Included as part of the PRECAUTIONS section.
CNS Depressant Effects And Next-Day Impairment
Intermezzo, 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 Intermezzo
and of other concomitant CNS depressants may be necessary when Intermezzo is
administered with such agents because of the potentially additive effects. The
use of Intermezzo with other sedative-hypnotics (including other zolpidem
products) at bedtime or the middle of the night is not recommended [see DOSAGE
In a driving study, healthy subjects who received
Intermezzo with fewer than four hours of bedtime remaining had evidence of
impaired driving compared to subjects who received placebo [see Clinical
Studies]. The risk of next-day driving impairment (and psychomotor
impairment) is increased if Intermezzo is taken with less than 4 hours of
bedtime remaining, if higher than recommended dose is taken, if co-administered
with other CNS depressants, or coadministered with other drugs that increase
the blood levels of zolpidem.
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 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 or anaphylaxis after treatment with zolpidem
should not be rechallenged with Intermezzo.
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 also 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 Specific Populations].
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-naive 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 and other CNS depressants increases
the risk of such behaviors, as does the use of zolpidem at doses exceeding the
maximum recommended dose. Due to the risk to the patient and the community,
discontinuation of Intermezzo 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.
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
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
Intermezzo 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 Intermezzo 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
Patient Counseling Information
See FDA-approved patient labeling (Medication Guide).
Inform patients and their families about the benefits and
risks of treatment with Intermezzo. Inform patients of the availability of a
Medication Guide and instruct them to read the Medication Guide prior to
initiating treatment with Intermezzo and with each prescription refill.
Review the Intermezzo Medication Guide with every patient
prior to initiation of treatment. Instruct patients or caregivers that
Intermezzo should be taken only as prescribed.
CNS Depressant Effects and Next-Day Impairment
Tell patients that Intermezzo 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 4 hours after dosing
and until they feel fully awake before driving or engaging in other activities
requiring full mental alertness.
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.
Sleep-driving and Other Complex Behaviors
Instruct patients to inform their families that zolpidem
has been associated with “ sleep-driving” and other complex behaviors while not
being fully awake (preparing and eating food, making phone calls, or having
sex), and tell patients and their families to call their healthcare providers
immediately if they develop any of these symptoms.
Tell patients to immediately report any suicidal
For detailed instructions on how to use Intermezzo, tell
patients to refer to the Patient Instructions for Use.
Tell patients that Intermezzo is to be taken only once per
night if needed if they wake in the middle of the night and have difficulty
returning to sleep. Tell patients that Intermezzo should only be taken if they
have 4 hours of bedtime remaining before the planned time of waking.
Instruct the patient to place the tablet under the
tongue, allowing it to disintegrate completely before swallowing. Tell the
patient that Intermezzo should not be swallowed whole. Tell patients that the
effect of Intermezzo may be slowed if taken with or immediately after a meal.
Instruct patients to remove the tablet from the unit-dose
pouch just prior to dosing. Advise patients NOT to take Intermezzo if they
drank alcohol that day or before bed.
Healthcare professionals can telephone Purdue Pharma's
Medical Services Department (1-888-726-7535) for information on this product.
Carcinogenesis, Mutagenesis, Impairment Of Fertility
Zolpidem was administered in the diet to rats and mice
for 2 years at doses of 4, 18, and 80 mg base/kg/day. In mice, these doses are
approximately 7, 30, and 140 times, respectively, the recommended human dose
(RHD) of 3.5 mg/day (approximately 2.8 mg zolpidem base) on a mg/m² basis.
In rats, these doses are approximately 15, 60, and 280 times, respectively, the
RHD on a mg/m² basis. 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
Oral administration of zolpidem (doses of 4, 20, and 100
mg base/kg/day) to rats prior to and during mating, and continuing in females
through postpartum day 25, resulted in irregular estrus cycles and prolonged
precoital intervals at the highest dose tested. The no-effect dose for these
findings is approximately 70 times the RHD on a mg/m² basis. There
was no impairment of fertility at any dose tested.
Use In Specific Populations
Pregnancy Category C
There are no adequate and well-controlled studies of
zolpidem in pregnant women. Studies in children to assess the effects of
prenatal exposure to zolpidem have not been conducted; however, cases of severe
neonatal respiratory depression have been reported when zolpidem was used at
the end of pregnancy, especially when taken with other CNS-depressants.
Children born to mothers taking sedative-hypnotic drugs may be at risk for
withdrawal symptoms during the postnatal period. Neonatal flaccidity has also
been reported in infants born to mothers who received sedative-hypnotic drugs
during pregnancy. Intermezzo should be used during pregnancy only if the
potential benefit outweighs the potential risk to the fetus.
Administration of zolpidem to pregnant rats and rabbits
resulted in adverse effects on offspring at doses greater than the recommended
human dose (RHD) of 3.5 mg/day (approximately 2.8 mg/day zolpidem base); however,
teratogenicity was not observed.
When zolpidem was administered at oral doses of 4, 20,
and 100 mg base/kg/day to pregnant rats during the period of organogenesis,
dose-related decreases in fetal skull ossification were observed at all but the
lowest dose, which is approximately 15 times the RHD on a mg/m² basis.
In rabbits treated during organogenesis with zolpidem at oral doses of 1, 4,
and 16 mg base/kg/day, increased embryo-fetal death and incomplete fetal skull
ossification were seen at the highest dose tested. The no-effect dose for
embryo-fetal toxicity in rabbits is approximately 30 times the RHD on a mg/m² basis. Administration of zolpidem to rats at oral doses of 4, 20, and 100
mg base/kg/day during the latter part of pregnancy and throughout lactation
produced decreased offspring growth and survival at all but the lowest dose,
which is approximately 15 times the RHD on a mg/m² basis.
Zolpidem is excreted in human milk. The effect of
zolpidem on the nursing infant is not known.
Intermezzo is not recommended for use in children. Safety
and effectiveness of Intermezzo have not been established in pediatric patients
below the age of 18.
In an 8-week study in pediatric patients (aged 6 to 17
years) with insomnia associated with ADHD, an oral solution of zolpidem
tartrate dosed at 0.25 mg/kg at bedtime did not decrease sleep latency compared
to placebo. Hallucinations were reported in 7% of the pediatric patients who
received zolpidem; none of the pediatric patients who received placebo reported
Intermezzo dosage adjustment is necessary in geriatric
patients. Sedating drugs may cause confusion and over-sedation in the elderly;
elderly patients generally should be started on low doses of Intermezzo and
observed closely [see DOSAGE AND ADMINISTRATION, and CLINICAL
Clinical trial experience with other zolpidem
formulations (5 mg to 10 mg oral zolpidem tartrate) given at bedtime:
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 oral
zolpidem tartrate 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 (see
Table 2: Adverse Reactions in Geriatric Patients in
Pooled Trials of 5 mg to 10 mg of Oral Zolpidem Tartrate Given at Bedtime
||5 to 10 mg Oral Zolpidem tartrate
Falls in Geriatric Patients
A total of 30/1,959 (2%) non-U.S. patients receiving
other zolpidem formulations (5 mg to 10 mg oral zolpidem tartrate) reported
falls, including 28/30 (93%) who were ≥ 70
years of age. Of these 28 patients, 23 (82%) were receiving zolpidem tartrate doses
> 10 mg. A total of 24/1,959 (1%) 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 tartrate doses > 10 mg.
The dose of Intermezzo in
elderly patients is 1.75 mg to minimize adverse effects related to impaired
motor and/or cognitive performance and unusual sensitivity to sedative-hypnotic
Gender Difference In Pharmacokinetics
Women cleared zolpidem tartrate
from the body after sublingual administration of a 3.5 mg dose of Intermezzo at
a lower rate than men (2.7 mL/min/kg vs. 4.0 mL/min/kg). 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
Intermezzo for women is 1.75 mg, and the recommended dose for adult men is 3.5