AMBIEN® (zolpidem tartrate)

AMBIEN® (zolpidem tartrate)

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AMBIEN® (zolpidem tartrate)

AMBIEN contains zolpidem tartrate, a gamma-aminobutyric acid (GABA) A receptor positive modulator of the imidazopyridine class. AMBIEN is available in 5 mg and 10 mg strength tablets for oral administration.

Chemically, zolpidem is N,N,6-trimethyl-2-p-tolylimidazo[1,2-a] pyridine-3-acetamide L-(+)-tartrate (2:1)

Zolpidem tartrate is a white to off-white crystalline powder that is sparingly soluble in water, alcohol, and propylene glycol. It has a molecular weight of 764.88.

Usage and administration

AMBIEN, a gamma-aminobutyric acid (GABA) A receptor positive modulator, is indicated for the short-term treatment of insomnia characterized by difficulties with sleep initiation.

Mechanism of Action

Zolpidem is a GABA A receptor positive modulator presumed to exert its therapeutic effects in the short-term treatment of insomnia through binding to the benzodiazepine site of α1 subunit containing GABA A receptors, increasing the frequency of chloride channel opening resulting in the inhibition of neuronal excitation.

Dosage and administration

  • Use the lowest dose effective for the patient and must not exceed a total of 10 mg daily
  • Recommended initial dose is a single dose of 5 mg for women and a single dose of 5 or 10 mg for men, immediately before bedtime with at least 7-8 hours remaining before the planned time of awakening
  • Geriatric patients and patients with mild to moderate hepatic impairment: Recommended dose is 5 mg for men and women
  • Lower doses of CNS depressants may be necessary when taken concomitantly with AMBIEN
  • The effect of AMBIEN may be slowed if taken with or immediately after a meal

Contraindications

  • Patients who have experienced complex sleep behaviors after taking AMBIEN
  • Known hypersensitivity to zolpidem

Warnings and precautions

Complex Sleep Behaviors: Complex sleep behaviors, including sleep-walking, sleep-driving, and engaging in other activities while not fully awake, may occur following the first or any subsequent use of AMBIEN. Patients can be seriously injured or injure others during complex sleep behaviors . Such injuries may result in a fatal outcome. Other complex sleep behaviors (e.g., preparing and eating food, making phone calls, or having sex) have also been reported. Patients usually do not remember these events. P

CNS-Depressant Effects: Impairs alertness and motor coordination including risk of morning impairment. Risk increases with dose and use with other CNS depressants and alcohol. Instruct patients on correct use.

Need to Evaluate for Comorbid Diagnoses: Re-evaluate if insomnia persists after 7 to 10 days of use.

Severe Anaphylactic/Anaphylactoid Reactions: Angioedema and anaphylaxis have been reported. Do not rechallenge if such reactions occur.

Abnormal Thinking and Behavioral Changes: Changes including decreased inhibition, bizarre behavior, agitation, and depersonalization have been reported. Immediately evaluate any new onset behavioral changes.

Depression: Worsening of depression or suicidal thinking may occur. Prescribe the least amount of tablets feasible to avoid intentional overdose.

Respiratory Depression: Consider this risk before prescribing in patients with compromised respiratory function.

Hepatic Impairment: Avoid AMBIEN use in patients with severe hepatic impairment.

Withdrawal Effects: Symptoms may occur with rapid dose reduction or discontinuation

Adverse reactions

Most commonly observed adverse reactions were: Short-term (<10 nights): Drowsiness, dizziness, and diarrhea

Long-term (28-35 nights): Dizziness and drugged feelings

Drug interactions

CNS Depressants: Coadministration of zolpidem with other CNS depressants increases the risk of CNS depression. Concomitant use of zolpidem with these drugs may increase drowsiness and psychomotor impairment, including impaired driving ability.

Imipramine, Chlorpromazine: Imipramine in combination with zolpidem produced no pharmacokinetic interaction other than a 20% decrease in peak levels of imipramine, but there was an additive effect of decreased alertness. Similarly, chlorpromazine in combination with zolpidem produced no pharmacokinetic interaction, but there was an additive effect of decreased alertness and psychomotor performance.

Haloperidol: A study involving haloperidol and zolpidem revealed no effect of haloperidol on the pharmacokinetics or pharmacodynamics of zolpidem. The lack of a drug interaction following single-dose administration does not predict the absence of an effect following chronic administration

Alcohol: An additive adverse effect on psychomotor performance between alcohol and oral zolpidem was demonstrated

Sertraline: Concomitant administration of zolpidem and sertraline increases exposure to zolpidem

Fluoxetine: After multiple doses of zolpidem tartrate and fluoxetine an increase in the zolpidem half-life (17%) was observed. There was no evidence of an additive effect in psychomotor performance.

Rifampin: Rifampin, a CYP3A4 inducer, significantly reduced the exposure to and the pharmacodynamic effects of zolpidem. Use of Rifampin in combination with zolpidem may decrease the efficacy of zolpidem and is not recommended

St. John’s wort: Use of St. John’s wort, a CYP3A4 inducer, in combination with zolpidem may decrease blood levels of zolpidem and is not recommended.

Ketoconazole: Ketoconazole, a potent CYP3A4 inhibitor, increased the exposure to and pharmacodynamic effects of zolpidem. Consideration should be given to using a lower dose of zolpidem when a potent CYP3A4 inhibitor and zolpidem are given together.

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Use in specific populations

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

Zolpidem crosses the placenta and may produce respiratory depression and sedation in neonates. Monitor neonates exposed to AMBIEN during pregnancy and labor for signs of excess sedation, hypotonia, and respiratory depression and manage accordingly.

Lactation: Limited data from published literature report the presence of zolpidem in human milk. There are reports of excess sedation in infants exposed to zolpidem through breastmilk. There is no information on the effects of zolpidem on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for AMBIEN and any potential adverse effects on the breastfed infant from AMBIEN or from the underlying maternal condition

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

Pediatric Use: AMBIEN is not recommended for use in children. Safety and effectiveness of zolpidem in pediatric patients below the age of 18 years have not been established.

Drug abuse and dependence

Controlled Substance: Zolpidem tartrate is classified as a Schedule IV controlled substance by federal regulation.

Abuse: Abuse and addiction are separate and distinct from physical dependence and tolerance. Abuse is characterized by misuse of the drug for non-medical purposes, often in combination with other psychoactive substances. Tolerance is a state of adaptation in which exposure to a drug induces changes that result in a diminution of one or more of the drug effects over time. Tolerance may occur to both desired and undesired effects of drugs and may develop at different rates for different effects.

Addiction is a primary, chronic, neurobiological disease with genetic, psychosocial, and environmental factors influencing its development and manifestations. It is characterized by behaviors that include one or more of the following: impaired control over drug use, compulsive use, continued use despite harm, and craving. Drug addiction is a treatable disease, using a multidisciplinary approach, but relapse is common.

Dependence: Physical dependence is a state of adaptation that is manifested by a specific withdrawal syndrome that can be produced by abrupt cessation, rapid dose reduction, decreasing blood level of the drug, and/or administration of an antagonist.

Sedative/hypnotics have produced withdrawal signs and symptoms following abrupt discontinuation. These reported symptoms range from mild dysphoria and insomnia to a withdrawal syndrome that may include abdominal and muscle cramps, vomiting, sweating, tremors, and convulsions. The following adverse events, which are considered to meet the DSMIII-R criteria for uncomplicated sedative/hypnotic withdrawal, were reported during U.S. clinical trials following placebo substitution occurring within 48 hours following last zolpidem treatment: fatigue, nausea, flushing, lightheadedness, uncontrolled crying, emesis, stomach cramps, panic attack, nervousness, and abdominal discomfort.

Overdosage

In postmarketing experience of overdose with zolpidem tartrate alone, or in combination with CNS-depressant agents, impairment of consciousness ranging from somnolence to coma, cardiovascular and/or respiratory compromise, and fatal outcomes have been reported

Recommended Treatment

General symptomatic and supportive measures should be used along with immediate gastric lavage where appropriate. Intravenous fluids should be administered as needed. Zolpidem’s sedative hypnotic effect was shown to be reduced by flumazenil and therefore may be useful; however, flumazenil administration may contribute to the appearance of neurological symptoms (convulsions). As in all cases of drug overdose, respiration, pulse, blood pressure, and other appropriate signs should be monitored and general supportive measures employed.

Hypotension and CNS depression should be monitored and treated by appropriate medical intervention. Sedating drugs should be withheld following zolpidem overdosage, even if excitation occurs. The value of dialysis in the treatment of overdosage has not been determined, although hemodialysis studies in patients with renal failure receiving therapeutic doses have demonstrated that zolpidem is not dialyzable.

As with the management of all overdosage, the possibility of multiple drug ingestion should be considered. The physician may wish to consider contacting a poison control center for up-to-date information on the management of hypnotic drug product overdosage.

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