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. Postmarketing reports
have shown that complex sleep behaviors may occur with AMBIEN alone at
recommended doses, with or without the concomitant use of alcohol or other
Central Nervous System (CNS) depressants [see DRUG INTERACTIONS].
Discontinue AMBIEN immediately if a patient experiences a complex sleep
behavior [see CONTRAINDICATIONS].
CNS-Depressant Effects And Next-Day Impairment
AMBIEN, like other sedative-hypnotic drugs, has
CNS-depressant effects. Coadministration with other CNS depressants (e.g.,
benzodiazepines, opioids, tricyclic antidepressants, alcohol) increases the
risk of CNS depression [see DRUG INTERACTIONS]. Dosage adjustments of
AMBIEN and of other concomitant CNS depressants may be necessary when AMBIEN is
administered with such agents because of the potentially additive effects. The
use of AMBIEN with other sedative-hypnotics (including other zolpidem products)
at bedtime or the middle of the night is not recommended [see DOSAGE AND ADMINISTRATION].
The risk of next-day psychomotor impairment, including
impaired driving, is increased if AMBIEN is taken with less than a full night
of sleep remaining (7 to 8 hours); if a higher than the recommended dose is
taken; if coadministered with other CNS depressants or alcohol; or if
coadministered with other drugs that increase the blood levels of zolpidem.
Patients should be warned against driving and other activities requiring
complete mental alertness if AMBIEN is taken in these circumstances [see
DOSAGE AND ADMINISTRATION, Clinical Studies].
Vehicle drivers and machine operators should be warned
that, as with other hypnotics, there may be a possible risk of adverse
reactions including drowsiness, prolonged reaction time, dizziness, sleepiness,
blurred/double vision, reduced alertness, and impaired driving the morning
after therapy. In order to minimize this risk a full night of sleep (7-8 hours)
Because AMBIEN can cause drowsiness and a decreased level
of consciousness, patients, particularly the elderly, are at higher risk of
Need To Evaluate For Comorbid Diagnoses
Because sleep disturbances may be the presenting
manifestation of a physical and/or psychiatric disorder, symptomatic treatment
of insomnia should be initiated only after a careful evaluation of the patient.
The failure of insomnia to remit after 7 to 10 days of treatment may indicate
the presence of a primary psychiatric and/or medical illness that should be
evaluated. Worsening of insomnia or the emergence of new thinking or behavior
abnormalities may be the consequence of an unrecognized psychiatric or physical
disorder. Such findings have emerged during the course of treatment with
sedative/hypnotic drugs, including zolpidem.
Severe Anaphylactic And Anaphylactoid Reactions
Cases of angioedema involving the tongue, glottis or
larynx have been reported in patients after taking the first or subsequent
doses of sedative-hypnotics, including zolpidem. Some patients have had
additional symptoms such as dyspnea, throat closing or nausea and vomiting that
suggest anaphylaxis. Some patients have required medical therapy in the
emergency department. If angioedema involves the throat, glottis or larynx,
airway obstruction may occur and be fatal. Patients who develop angioedema
after treatment with zolpidem should not be rechallenged with the drug.
Abnormal Thinking And Behavioral Changes
Abnormal thinking and behavior changes have been reported
in patients treated with sedative/hypnotics, including AMBIEN. 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 of AMBIEN 10 mg taken at bedtime
<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
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.
Use In Patients With Depression
In primarily depressed patients treated with
sedative-hypnotics, worsening of depression, and suicidal thoughts and actions
(including completed suicides), have been reported. Suicidal tendencies may be
present in such patients and protective measures may be required. Intentional overdosage
is more common in this group of patients; therefore, the lowest number of tablets
that is feasible should be prescribed for the patient at any one time.
Although studies with 10 mg zolpidem tartrate did not
reveal respiratory depressant effects at hypnotic doses in healthy subjects or
in patients with mild to moderate chronic obstructive pulmonary disease (COPD),
a reduction in the Total Arousal Index, together with a reduction in lowest
oxygen saturation and increase in the times of oxygen desaturation below 80%
and 90%, was observed in patients with mild to moderate sleep apnea when
treated with zolpidem compared to placebo. Since sedative-hypnotics have the
capacity to depress respiratory drive, precautions should be taken if AMBIEN is
prescribed to patients with compromised respiratory function. Postmarketing
reports of respiratory insufficiency in patients receiving 10 mg of zolpidem
tartrate, most of whom had pre-existing respiratory impairment, have been
reported. The risk of respiratory depression should be considered prior to
prescribing AMBIEN in patients with respiratory impairment including sleep
apnea and myasthenia gravis.
Precipitation Of Hepatic Encephalopathy
Drugs affecting GABA receptors, such as zolpidem
tartrate, have been associated with precipitation of hepatic encephalopathy in patients
with hepatic insufficiency. In addition, patients with hepatic insufficiency do
not clear zolpidem tartrate as rapidly as patients with normal hepatic
function. Avoid AMBIEN use in patients with severe hepatic impairment as it may
contribute to encephalopathy [see DOSAGE AND ADMINISTRATION, Use In Specific
Populations, CLINICAL PHARMACOLOGY].
There have been reports of withdrawal signs and symptoms
following the rapid dose decrease or abrupt discontinuation of zolpidem.
Monitor patients for tolerance, abuse, and dependence [see Drug Abuse And Dependence].
Patient Counseling Information
Advise the patient to read the FDA-approved patient
Inform patients and their families about the benefits and
risks of treatment with AMBIEN. Inform patients of the availability of a
Medication Guide and instruct them to read the Medication Guide prior to
initiating treatment with AMBIEN and with each prescription refill. Review the
AMBIEN Medication Guide with every patient prior to initiation of treatment.
Instruct patients or caregivers that AMBIEN should be taken only as prescribed.
Complex Sleep Behaviors
Instruct patients and their families that AMBIEN may
cause complex sleep behaviors, including sleep-walking, sleep-driving,
preparing and eating food, making phone calls, or having sex while not being
fully awake. Serious injuries and death have occurred during complex sleep
behavior episodes. Tell patients to discontinue AMBIEN and notify their
healthcare provider immediately if they develop any of these symptoms [see BOXED
WARNING, WARNINGS AND PRECAUTIONS].
CNS-Depressant Effects And Next-Day Impairment
Tell patients that AMBIEN has the potential to cause next-day
impairment, and that this risk is increased if dosing instructions are not
carefully followed. Tell patients to wait for at least 8 hours after dosing
before driving or engaging in other activities requiring full mental alertness.
Inform patients that impairment can be present despite feeling fully awake.
Advise patients that increased drowsiness and decreased consciousness may
increase the risk of falls in some patients [see WARNINGS AND PRECAUTIONS].
Severe Anaphylactic And Anaphylactoid Reactions
Inform patients that severe anaphylactic and
anaphylactoid reactions have occurred with zolpidem. Describe the
signs/symptoms of these reactions and advise patients to seek medical attention
immediately if any of them occur [see WARNINGS AND PRECAUTIONS].
Tell patients to immediately report any suicidal
Alcohol And Other Drugs
Ask patients about alcohol consumption, medicines they
are taking, and drugs they may be taking without a prescription. Advise
patients not to use AMBIEN if they drank alcohol that evening or before bed.
Tolerance, Abuse, And Dependence
Tell patients not to increase the dose of AMBIEN on their
own, and to inform you if they believe the drug “does not work.”
Patients should be counseled to take AMBIEN right before
they get into bed and only when they are able to stay in bed a full night (7-8
hours) before being active again. AMBIEN tablets should not be taken with or
immediately after a meal. Advise patients NOT to take AMBIEN if they drank
alcohol that evening.
Advise patients to notify their healthcare provider if
they become pregnant or intend to become pregnant during treatment with AMBIEN.
Advise patients that use of AMBIEN late in the third trimester may cause
respiratory depression and sedation in neonates. Advise mothers who used AMBIEN
during the late third trimester of pregnancy to monitor neonates for signs of
sleepiness (more than usual), breathing difficulties, or limpness [see Use In
Advise breastfeeding mothers using AMBIEN to monitor
infants for increased sleepiness, breathing difficulties, or limpness. Instruct
breastfeeding mothers to seek immediate medical care if they notice these
signs. A lactating woman may consider pumping and discarding breastmilk during
treatment and for 23 hours after AMBIEN administration to minimize drug
exposure to a breastfed infant [see Use In Specific Populations].
Carcinogenesis, Mutagenesis, Impairment Of Fertility
Zolpidem was negative in in vitro (bacterial reverse
mutation, mouse lymphoma, and chromosomal aberration) and in vivo (mouse
micronucleus) genetic toxicology assays.
Impairment Of Fertility
Zolpidem was administered to rats at 4, 20, and 100 mg
base/kg/day, which are approximately 5, 25, and 120 times the MRHD of 10 mg/day
(8 mg zolpidem base) based on mg/m² body surface area, prior to and during
mating, and continuing in females through postpartum day 25. Zolpidem caused
irregular estrus cycles and prolonged precoital intervals at the highest dose
tested, which is approximately 120 times the MRHD based on mg/m² body surface
area. The NOAEL for these effects is 25 times the MRHD based on a mg/m² body
surface area. There was no impairment of fertility at any dose tested.
Use In Specific Populations
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 Considerations and 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
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%,
Fetal/Neonatal Adverse Reactions
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.
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.
Oral administration of zolpidem to pregnant rats during
the period of organogenesis at 4, 20, and 100 mg base/kg/day, which are
approximately 5, 25, and 120 times the maximum recommended human dose (MRHD) of
10 mg/day (8 mg zolpidem base) based on mg/m² body surface area, caused delayed
fetal development (incomplete fetal skeletal ossification) at maternally toxic
(ataxia) doses 25 and 120 times the MRHD based on mg/m² body 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 2.5, 10, and 40 times the MRHD of 10 mg/day (8 mg zolpidem base)
based on mg/m² body surface area caused embryo-fetal death and delayed fetal
development (incomplete fetal skeletal ossification) at a maternally toxic
(decreased body weight gain) dose 40 times the MRHD based on mg/m² body surface
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 5, 25, and 120 times the MRHD of 10 mg/day (8 mg zolpidem base)
based on mg/m² body surface area, delayed offspring growth and decreased
survival at doses 25 and 120 times, respectively, the MRHD based on mg/m² body
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 motherâ€™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.
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.
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].
Ten patients on zolpidem (7.4%) discontinued treatment due to an adverse
A total of 154 patients in U.S. controlled clinical
trials and 897 patients in non-U.S. clinical trials who received zolpidem were
≥60 years of age. For a pool of U.S. patients receiving zolpidem at doses
of ≤10 mg or placebo, there were three adverse reactions occurring at an
incidence of at least 3% for zolpidem and for which the zolpidem incidence was
at least twice the placebo incidence (i.e., they could be considered drug
A total of 30/1,959 (1.5%) non-U.S. patients receiving
zolpidem reported falls, including 28/30 (93%) who were ≥70 years of age.
Of these 28 patients, 23 (82%) were receiving zolpidem doses >10 mg. A total
of 24/1,959 (1.2%) non-U.S. patients receiving zolpidem reported confusion,
including 18/24 (75%) who were ≥70 years of age. Of these 18 patients, 14
(78%) were receiving zolpidem doses >10 mg.
The dose of AMBIEN in elderly patients is 5 mg to
minimize adverse effects related to impaired motor and/or cognitive performance
and unusual sensitivity to sedative/hypnotic drugs [see WARNINGS AND
Gender Difference In Pharmacokinetics
Women clear zolpidem tartrate from the body at a lower
rate than men. Cmax and AUC parameters of zolpidem were approximately 45%
higher at the same dose in female subjects compared with male subjects. Given
the higher blood levels of zolpidem tartrate in women compared to men at a
given dose, the recommended initial dose of AMBIEN for adult women is 5 mg, and
the recommended dose for adult men is 5 or 10 mg.
In geriatric patients, clearance of zolpidem is similar
in men and women. The recommended dose of AMBIEN in geriatric patients is 5 mg
regardless of gender.
The recommended dose of AMBIEN in patients with mild to
moderate hepatic impairment is 5 mg once daily immediately before bedtime.
Avoid AMBIEN use in patients with severe hepatic impairment as it may
contribute to encephalopathy [see DOSAGE AND ADMINISTRATION, WARNINGS
AND PRECAUTIONS, CLINICAL PHARMACOLOGY].
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