Ambien

AMBIEN CR (zolpidem tartrate extended-release tablets) is indicated for the short-term treatment of insomnia characterized by difficulties with sleep onset and/or sleep maintenance (as measured by wake time after sleep onset).

The clinical trials performed in support of efficacy were up to 3 weeks (using polysomnography measurement up to 2 weeks in both adult and elderly patients) and 24 weeks (using patient reported assessment in adult patients only) in duration [see

• Use the lowest dose effective for the patient and must not exceed a total of 12.5 mg daily (
  
  
  2.1 Dosage in Adults

  Use the lowest effective dose for the patient. The recommended initial dose is 6.25 mg for women and either 6.25 or 12.5 mg for men, taken only once per night immediately before bedtime with at least 7–8 hours remaining before the planned time of awakening. If the 6.25 mg dose is not effective, the dose can be increased to 12.5 mg. In some patients, the higher morning blood levels following use of the 12.5 mg dose increase the risk of next-day impairment of driving and other activities that require full alertness

  [see Warnings and Precautions (5.2)]

  . The total dose of AMBIEN CR should not exceed 12.5 mg once daily immediately before bedtime. AMBIEN CR should be taken as a single dose and should not be readministered during the same night.

  The recommended initial doses for women and men are different because zolpidem clearance is lower in women.

  Treatment with AMBIEN CR should be as short as possible. Extended treatment should not take place without re-evaluation of the patient’s status, since the risk of abuse and dependence increases with duration of treatment [see

  Drug Abuse and Dependence (9.3)]

  .
  )
  
• Treatment should be as short as possible (
  
  
  2.1 Dosage in Adults

  Use the lowest effective dose for the patient. The recommended initial dose is 6.25 mg for women and either 6.25 or 12.5 mg for men, taken only once per night immediately before bedtime with at least 7–8 hours remaining before the planned time of awakening. If the 6.25 mg dose is not effective, the dose can be increased to 12.5 mg. In some patients, the higher morning blood levels following use of the 12.5 mg dose increase the risk of next-day impairment of driving and other activities that require full alertness

  [see Warnings and Precautions (5.2)]

  . The total dose of AMBIEN CR should not exceed 12.5 mg once daily immediately before bedtime. AMBIEN CR should be taken as a single dose and should not be readministered during the same night.

  The recommended initial doses for women and men are different because zolpidem clearance is lower in women.

  Treatment with AMBIEN CR should be as short as possible. Extended treatment should not take place without re-evaluation of the patient’s status, since the risk of abuse and dependence increases with duration of treatment [see

  Drug Abuse and Dependence (9.3)]

  .
  )
  
• Recommended initial dose is a single dose of 6.25 mg for women and a single dose of 6.25 or 12.5 mg for men, immediately before bedtime with at least 7–8 hours remaining before the planned time of awakening (
  
  
  2.1 Dosage in Adults

  Use the lowest effective dose for the patient. The recommended initial dose is 6.25 mg for women and either 6.25 or 12.5 mg for men, taken only once per night immediately before bedtime with at least 7–8 hours remaining before the planned time of awakening. If the 6.25 mg dose is not effective, the dose can be increased to 12.5 mg. In some patients, the higher morning blood levels following use of the 12.5 mg dose increase the risk of next-day impairment of driving and other activities that require full alertness

  [see Warnings and Precautions (5.2)]

  . The total dose of AMBIEN CR should not exceed 12.5 mg once daily immediately before bedtime. AMBIEN CR should be taken as a single dose and should not be readministered during the same night.

  The recommended initial doses for women and men are different because zolpidem clearance is lower in women.

  Treatment with AMBIEN CR should be as short as possible. Extended treatment should not take place without re-evaluation of the patient’s status, since the risk of abuse and dependence increases with duration of treatment [see

  Drug Abuse and Dependence (9.3)]

  .
  )
  
• Geriatric patients and patients with mild to moderate hepatic impairment: Recommended dose is 6.25 mg for men and women (
  
  
  2.2 Special Populations

  Elderly or debilitated patients may be especially sensitive to the effects of zolpidem tartrate. The recommended dose of AMBIEN CR in these patients is 6.25 mg once daily immediately before bedtime

  [see Warnings and Precautions (5.2), Use in Specific Populations (8.5)].

  Patients with mild to moderate hepatic impairment do not clear the drug as rapidly as normal subjects. The recommended dose of AMBIEN CR in these patients is 6.25 mg once daily immediately before bedtime. Avoid AMBIEN CR use in patients with severe hepatic impairment as it may contribute to encephalopathy

  [see Warnings and Precautions (5.8), Use in Specific Populations (8.7), Clinical Pharmacology (12.3)]

  .
  )
  
• Lower doses of CNS depressants may be necessary when taken concomitantly with AMBIEN CR (
  
  
  2.3 Use with CNS Depressants

  Dosage adjustment may be necessary when AMBIEN CR is combined with other CNS-depressant drugs because of the potentially additive effects

  [see Warnings and Precautions (5.2, 5.7)]

  .
  )
  
• Tablets to be swallowed whole, not to be crushed, divided or chewed (
  
  
  2.4 Administration

  AMBIEN CR extended-release tablets should be swallowed whole, and not be divided, crushed, or chewed. The effect of AMBIEN CR may be slowed by ingestion with or immediately after a meal.
  )
  
• The effect of AMBIEN CR may be slowed if taken with or immediately after a meal (
  
  
  2.4 Administration

  AMBIEN CR extended-release tablets should be swallowed whole, and not be divided, crushed, or chewed. The effect of AMBIEN CR may be slowed by ingestion with or immediately after a meal.
  )
  

AMBIEN CR is available as extended-release tablets containing 6.25 mg or 12.5 mg of zolpidem tartrate for oral administration. Tablets are not scored.

AMBIEN CR 6.25 mg tablets are pink, round, bi-convex, and debossed with A~ on one side.

AMBIEN CR 12.5 mg tablets are blue, round, bi-convex, and debossed with A~ on one side.

• Pregnancy: May cause respiratory depression and sedation in neonates with exposure late in the third trimester. (
  
  
  8.1 Pregnancy

  Risk Summary

  Neonates born to mothers using zolpidem late in the third trimester of pregnancy have been reported to experience symptoms of respiratory depression and sedation

  [see Clinical Considerationsand Data]

  . Published data on the use of zolpidem during pregnancy have not reported a clear association with zolpidem and major birth defects

  [see Data]

  . Oral administration of zolpidem to pregnant rats and rabbits did not indicate a risk for adverse effects on fetal development at clinically relevant doses

  [see Data]

  .

  The estimated background risk of major birth defects and miscarriage for the indicated populations are unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2%–4% and 15%–20%, respectively.

  Clinical Considerations

  Fetal/neonatal adverse reactions

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

  Data

  Human data

  Published data from observational studies, birth registries, and case reports on the use of zolpidem during pregnancy do not report a clear association with zolpidem and major birth defects.

  There are limited postmarketing reports of severe to moderate cases of respiratory depression that occurred after birth in neonates whose mothers had taken zolpidem during pregnancy. These cases required artificial ventilation or intratracheal intubation. The majority of neonates recovered within hours to a few weeks after birth once treated.

  Zolpidem has been shown to cross the placenta.

  Animal data

  Oral administration of zolpidem to pregnant rats during the period of organogenesis at 4, 20, and 100 mg base/kg/day, which are approximately 4, 20, and 100 times the maximum recommended human dose (MRHD) of 12.5 mg/day (10 mg zolpidem base) based on mg/m²body surface area, caused delayed fetal development (incomplete fetal skeletal ossification) at maternally toxic (ataxia) doses 20 and 100 times the MRHD based on mg/m²body surface area.

  Oral administration of zolpidem to pregnant rabbits during the period of organogenesis at 1, 4, and 16 mg base/kg/day, which are approximately 2, 8, and 30 times the MRHD of 12.5 mg/day (10 mg zolpidem base) based on mg/m²body surface area caused embryo-fetal death and delayed fetal development (incomplete fetal skeletal ossification) at a maternally toxic (decreased body weight gain) dose 30 times the MRHD based on mg/m²body surface area.

  Oral administration of zolpidem to pregnant rats from day 15 of gestation through lactation at 4, 20, and 100 mg base/kg/day, which are approximately 4, 20, and 100 times the MRHD of 12.5 mg/day (10 mg zolpidem base) based on a mg/m²body surface area, delayed offspring growth and decreased survival at doses 20 and 100 times, respectively, the MRHD based on mg/m²body surface area.
  )
  
• Lactation: A lactating woman may pump and discard breast milk during treatment and for 23 hours after AMBIEN CR administration. (
  
  
  8.2 Lactation

  Risk Summary

  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

  [see Clinical Considerations].

  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 CR and any potential adverse effects on the breastfed infant from AMBIEN CR or from the underlying maternal condition.

  Clinical Considerations

  Infants exposed to AMBIEN CR 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 CR administration in order to minimize drug exposure to a breast fed infant.
  )
  
• Pediatric use: Safety and effectiveness not established. Hallucinations (incidence rate 7%) and other psychiatric and/or nervous system adverse reactions were observed frequently in a study of pediatric patients with Attention-Deficit/Hyperactivity Disorder. (
  
  
  5.5 Abnormal Thinking and Behavioral Changes

  Abnormal thinking and behavior changes have been reported in patients treated with sedative/hypnotics, including AMBIEN CR. Some of these changes included decreased inhibition (e.g., aggressiveness and extroversion that seemed out of character), bizarre behavior, agitation and depersonalization. Visual and auditory hallucinations have been reported.

  In controlled trials, <1% of adults with insomnia reported hallucinations. In a clinical trial, 7% of pediatric patients treated with Ambien 0.25 mg/kg taken at bedtime reported hallucinations versus 0% treated with placebo

  [see Use in Specific Populations (8.4)]

  . There have been postmarketing reports of delirium with zolpidem use

  [see Adverse Reactions (6.2)]

  .

  It can rarely be determined with certainty whether a particular instance of the abnormal behaviors listed above is drug induced, spontaneous in origin, or a result of an underlying psychiatric or physical disorder. Nonetheless, the emergence of any new behavioral sign or symptom of concern requires careful and immediate evaluation.
  ,
  
  
  8.4 Pediatric Use

  AMBIEN CR 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.

  In an 8-week study in pediatric patients (aged 6–17 years) with insomnia associated with attention-deficit/hyperactivity disorder (ADHD) an oral solution of zolpidem tartrate dosed at 0.25 mg/kg at bedtime did not decrease sleep latency compared to placebo. Psychiatric and nervous system disorders comprised the most frequent (>5%) treatment emergent adverse reactions observed with zolpidem versus placebo and included dizziness (23.5% vs 1.5%), headache (12.5% vs 9.2%), and hallucinations were reported in 7% of the pediatric patients who received zolpidem; none of the pediatric patients who received placebo reported hallucinations

  [see Warnings and Precautions (5.5)]

  . Ten patients on zolpidem (7.4%) discontinued treatment due to an adverse reaction.

  FDA has not required pediatric studies of AMBIEN CR in the pediatric population based on these efficacy and safety findings.
  )