>I wish I had more info on Ambien (Zolpidem).

zolpidem  / Ambien(R)
SEDATIVE / Sleeping

Description: Zolpidem tartrate is a non-benzodiazepine sedative-hypnotic fo=
r
the short-term treatment of insomnia. Although chemically unrelated to othe=
r
hypnotics such as the benzodiazepines or barbiturates, zolpidem does share
some pharmacological actions with these drugs. Unlike the benzodiazepines,
zolpidem produces muscle relaxation and anticonvulsant effects only at dose=
s
much higher than the hypnotic dose. Zolpidem has a short half-life and no
active metabolites. This reduces the possibility of residual next-day
effects from excessive sedation, and CNS depression with impairment of
cognitive and motor function, commonly seen with barbiturates or long-actin=
g
benzodiazepines in the treatment for insomnia. A next-day "hangover" effect
and CNS depression are less for zolpidem than the barbiturates. Zolpidem ha=
s
a rapid onset of action and should only be taken immediately before
retiring. Treatment of insomnia with zolpidem should be restricted to a
period of 7-10 days. Rebound insomnia or signs of withdrawal have not been
significantly greater than placebo after discontinuation of treatment when
zolpidem was administered at the recommended dose of 10 mg. Zolpidem
received FDA approval in 1993.

Mechanism of Action: Zolpidem tartrate is highly specific for the
gamma-aminobutyric acid (GABA)-chloride channel complex within type 1
benzodiazepine receptors in the CNS. Benzodiazepines, in contrast, bind als=
o
to type 2 and peripheral type 3 benzodiazepine receptors. The selectivity o=
f
zolpidem for the type 1 receptor may explain its lack of muscle relaxant,
anticonvulsant, and anxiolytic effects, relative to the benzodiazepines.
Zolpidem induces sedation by modulation of the actions of GABA. The site of
action is located within the GABA-A receptor complex on the =F0 subunit, whic=
h
is known as the benzodiazepine (BZ) or omega receptor. The omega receptor
can be subdivided into at least three types, and the omega-1 receptor has
been identified as the site of action of zolpidem. Flumazenil, a
benzodiazepine antagonist, can also antagonize the sedative actions of
zolpidem. Zolpidem appears to modestly reduce time spent in REM sleep,
however, no conclusions can be made regarding the dose-response nature of
this effect.=A5

Nonspecific modulation of the GABA-A receptor chloride channel
macromolecular complex are thought to be responsible for sedative,
anticonvulsant, anxiolytic, and myorelaxant properties. GABA mediates the
inhibitory actions of local interneurons in the brain. Inhibition of the
GABA-ergic pathways may be partially responsible for reduced muscle
hypertonia and spread of seizure activity.

Pharmacokinetics: Zolpidem is administered orally and is rapidly absorbed
from the GI tract. The presence of food reduces the amount of absorption an=
d
increases the time taken to achieve maximum concentration, delaying sleep
onset slightly. Zolpidem pharmacokinetics follow a linear profile in the
dosage range 5-20 mg. Pharmacokinetic parameters in patients with end-stage
renal failure undergoing hemodialysis, are not significantly different from
healthy patients. Zolpidem is about 92% bound to plasma protein.

Metabolism produces inactive metabolites that are primarily excreted in the
urine. The elimination half-life is about 2.6 hours in patients with normal
hepatic and renal function. The mean half-life in healthy patients is 2.2
hours, increased to 2.9 hours in elderly patients and to 9.9 hours for thos=
e
with chronic hepatic impairment, allowing use of reduced dosage in the
elderly and hepatically impaired. Zolpidem is not removed by hemodialysis.
Patients with hepatic insufficiency do not clear the drug as rapidly as
normals.

CONTRAINDICATIONS/PRECAUTIONS:
Zolpidem is only recommended for use in the short-term treatment of
insomnia. Problems associated with abrupt discontinuation of hypnotic drugs
are more likely to occur following chronic therapy. There is no reliable
data documenting the occurrence of withdrawal symptoms following
discontinuation of zolpidem, but evidence of fatigue, nausea/vomiting,
flushing, lightheadedness, inconsolable crying, stomach cramps, panic
attack, nervousness, and abdominal discomfort may constitute a withdrawal
syndrome. Withdrawal of some hypnotics also precipitates a rebound insomnia=
.
If therapy is continued for more than 2 weeks the possibility of a
withdrawal syndrome should be considered and abrupt discontinuation of
therapy avoided. The possibility of physical and psychological dependence t=
o
zolpidem requires close monitoring. Zolpidem should be used cautiously in
patients with a history of substance abuse.

Sleep disturbance may indicate an underlying physical or psychiatric
problem. Thus, zolpidem should be used cautiously in patients with major
depression. These patients may become more susceptible to suicidal ideation=
.

Elderly and/or debilitated patients may be more sensitive to the effects of
zolpidem. The impairment of cognitive and motor function may be more marked
in this patient group and lower initial dosage is recommended together with
close monitoring.

Zolpidem should be administered cautiously to patients with severe hepatic
disease because the elimination half-life of the drug can be prolonged, wit=
h
possible resultant toxicity. Patients with hepatic disease should receive a
lower initial dosage to avoid adverse CNS reactions.

Zolpidem is classified as pregnancy category B. Animal studies have shown n=
o
evidence of teratogenicity. However lack of information on the effects of
zolpidem in pregnant women precludes its use unless clearly needed. There i=
s
some risk that babies born to mothers taking sedatives may suffer withdrawa=
l
symptoms and possible neonatal flaccidity. Small amounts of zolpidem are
excreted into breast milk. Since the effects on the infant have not been
evaluated, the use of zolpidem in breast-feeding women is not recommended.

Safe use of zolpidem in children under age 18 years has not been evaluated.

Zolpidem should be used with caution in patients with pre-existing
respiratory depression, pulmonary disease such as severe COPD (chronic
obstructive pulmonary disease), or sleep apnea to avoid the risk of
depressing ventilatory function.

Although evidence to date does not indicate any need to use lower doses of
zolpidem in patients with renal disease, chronic renal impairment may reduc=
e
clearance of zolpidem. These patients should be closely monitored for drug
accumulation and changes in pharmacokinetic parameters.

DRUG INTERACTIONS:
Evidence of drug interactions between zolpidem and other CNS agents is
limited. Some single-dose interactions have been studied but reactions may
differ during chronic therapy. Single-dose results indicate that haloperido=
l
has no effect on the pharmacokinetics or pharmacodynamics of zolpidem.
Ethanol has an additive effect on psychomotor performance when given with
zolpidem. Other CNS depressant drugs may have cumulative effects when
administered concurrently and they should be used cautiously with zolpidem.

Zolpidem reduced peak serum concentrations of imipramine by 20%, but other
pharmacokinetic parameters were not affected. Loss of alertness was
exacerbated when the drugs were administered concurrently. Interactions wit=
h
other tricyclic antidepressants have not been studied, but additive
drowsiness is also possible. Chlorpromazine and zolpidem together produced
no change in pharmacokinetic parameters, but had an additive effect on loss
of mental alertness and psychomotor function. Concurrent use of zolpidem
with chlorpromazine or other phenothiazines should be undertaken with
caution.

Flumazenil, a benzodiazepine antagonist, can reverse the sedative/hypnotic
effects of zolpidem. Flumazenil and zolpidem are pharmacological opposites.
Thus, this represents a pharmacodynamic interaction and not a
pharmacokinetic one.

Some studies of possible interaction between zolpidem and other drugs have
been undertaken. Cimetidine or ranitidine did not affect the
pharmacokinetics or pharmacodynamics of zolpidem. Concurrent use of digoxin
showed no effect on the pharmacokinetics of digoxin or zolpidem. Concurrent
use of zolpidem with warfarin did not affect prothrombin time. Long term
studies have not been undertaken and concurrent use of any drug during
chronic therapy may produce different results.

ADVERSE REACTIONS:
Most of the adverse effects associated with zolpidem therapy are
dose-dependent and CNS-related. The most frequently reported are headache,
drowsiness, dizziness, amnesia, lethargy and a drugged feeling, although in
one study of elderly volunteers, headache was reported by equal numbers of
subjects taking placebo as those taking 20 mg doses of zolpidem.=A5 According
to the manufacturer, the incidence of headache, dizziness, drowsiness, and
diarrhea were greater for zolpidem (short-term treatment with up to 10
mg/day) as compared to placebo. During long-term (28-35 nights) treatment
with doses up to 10 mg/day, the only adverse effects that were significantl=
y
different from placebo were dizziness and drugged feelings. Symptoms of CNS
stimulation including euphoria, hallucination, agitation, nightmares and
hyperactivity are paradoxical effects that can occur with zolpidem therapy.
If there is evidence of CNS stimulation zolpidem should be discontinued.

Gastrointestinal adverse events resulting from zolpidem use also appear to
be dose related, most commonly observed were diarrhea and nausea/vomiting.
Dyspepsia and constipation have been reported.

Sedatives and hypnotics have been implicated in producing signs of
withdrawal following abrupt discontinuation of treatment. Reliable
determinations regarding possible drug dependancy on zolpidem have not been
undertaken. There is some evidence that symptoms of fatigue,
nausea/vomiting, flushing, lightheadedness, inconsolable crying, stomach
cramps, panic attack, nervousness, and abdominal discomfort that may
constitute a withdrawal syndrome. Drug dependency may be related to dosage
and duration of treatment. A dosage-tapering schedule may be adopted if dru=
g
dependency is suspected. Withdrawal of some hypnotics can precipitate a
rebound insomnia and elderly patients may be more susceptible to sleep
impairment following discontinuation of therapy, especially at doses above =
5
mg of zolpidem.

PATIENT INFORMATION:
What do zolpidem tablets do?
ZOLPIDEM (Ambien(R)) helps to relieve insomnia (sleeplessness) which can be=
:
trouble falling asleep, waking up too early in the morning, or waking up to=
o
often during the night. Zolpidem helps people with temporary sleep problems
and should not be taken for long periods, except on your doctor's advice.
Zolpidem belongs to a group of medicines known as sedatives/hypnotics.
Federal law prohibits the transfer of zolpidem to any person other than the
patient for whom it was prescribed. Do not share your medicine with anyone
else. Generic zolpidem tablets are not yet available.

What should my doctor, dentist, or pharmacist know before I take zolpidem?
They need to know if you have any of these conditions:
*an alcohol or drug abuse problem
*liver disease
*lung or respiratory disease (breathing difficulties)
*mental depression
*an unusual or allergic reaction to zolpidem, other medicines, foods, dyes,
or preservatives
*breast-feeding

How should I take this medicine?
Take zolpidem tablets by mouth. Follow the directions on the prescription
label. Swallow the tablets with a drink of water. It is better to take
zolpidem on an empty stomach (without food) and only when you are ready for
bed. Do not take your medicine more often than directed.

Special precautions for use in children: This medicine is not for children
under 18 years old.

Elderly patients over age 65 years may have a stronger reaction to this
medicine and need smaller doses.

What if I miss a dose?
This does not apply. Zolpidem should only be taken immediately before
getting into bed (or in bed). Do not take double or extra doses.
What other medicines can interact with zolpidem?
*alcohol
*flumazenil

Tell your doctor or pharmacist: about all other medicines you are taking,
including non-prescription medicines; if you are a frequent user of drinks
with caffeine or alcohol; if you smoke; or if you use illegal drugs. These
may affect the way your medicine works. Check before stopping or starting
any of your medicines.

What side effects may I notice from taking zolpidem?
Serious side effects with zolpidem include:
*lightheadedness or fainting spells
*confusion
*hallucinations (seeing, hearing, or feeling things that are not really
there)
*mental depression
*slurred speech
*unusual weakness
*staggering, tremors
*blurred vision
*hostility, restlessness, excitability
Call your doctor as soon as you can if you get any of these side effects.

Minor side effects with zolpidem include:
*dizziness, drowsiness "hangover" effect
*nightmares
*stomach upset
*diarrhea
*loss of memory
Let your doctor know about these side effects if they do not go away or if
they annoy you.

What do I need to watch for while I take zolpidem?
Visit your doctor for regular checks on your progress. If sleep medicine is
taken every night for a long time it may no longer help you to sleep. In
most cases zolpidem should only be taken for a few days and for not longer
than 1 or 2 weeks. Consult your doctor if you still have difficulty in
sleeping. If you have been taking zolpidem regularly and suddenly stop
taking it, you may get unpleasant withdrawal symptoms. Your doctor may want
to gradually reduce the dose. Do not stop taking except on your doctor's
advice. After you stop taking zolpidem you may get rebound insomnia. This
means that for a few nights you may have trouble sleeping, but this usually
goes away after 1 or 2 nights.

You may get drowsy or dizzy. Do not drive, use machinery, or do anything
that needs mental alertness until you know how zolpidem affects you. To
reduce dizzy or fainting spells, do not sit or stand up quickly, especially
if you are an older patient. Alcohol can increase possible unpleasant
effects. Avoid alcoholic drinks.

If you are going to have surgery, tell your doctor or dentist that you are
taking zolpidem.

Ronald Vetter  1936, dz PD 1984, carbidopa/levodopa, Mirapex, selegiline
[log in to unmask]     Ridgecrest, California
http://www.ridgecrest.ca.us/~rfvetter