the metabolism of CYP3A4 Substrates. Risk D: Consider therapy modification
Cyproterone: May decrease the serum concentration of CYP1A2 Substrates. Risk C: Monitor therapy
Dasatinib: May increase the serum concentration of CYP3A4 Substrates. Risk C: Monitor therapy
Deferasirox: May decrease the serum concentration of CYP3A4 Substrates. Risk C: Monitor therapy
Droperidol: May enhance the CNS depressant effect of CNS Depressants. Management: Consider dose reductions of droperidol or of other CNS agents (e.g., opioids, barbiturates) with concomitant use. Risk D: Consider therapy modification
Flumazenil: May diminish the sedative effect of Hypnotics (Nonbenzodiazepine). Risk C: Monitor therapy
Herbs (CYP3A4 Inducers): May increase the metabolism of CYP3A4 Substrates. Risk C: Monitor therapy
HydrOXYzine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Ivacaftor: May increase the serum concentration of CYP3A4 Substrates. Risk C: Monitor therapy
Methotrimeprazine: CNS Depressants may enhance the CNS depressant effect of Methotrimeprazine. Methotrimeprazine may enhance the CNS depressant effect of CNS Depressants. Management: Reduce adult dose of CNS depressant agents by 50% with initiation of concomitant methotrimeprazine therapy. Further CNS depressant dosage adjustments should be initiated only after clinically effective methotrimeprazine dose is established. Risk D: Consider therapy modification
Peginterferon Alfa-2b: May decrease the serum concentration of CYP2D6 Substrates. Risk C: Monitor therapy
Rifamycin Derivatives: May decrease the serum concentration of Zolpidem. Risk C: Monitor therapy
Selective Serotonin Reuptake Inhibitors: CNS Depressants may enhance the adverse/toxic effect of Selective Serotonin Reuptake Inhibitors. Specifically, the risk of psychomotor impairment may be enhanced. Risk C: Monitor therapy
Telaprevir: May decrease the serum concentration of Zolpidem. Risk C: Monitor therapy
Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates. Risk C: Monitor therapy
Ethanol/Nutrition/Herb Interactions
Ethanol: May enhance the adverse/toxic effects of zolpidem. Management: Avoid use of ethanol.
Food: Maximum plasma concentration and bioavailability are decreased with food; time to peak plasma concentration is increased; half-life remains unchanged. Grapefruit juice may decrease the metabolism of zolpidem. Management: Avoid grapefruit juice.
Herb/Nutraceutical: St John's wort may decrease the levels/effects of zolpidem. Some herbal medications should be avoided due to the risk of increased CNS depression. Management: Avoid concomitant use of St John's wort. Avoid valerian, kava kava, and gotu kola.
Storage
Ambien®, Edluar™: Store at 20°C to 25°C (68°F to 77°F). Protect sublingual tablets from light and moisture.
Ambien CR®: Store at 15°C to 25°C (59°F to 77°F); limited excursions permitted up to 30°C (86°F).
Zolpimist®: Store at 25°C (77°F); do not freeze. Avoid prolonged exposure to temperatures >30°C (86°F).
Sublinox™ (Canadian availability; not available in U.S.): Store at 15°C to 30°C (59°F to 86°F); protect from light and moisture.
Mechanism of Action
Zolpidem, an imidazopyridine hypnotic that is structurally dissimilar to benzodiazepines, enhances the activity of the inhibitory neurotransmitter, γ-aminobutyric acid (GABA), via selective agonism at the benzodiazepine-1 (BZ1) receptor; the result is increased chloride conductance, neuronal hyperpolarization, inhibition of the action potential, and a decrease in neuronal excitability leading to sedative and hypnotic effects. Because of its selectivity for the BZ1 receptor site over the BZ2 receptor site, zolpidem exhibits minimal anxiolytic, myorelaxant, and anticonvulsant properties (effects largely attributed to agonism at the BZ2 receptor site).
Pharmacodynamics/Kinetics
Onset of action: Immediate release: 30 minutes
Duration: Immediate release: 6-8 hours
Absorption: Rapid
Distribution: Vd: 0.54 L/kg
Protein binding: ~93%
Metabolism: Hepatic methylation and hydroxylation via CYP3A4 (~60%), CYP2C9 (~22%), CYP1A2 (~14%), CYP2D6 (~3%), and CYP2C19 (~3%) to three inactive metabolites
Bioavailability: 70%
Half-life elimination:
Immediate release, Extended release: ~2.5 hours (range 1.4-4.5 hours); Cirrhosis: Up to 9.9 hours; Elderly: Prolonged up to 32%
Spray: ~3 hours (range: 1.7-8.4)
Sublingual: ~3 hours (range: 1.6-6.7 hours)
Time to peak, plasma:
Immediate release: 1.6 hours; 2.2 hours with food
Extended release: 1.5 hours; 4 hours with food
Spray: ~0.9 hours
Sublingual: ~1.4 hours; ~1.8 hours with food
Excretion: Urine (48% to 67%, primarily as metabolites); feces (29% to 42%, primarily as metabolites)
Dosage
Oral:
Adults:
Immediate release tablet, spray, sublingual tablet: 10 mg immediately before bedtime; maximum dose: 10 mg
Extended release tablet: 12.5 mg immediately before bedtime
Elderly:
Immediate release tablet, spray: 5 mg immediately before bedtime
Sublingual tablet:
U.S. labeling (Edluar™): 5 mg immediately before bedtime
Canadian labeling (Sublinox™): Not recommended; tablet cannot not be split for a reduced dose.
Extended release tablet: 6.25 mg immediately before bedtime
Dosing adjustment in renal impairment: Dose adjustment not required; monitor closely
Hemodialysis: Not dialyzable
Dosing adjustment in hepatic impairment:
U.S. labeling:
Immediate release tablet, spray, sublingual tablet: 5 mg
Extended release tablet: 6.25 mg
Canadian labeling: Sublingual tablet:
Mild-to-moderate impairment: Use is not recommended; tablet cannot be split for reduced dose.
Severe impairment: Use is contraindicated.
Administration: Oral
Ingest immediately before bedtime due to rapid onset of action.
Ambien CR® tablets should be swallowed whole; do not divide, crush, or chew.
Edluar™ or Sublinox™ (Canadian availability; not available in U.S.) sublingual tablets should be placed under the tongue and allowed to disintegrate; do not swallow or administer with water. Do not administer with or immediately after a meal.
Zolpimist® oral spray should be sprayed directly into the mouth over the tongue. Prior to initial use, pump should be primed by spraying 5 times. If pump is not used for at least 14 days, re-prime pump with 1 spray.
Monitoring Parameters
Daytime alertness; respiratory rate; behavior profile
Test Interactions
Increased aminotransferase [ALT/AST], bilirubin (S); decreased RAI uptake
Dietary Considerations
For faster sleep onset, do not administer with (or immediately after) a meal.
Patient Education
Take immediately before going to bed. Spray mist into mouth over tongue. Only use this medication if you can get a full night's sleep (at least 7-8 hours). Drug may cause physical and/or psychological dependence. While using this medication, do not use alcohol. Avoid grapefruit or grapefruit juice when taking this medication. Do not drive or operate machinery after taking this medication. Report CNS changes (confusion, memory problems, depression, excitation, headache, abnormal thinking or behavior, nightmares); or respiratory difficulty. Report episodes of "sleep driving" or other complex behaviors, such as driving a vehicle, preparing food, or other activities which you have no memory of performing.
Geriatric Considerations
In doses >5 mg, there was subjective evidence of impaired sleep on the first post-treatment night. There have been few reports of increased hypotension and/or falls in the elderly with this drug. Can be considered a drug of choice in the elderly when a hypnotic is indicated. With Ambien CR®, the adverse event profile of 6.25 mg in elderly patients was similar to the 12.5 mg dose in younger adults. Until there is more experience with this dosage form, use with caution in the elderly.
Additional Information
Causes fewer disturbances in sleep stages as compared to benzodiazepines. Time spent in sleep stages 3 and 4 are maintained; zolpidem decreases sleep latency; should not be prescribed in quantities exceeding a 1-month supply.
Anesthesia and Critical Care Concerns/Other Considerations
Clinical Pearls/Comments: Causes fewer disturbances in sleep stages as compared to benzodiazepines. Time spent in sleep stages 3 and 4 are maintained; zolpidem decreases sleep latency; should not be prescribed in quantities exceeding a 1-month supply.
Dental Health: Effects on Dental Treatment
Key adverse event(s) related to dental treatment: Xerostomia (normal salivary flow resumes upon discontinuation).
Dental Health: Vasoconstrictor/Local Anesthetic Precautions
No information available to require special precautions
Mental Health: Child/Adolescent Considerations
An 8-week double-blind placebo-controlled study in 6–11 year olds (n=111) and 12–17 year olds (n=90) with ADHD and insomnia found zolpidem 0.25 mg/kg/day was ineffective in reducing latency to persistent sleep according to polysomnographic readings. The mean reduction to persistent sleep was 20.28 minutes in the zolpidem group and 21.27 minutes in the placebo group. There was a trend toward greater efficacy versus placebo in the 12-17 year age group. Over 90% of patients in both groups were taking stable doses of psychostimulants for more than 1 month prior to the initiation of zolpidem. Ten (7.4%) patients discontinued treatment due to adverse effects. There were 13 hallucinatory episodes (8 mild, 5 severe) among 10 patients. Younger patients were more likely to experience the hallucinatory events.
Blumer JL, Findling RL, Shih WJ, et al, "Controlled Clinical Trial of Zolpidem for the Treatment of Insomnia Associated With Attention-Deficit/Hyperactivity Disorder in Children 6-17 Years of Age," Pediatrics, 2009, 123(5):e770-6.
Mental Health: Comment
In 2007, the FDA requested that all manufacturers of sedative-hypnotic drug products revise labeling to include a greater emphasis on the risks of adverse effects. These risks include severe allergic reactions (anaphylaxis, angioedema) and complex sleep-related behaviors, which may include sleep-driving (driving while not fully awake and with no memory of the event), making phone calls, and preparing and eating food while asleep. Zolpidem may be associated with a lower potential for abuse compared to benzodiazepines. When studied for the unapproved use of insomnia associated with ADHD in children, a higher incidence (~7%) of hallucinations was reported.
Nursing: Physical Assessment/Monitoring
For short-term use. Assess for history of addiction; long-term use can result in dependence, abuse, or tolerance; behaviors that patient has no memory of performing after taking (driving, preparing food, or eating); periodically evaluate need for continued use. Monitor for CNS depression. For inpatient use, institute safety measures to prevent falls.
Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Solution, oral, as tartrate [spray]:
Zolpimist®: 5 mg/actuation (8.2 g) [contains benzoic acid, propylene glycol; cherry flavor; 60 metered actuations]
Tablet, oral, as tartrate: 5 mg, 10 mg
Ambien®: 5 mg, 10 mg
Tablet, sublingual, as tartrate:
Edluar™: 5 mg, 10 mg
Tablet, extended release, oral, as tartrate: 6.25 mg, 12.5 mg
Ambien CR®: 6.25 mg, 12.5 mg
Pricing: U.S. (www.drugstore.com)
Sublingual (Edluar)
5 mg (30): $179.99
10 mg (30): $168.99
Tablet, controlled release (Ambien CR)
6.25 mg (30): $193.99
12.5 mg (30): $190.99
Tablet, controlled release (Zolpidem Tartrate)
6.25 mg (30): $155.99
12.5 mg (30): $155.99
Tablets (Ambien)
5 mg (30): $203.64
10 mg (30): $209.98
Tablets (Zolpidem Tartrate)
5 mg (30): $17.99
10 mg (30): $17.99
References
American Academy of Pediatrics Committee on Drugs, "Transfer of Drugs and Other Chemicals Into Human Milk," Pediatrics, 2001, 108(3):776-89.
Durand A, Thénot JP, Bianchetti G, et al, “Comparative Pharmacokinetic Profile of Two Imidazopyridine Drugs: Zolpidem and Alpidem,” Drug Metab Rev, 1992, 24(2):239-66.
Holm KJ and Goa KL, “Zolpidem: An Update of Its Pharmacology, Therapeutic Efficacy and Tolerability in the Treatment of Insomnia,” Drugs, 2000, 59(4):865-89.
Lange CL, “Medication-Associated Somnambulism,” J Am Acad Child Adolesc Psychiatry, 2005, 44(3):211-2.
Langtry HD and Benfield P, “Zolpidem: A Review of Its Pharmacodynamic and Pharmacokinetic Properties and Therapeutic Potential,” Drugs, 1990, 40(2):291-313.
Salva P and Costa J, “Clinical Pharmacokinetics and Pharmacodynamics of Zolpidem. Therapeutic Implications,” Clin Pharmacokinet, 1995, 29(3):142-53.
Sanger DJ, “The Pharmacology and Mechanisms of Action of New Generation, Non-Benzodiazepine Hypnotic Agents,” CNS Drugs, 2004, 18 (Suppl 1):9-15.
Taylor JR, Vazquez CM, and Campbell KM, “Pharmacologic Management of Chronic Insomnia,” South Med J, 2006, 99(12):1373-7.
International Brand Names
Lexi-Comp.com
Last full review/revision March 2012
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