Included as part of the PRECAUTIONS section.
CNS Depressant Effects And Next-Day Impairment
Edluar, like other sedative-hypnotic drugs, has central
nervous system (CNS) depressant effects. Co-administration with other CNS
depressants (e.g., benzodiazepines, opioids, tricyclic antidepressants,
alcohol) increases the risk of CNS depression. Dosage adjustments of Edluar and
of other concomitant CNS depressants may be necessary when Edluar is
administered with such agents because of the potentially additive effects. The
use of Edluar with other sedativehypnotics (including other zolpidem products)
at bedtime or the middle of the night is not recommended [see DOSAGE AND
The risk of next-day psychomotor impairment, including
impaired driving, is increased if Edluar 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 co-administered with other CNS depressants; or if coadministered with
other drugs that increase the blood level of zolpidem. Patients should be cautioned
against driving and other activities requiring complete mental alertness if
Edluar is taken in these circumstances.
Need To Evaluate For Co-morbid 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 tartrate. 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 Edluar 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 zolpidem. 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 zolpidem tartrate 10 mg taken at bedtime, <1% of adults
with insomnia who received zolpidem reported hallucinations. In a clinical
trial, 7% of pediatric patients treated with zolpidem tartrate 0.25 mg/kg taken
at bedtime reported hallucinations, versus 0% treated with placebo [see Use In
Complex behaviors such as “sleep-driving” (i.e., driving
while not fully awake after ingestion of a sedative-hypnotic, with amnesia for
the event) have been reported in sedative-hypnotic-naÃ¯ve as well as in
sedative-hypnotic-experienced persons. Although behaviors such as
“sleep-driving” have occurred with zolpidem alone at therapeutic doses, the
co-administration of zolpidem with alcohol or other CNS depressants increases
the risk of such behaviors, as does the use of Edluar at doses exceeding the
maximum recommended dose. Due to the risk to the patient and the community,
discontinuation of Edluar should be strongly considered for patients who report
a “sleep-driving” episode.
Other complex behaviors (e.g., preparing and eating food,
making phone calls, or having sex) have been reported in patients who are not
fully awake after taking a sedative-hypnotic. As with “sleep-driving”, patients
usually do not remember these events. Amnesia, anxiety and other neuro-psychiatric
symptoms may also occur.
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 least amount of drug
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 time 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 Edluar is
prescribed to patients with compromised respiratory function. Post-marketing
reports of respiratory insufficiency in patients receiving 10 mg of zolpidem
tartrate, most of whom had pre-existing respiratory impairment, have been
reported. The risks of respiratory depression should be considered prior to
prescribing Edluar in patients with respiratory impairment including sleep
apnea and myasthenia gravis.
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
See FDA-approved patient
labeling (Medication Guide).
Inform patients and their
families about the benefits and risks of treatment with Edluar. Inform patients
of the availability of a Medication Guide and instruct them to read the
Medication Guide prior to initiating treatment with Edluar and with each
prescription refill. Review the Edluar Medication Guide with every patient
prior to initiation of treatment. Instruct patients or caregivers that Edluar
should be taken only as prescribed.
CNS-Depressant Effects And Next-Day
Tell patients that Edluar 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.
Severe Anaphylactic And Anaphylactoid
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.
Sleep-Driving And Other Complex
Instruct patients and their
families that sedative hypnotics can cause abnormal thinking and behavior
change, including “sleep-driving” and other complex behaviors while not being
fully awake (preparing and eating food, making phone calls, or having sex).
Tell patients to call you immediately if they develop any of these symptoms.
Tell patients to immediately
report any suicidal thoughts.
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 Edluar if they drank alcohol that
evening or before bed.
Tolerance, Abuse, And Dependence
Tell patients not to increase
the dose of Edluar on their own, and to inform you if they believe the drug
“does not work”.
Advise patients to notify their
healthcare provider if they become pregnant or intend to become pregnant during
treatment with Edluar. Advise patients that use of Edluar late in the third trimester
may cause respiratory depression and sedation in neonates. Advise mothers who
used Edluar during the late third trimester of pregnancy to monitor neonates
for signs of sleepiness (more than usual), breathing difficulties, or limpness [see
Use In Specific Populations].
Advise breastfeeding mothers
using Edluar to monitor infants for increased sleepiness, breathing difficulties,
or limpness. Instruct nursing 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 Edluar administration to
minimize drug exposure to a breastfed infant [see Use In Specific
Patients should be counseled to
take Edluar 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. Edluar tablets
should not be taken with or immediately after a meal. Advise patients NOT to
take Edluar when drinking alcohol that evening or before bed. Edluar sublingual
tablet should be placed under the tongue, where it will disintegrate. The
tablet should not be swallowed and the tablet should not be taken with water.
Impairment Of Fertility
Zolpidem was administered to
mice and rats for 2 years at oral doses of 4, 18, and 80 mg base/kg/day. In
mice, these doses are approximately 2.5, 10, and 50 times the maximum recommended
human dose (MRHD) of 10 mg/day (8 mg zolpidem base) based on mg/m² body surface
area and in rats, these doses are approximately 5, 20, and 100 times the MRHD
based on mg/m² body surface area. No evidence of carcinogenic potential was
observed in mice. In rats, renal tumors (lipoma, liposarcoma) were seen at the
mid and high doses.
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 maximum recommended human dose (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 identified a
drug-associated risk of 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 to 4% and 15 to 20%, respectively.
Fetal/Neonatal Adverse Reactions
Zolpidem crosses the placenta and may produce respiratory
depression and sedation in neonates. Monitor neonates exposed to Edluar 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 have not
identified a drug-associated risk of 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 intra-tracheal 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 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 surface
Limited data from published literature reports 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 Edluar and any potential adverse effects on the
breastfed infant from Edluar or from the underlying maternal condition.
Infants exposed to Edluar 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 Edluar administration in order to minimize drug exposure
to a breast fed infant.
Edluar is not recommended for use in children. Safety and
effectiveness in pediatric patients have not been established in pediatric
patients below the age of 18.
In an 8-week controlled study in 201 pediatric patients
(aged 6-17 years) with insomnia associated with attention-deficit/hyperactivity
disorder (ADHD), an oral solution of zolpidem tartrate dosed at 0.25mg/kg at
bedtime did not decrease sleep latency compared to placebo. Ten patients on
zolpidem (7.4%) discontinued treatment due to an adverse reaction.
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 reported in 7% of the pediatric patients who
received zolpidem; none of the pediatric patients who received placebo reported
hallucinations [see WARNINGS AND PRECAUTIONS].
A total of 154 patients in U.S. controlled clinical
trials and 897 patients in non-U.S. clinical trials who received oral zolpidem
were ≥60 years of age. For a pool of U.S. patients receiving zolpidem
tartrate at doses of ≤10 mg or placebo, there were three adverse events
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-related).
A total of 30/1,959 (1.5%) non-U.S. patients receiving
zolpidem tartrate 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 Edluar 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 DOSAGE AND
ADMINISTRATION, WARNINGS AND PRECAUTIONS, CLINICAL PHARMACOLOGY
and Clinical Studies].
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 dose of Edluar 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 Edluar in geriatric patients is 5 mg
regardless of gender.