Product Information – Australia

APO-ZOLPIDEM TABLETS

WARNING: Zolpidem may be associated with potentially dangerous complex sleep-related

behaviours which may include sleep walking, sleep driving and other bizarre behaviours. Zolpidem
is not to be taken with alcohol. Caution is needed with other CNS depressant drugs. Limit use to
four weeks maximum under close medical supervision.

NAME OF THE MEDICINE

Zolpidem tartrate

Chemical Name: (bis[N,N-dimethyl-2-[6-methyl-2-(4-methylphenyl)imidazo[1,2-a]pyridin-3-

yl]acetamide] (2R,3R)-2,3-dihydroxybutanedioate).

Structural Formula:

Molecular Formula: C42H48N6O8

Molecular Weight: 764.9

CAS Registry Number: 99294-93-6 (zolpidem tartrate)

82626-48-0 (zolpidem)

DESCRIPTION
Zolpidem tartrate is a white to off white colourless, crystalline powder, slightly soluble in water.

Each tablet contains Zolpidem tartrate as the active ingredient. In addition, each tablet contains the
following inactive ingredients:
Microcrystalline cellulose, sodium starch glycollate, magnesium stearate, hypromellose, hyprolose,
macrogol 8000, iron oxide red (CI77491) (5 mg only) and titanium dioxide.

PHARMACOLOGY
Pharmacological Actions
Zolpidem belongs to the imidazopyridine group of compounds and is structurally unrelated to other hypnotic
agents. Zolpidem selectively binds the omega-1 receptor subtype (also known as the benzodiazepine-1
subtype) which is the alpha unit of the GABA-A receptor complex.

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Whereas benzodiazepines non-selectively bind all three omega receptor subtypes, zolpidem preferentially
binds the omega-1 subtype. The modulation of the chloride anion channel via this receptor leads to the
specific sedative effects demonstrated by zolpidem, i.e. the preservation of deep sleep (stages 3 and 4
slow wave sleep).

These effects are reversed by the benzodiazepine antagonist flumazenil.

In animals, the selective binding of zolpidem to omega-1 receptors may explain the virtual absence at
hypnotic doses of myorelaxant and anticonvulsant effects in animals which are normally exhibited by
benzodiazepines which are not selective for omega-1 sites.

In humans the preservation of deep sleep (stages 3 and 4 slow wave sleep) may be explained by the
selective omega-1 binding by zolpidem. All identified effects of zolpidem are reversed by the
benzodiazepine antagonist flumazenil.

Pharmacokinetics
Absorption
Zolpidem has both a rapid absorption and onset of hypnotic action.

Peak plasma concentration is reached at between 0.5 and 3 hours.

Following oral administration, bioavailability is 70% due to a moderate first-pass metabolism.

The elimination half-life is short, with a mean value of 2.4 hours (+/- 0.2 h) and a duration of action of up to
6 hours.

Zolpidem pharmacokinetic profile is linear in the therapeutic dose range, and is not modified upon repeated
administration.

Distribution
Protein binding amounts to approximately 90%. The distribution volume in adults is 0.54 ± 0.02 L/kg and
decreases to 0.34 ± 0.05 L/kg in the very elderly.

Metabolism
The main cytochrome P450 enzyme involved in the hepatic biotransformation of zolpidem is CYP3A4.
CYP1A2 and CYP2D6 contribute minimally to the metabolism of zolpidem (see INTERACTIONS WITH
OTHER MEDICINES).

Excretion
All metabolites are pharmacologically inactive and are eliminated in the urine (56%) and in the faeces
(37%). Furthermore, they do not interfere with zolpidem plasma binding.

Effect of Food
A food effect study in 30 healthy male volunteers compared the pharmacokinetics of zolpidem 10 mg when
administered while fasting or 20 minutes after a meal. Results demonstrated that with food, mean AUC and
Cmax were decreased by 15 and 25%, respectively, while mean Tmax was prolonged by 60% (from 1.4 to
2.2 hours). The half-life remained unchanged. These results suggest that, for faster sleep onset, zolpidem
tablets should not be administered with or immediately after a meal.

Special Populations
Zolpidem did not accumulate in young adults following nightly dosing with zolpidem tartrate 20 mg tablets
for two weeks.

In the elderly, the recommended dose for zolpidem is 5 mg (see PRECAUTIONS, DOSAGE AND
ADMINISTRATION). This recommendation is based on several studies in which the mean Cmax, T1/2 and
AUC were significantly increased when compared to results in young adults.

Zolpidem did not accumulate in elderly subjects following nightly oral dosing of 10 mg for 1 week.

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The pharmacokinetics of zolpidem in eight patients with chronic hepatic insufficiency were compared to
results in healthy subjects. Following a single oral zolpidem 20 mg dose, mean Cmax and AUC were found
to be two times (250 versus 499 ng/mL) and five times (788 versus 4,203 ng.hr/mL) higher, respectively, in
hepatically compromised patients. Tmax did not change. The mean half-life in cirrhotic patients of 9.9 hours
(range 4.1 to 25.8 hours) was greater than that observed in normals of 2.2 hours (range 1.6 to 2.4 hours).
Dosing should be modified accordingly in patients with hepatic insufficiency (see PRECAUTIONS and
DOSAGE AND ADMINISTRATION).

In patients with renal insufficiency, whether dialysed or not, there is a moderate reduction in clearance. The
other pharmacokinetic parameters are unaffected. Zolpidem has been shown to be non-dialysable.

CLINICAL TRIALS
Insomnia in Non-Elderly Adults
Short-term (1 to 2 nights) placebo controlled studies in 620 volunteers showed that zolpidem 2.5 to
10 mg decreased the latency of persistent sleep in a dose dependent manner. No further increase in
efficacy was seen in doses up to zolpidem 40 mg.

The efficacy of zolpidem 2.5 to 20 mg was investigated in 11 placebo controlled studies in 1,606
(513 received zolpidem 10 mg) non-elderly insomniacs over a period of 2 to 35 nights. Zolpidem
10 mg was superior to placebo using both objective (polysomnography) and subjective methods of
assessment. Zolpidem 20 mg showed little increase in efficacy.

Insomnia in the Elderly

Four studies in 145 elderly (> 65 years) patients showed, using objective (2 studies) and subjective
(4 studies) methods of assessment, that zolpidem 5 mg was the dose giving the optimum efficacy/ safety
ratio.

Next Day Residual Effects

There was no evidence of residual next day effects seen with zolpidem in several studies utilising the
Multiple Sleep Latency Test (MSLT), the Digit Symbol Substitution Test (DSST), and patient ratings of
alertness. In one study involving elderly patients, there was a small but statistically significant decrease in
one measure of performance, the DSST, but no impairment was seen in the MSL T in this study.

Rebound Effects
Although there were no studies to exclude this effect, there was no objective (polysomnographic) evidence
of rebound insomnia at recommended doses seen in studies evaluating sleep on the nights following
discontinuation of zolpidem. There was subjective evidence of impaired sleep in the elderly on the first post-
treatment night at doses above the recommended elderly dose of 5 mg.

Memory Impairment
Two small studies (n = 6 and n = 9) using objective measures of memory yielded little evidence for memory
impairment following the administration of zolpidem. There was subjective evidence from adverse event
data for anterograde amnesia occurring in association with the administration of zolpidem, predominantly
at doses above 10 mg.

Effects on Sleep Stages

In studies that measured the percentage of sleep time spent in each sleep stage, zolpidem has generally
been shown to preserve sleep stages. Sleep time spent in stages 3 and 4 (deep sleep) was found
comparable to placebo with only inconsistent, minor changes in REM (paradoxical) sleep at the
recommended dose.

The hypnotic efficacy and safety of Zolpidem has not been assessed in children and pregnant women.

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INDICATIONS
APO- Zolpidem tablets are indicated for the short term treatment of insomnia in adults (see DOSAGE AND
ADMINISTRATION).

CONTRAINDICATIONS
 Sleep apnoea.
 Known hypersensitivity to zolpidem or other ingredients in the tablet.
 Myasthenia gravis.
 Severe hepatic insufficiency.
 Acute and/or severe pulmonary insufficiency.
 Prior or concomitant intake with alcohol.
 Zolpidem should not be prescribed for children under 18 years of age.

PRECAUTIONS
The cause of insomnia should be identified wherever possible and the underlying factors treated before a
hypnotic is prescribed.

The failure of insomnia to remit after a 7 to 14 day course of treatment may indicate the presence of a
primary psychiatric or physical disorder, and the patient should be carefully re-evaluated at regular intervals.

Withdrawal, Rebound, Dependence and Tolerance

Tolerance
Continuous long-term use of zolpidem is not recommended and should not exceed four weeks.

Some loss of efficacy to the hypnotic effects of sedative/ hypnotic agents may develop after repeated use
for a few weeks.

Dependence
Use of sedative/hypnotic agents may lead to the development of physical and psychological dependence.
The risk of dependence increases with dose and duration of treatment; it is also greater in patients with a
history of psychiatric disorders and/or alcohol or drug abuse. These patients should be under careful
surveillance when receiving hypnotics.

Once physical dependence has developed, abrupt termination of treatment will be accompanied by
withdrawal symptoms. These may consist of headaches or muscle pain, extreme anxiety and tension,
restlessness, confusion and irritability. In severe cases the following symptoms may occur: derealisation,
depersonalisation, hyperacusis, numbness and tingling of the extremities, hypersensitivity to light, noise
and physical contact, hallucinations or epileptic seizures.

Rebound Insomnia
A transient syndrome whereby the symptoms that led to treatment with sedative/hypnotic agents recur in
an enhanced form may occur on withdrawal of hypnotic treatment. It may be accompanied by other
reactions including mood changes, anxiety and restlessness.

It is important that the patient should be aware of the possibility of rebound phenomena, thereby minimising
anxiety over such symptoms should they occur when the medicinal product is discontinued.

There are indications that, in the case of sedative/hypnotic agents with a short duration of action, withdrawal
phenomena can manifest within the dosage interval, especially when the dosage is high.

When zolpidem is used in accordance with the recommendations for dosage, duration of treatment and
warnings, the risk of withdrawal symptoms or rebound phenomena occurring is minimal.

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Severe injuries
Due to its pharmacological properties, zolpidem can cause drowsiness and a decreased level of
consciousness, which may lead to falls and consequently to severe injuries

Patients with Long QT syndrome

An in vitro cardiac electrophysiological test showed that under experimental conditions, using very high
concentration and pluripotent stem cells, zolpidem may reduce the hERG related potassium currents. As a
precaution, the benefit/risk ratio of zolpidem treatment in patients with known congenital long QT syndrome
should be carefully considered.

CNS Effects
As with all patients taking CNS-depressant medications, patients receiving zolpidem should be warned not
to operate dangerous machinery or motor vehicles until it is known that they do not become drowsy or dizzy
from zolpidem therapy. Patients should be advised that their tolerance for other CNS depressants will be
diminished and that these medications should either be eliminated or given in reduced dosage in the
presence of zolpidem. Prior or concomitant intake with alcohol is contraindicated (see
CONTRAINDICATIONS).

Respiratory Function
Both animal and human pharmacology studies performed with zolpidem have not observed any effect on
the respiratory centre. However, as other sedative/hypnotics have the capacity to depress respiratory drive,
caution is advised when zolpidem is administered to patients with respiratory insufficiency (see
CONTRAINDICATIONS).

Use in the Elderly or Debilitated Patient

Elderly and debilitated patients may be particularly sensitive to the effects of zolpidem, therefore a 5 mg
dose is recommended. This dose should not be exceeded in these patients (see DOSAGE AND
ADMINISTRATION).

Hepatic Impairment
As clearance and metabolism of zolpidem is reduced in hepatic impairment, dosage should begin at
5 mg with particular caution being exercised in elderly patients. In adults (under 65 years) dosage may be
increased to 10 mg only where the clinical response is inadequate and the drug is well tolerated (see
PRECAUTIONS, Use in the Elderly and DOSAGE AND ADMINISTRATION). Zolpidem must not be used
in patients with severe hepatic impairment as it may contribute to encephalopathy.

Renal Impairment
Dosage reduction is not necessary in patients with renal impairment, however, as a general precaution,
these patients should be monitored closely (see DOSAGE AND ADMINISTRATION).

Memory Impairment
Sedative/hypnotic agents may induce anterograde amnesia. The condition occurs most often several hours
after ingesting the product and therefore to reduce the risk patients should ensure that they will be able to
have an uninterrupted sleep of 7 to 8 hours.

Suicidality, Depression, Psychosis and Schizophrenia

Several epidemiological studies show an increased incidence of suicide and suicide attempt in patients
with or without depression, treated with benzodiazepines and other hypnotics, including zolpidem.
Zolpidem is not recommended as primary therapy in patients with depression and psychosis. In such
conditions, psychiatric assessment and supervision are necessary as depression may increase in some
patients and may contribute to deterioration in severely disturbed schizophrenics with confusion and
withdrawal. Pre-existing depression may be unmasked during the use of zolpidem. Suicidal tendencies
may be present or uncovered 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 anyone time.

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Other Psychiatric and Paradoxical Reactions

Other psychiatric and paradoxical reactions such as acute rage, restlessness, insomnia exacerbated,
agitation, irritability, aggression, delusions, anger, nightmares, hallucinations, stimulation or excitement,
abnormal behaviour and other adverse behavioural effects are known to occur when using
sedative/hypnotic agents like zolpidem. Should such reactions occur, zolpidem should be discontinued.
These reactions are more likely to occur in the elderly.

Somnambulism and Associated Behaviours

Sleep walking and other associated behaviours such as "sleep driving", preparing and eating food, making
phone calls or having sex, with amnesia for the event, have been reported in patients who had taken
zolpidem and were not fully awake. The use of alcohol and other CNS depressants with zolpidem appears
to increase the risk of such behaviours, as does the use of zolpidem at doses exceeding the maximum
recommended dose. Discontinuation of zolpidem should be strongly considered for patients who report
such behaviours (for example, sleep driving) due to the risk to the patient and others (see INTERACTIONS
WITH OTHER MEDICINES and ADVERSE EFFECTS). These events can occur in sedative-hypnotic
naive as well as sedative-hypnotic experienced patients.

Psychomotor Impairment
The risk of psychomotor impairment, including impaired driving ability, is increased if zolpidem is
taken within less than 7-8 hours before performing activities that require mental alertness, a dose higher
than the recommended dose is taken, or zolpidem is co-administered with other CNS depressants,
alcohol, or with other drugs that increase the blood levels of zolpidem.

Interactions with Alcohol

Prior or concomitant intake with alcohol is contraindicated (see CONTRAINDICATIONS). Patients should
be advised that their tolerance for alcohol and other CNS depressants might be reduced and have an
additive effect on psychomotor performance (see PRECAUTIONS, Somnambulism and Associated
Behaviours, above).

Severe Anaphylactic and Anaphylactoid Reactions

Rare 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 dyspnoea, throat closing, or nausea and vomiting that suggest anaphylaxis. Some
patients have required medical therapy in the emergency department. If angioedema involves the tongue,
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.

Epilepsy
Abrupt withdrawal of CNS-depressant drugs in persons with convulsive disorders has been associated with
a temporary increase in the frequency and/or severity of seizures.

As with other sedative/hypnotics, caution is advised when zolpidem is used in these patients.

Abuse
Caution must be exercised in administering zolpidem to individuals known to be addiction prone or those
whose history suggests they may increase the dosage on their own initiative. It is desirable to limit repeat
prescription without adequate medical supervision.

Effects on Ability to Drive and Use Machinery

This preparation is to aid sleep. Patients should not drive or operate machinery for 8 hours after taking
zolpidem.

Adverse effects including drowsiness, prolonged reaction time, dizziness, sleepiness, blurred/double vision,
reduced alertness and/or impaired driving may continue the following day. In order to minimise this risk a
full night of sleep (7-8 hours) is recommended. After ingesting the medicine, patients should be cautioned
against engaging in hazardous occupations requiring complete mental alertness or motor co-ordination
such as operating machinery or driving a motor vehicle, including potential impairment of the performance
of such activities that may occur the day following ingestion of zolpidem. Furthermore, the co- administration

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of zolpidem with alcohol and other CNS depressants increases the risk of such effects. Patients should be
warned not to use alcohol or other psychoactive substances when taking zolpidem.

Genotoxicity
Zolpidem was not genotoxic in assays for gene mutations (Salmonella typhimurium histidine reversion
assay, L5178Y mouse lymphoma assay), for chromosomal aberrations (human lymphocytes, mouse
micronucleus assay) and for DNA repair assays (in human fibroblasts and rat hepatocytes). The mutagenic
activity of zolpidem and/or its metabolites was equivocal in a Chinese hamster V79/HRPT gene mutation
assay in the presence of metabolic activation.

Carcinogenicity
Two year dietary carcinogenicity studies on zolpidem were conducted in rats and mice. No evidence of
carcinogenic potential was observed in mice at plasma concentrations (AUC) of zolpidem and its major
human metabolite of about 2 and 7-12 times, respectively, the anticipated clinical exposure at the maximum
recommended clinical dose. An increased incidence of renal liposarcomas was observed in male rats (6%
cf. 0 in controls) at plasma concentrations (AUC) of zolpidem and its major metabolite of at least 22 and 9
times, respectively, the anticipated human exposure.

Use in Pregnancy (Category B3)

Category B3 Definition: Drugs which have been taken by only a limited number of pregnant women and
women of childbearing age, without an increase in the frequency of malformation or other direct or indirect
harmful effects on the human fetus having been observed. Studies in animals have shown evidence of an
increased occurrence of fetal damage, the significance of which is considered uncertain in humans. As a
precautionary measure, it is preferable to avoid the use of zolpidem in pregnancy.

Teratogenic Effects
In reproductive toxicity studies, rats treated with oral zolpidem with estimated exposures (AUC) to zolpidem
and its major metabolite of 41 and 15 times, respectively, the anticipated clinical exposure did not exhibit
teratogenic effects but post-implantation survival index and postpartum viability of the offspring were
significantly reduced. In rats, delayed ossification of foetal skull bones occurred at zolpidem and metabolite
exposure levels of 8 and 3 times, respectively, the anticipated clinical exposure.

Rabbits treated with oral zolpidem with estimated exposure to zolpidem of 0.6-2.6 times the anticipated
clinical exposure did not exhibit teratogenic effects, but there was increased post-implantation loss.

Although animal studies have not shown any teratogenic effects with zolpidem, the safety of zolpidem in
human pregnancy has not been established.

Non-Teratogenic Effects
Cases of severe neonatal respiratory depression have been reported when zolpidem was used with other
CNS depressants at the end of pregnancy.

Infants born to mothers who took hypnotics chronically during the latter stages of pregnancy may have
developed physical dependence and may be at some risk for developing withdrawal symptoms in the
postnatal period.

Use in Lactation
The use of zolpidem in nursing women is not recommended as small quantities of zolpidem are excreted
into breast milk.

Paediatric Use
The use of zolpidem in children under 18 years is contraindicated.

Use in the Elderly or Debilitated

Such patients may be particularly susceptible to the sedative effects of the medication and associated
giddiness, ataxias and confusion, which may increase the possibility of a fall.

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INTERACTIONS WITH OTHER MEDICINES

Central Nervous System Depressants
Coadministration of Zolpidem with other CNS depressants should be exercised with caution since the
central depressant effect may be additive. CNS depressants include alcohol, benzodiazepines,
barbiturates, sedative/hypnotics, anxiolytics, tricyclic antidepressants, MAOIs, antipsychotics,
phenothiazines, skeletal muscle relaxants, antihistamines, neuroleptics, antiepileptic drugs, narcotic
analgesics or anaesthetics. Concomitant use of zolpidem with these drugs may increase drowsiness and
psychomotor impairment, including impaired driving ability. In the case of narcotic analgesics enhancement
of euphoria may also occur.

Alcohol
Prior or concomitant intake with alcohol is contraindicated (see CONTRAINDICATIONS).

Patients should be advised that their tolerance for alcohol and other CNS depressants might be reduced
and have an additive effect on psychomotor performance. The use of alcohol and other CNS depressants
with zolpidem appears to increase the risk of somnambulism and associated behaviours (see
PRECAUTIONS, Somnambulism and Associated Behaviours).

Imipramine
The sedative effects of imipramine 75 mg and zolpidem 20 mg were shown to be additive when the two
compounds were given concomitantly in healthy volunteers. No pharmacokinetic interaction was shown
between zolpidem and imipramine or its metabolite, desipramine.

Chlorpromazine
The combination of zolpidem 10 mg and chlorpromazine 50 mg in healthy volunteers produced an addition
of effects seen in psychometric tests and decreased alertness and psychomotor performance. No
pharmacokinetic interaction was observed.

Haloperidol
No evidence of pharmacokinetic interaction between zolpidem 20 mg and haloperidol 2 mg was seen when
they were given concurrently to healthy volunteers.

Caffeine
No change in the sleep inducing effect of zolpidem was seen when caffeine 300 mg was given in the
evening 45 minutes before administration of zolpidem 20 mg to 8 healthy volunteers.

Warfarin
Prothrombin times were not prolonged in healthy adults when zolpidem 20 mg was administered for four
consecutive nights concomitantly with warfarin. Warfarin had been given for at least ten days previously to
produce a 1.5 times prolongation of baseline prothrombin time in the volunteers. Zolpidem does not appear
to modify the anticoagulant activity of warfarin.

Digoxin
The concurrent administration of zolpidem 10 mg once daily and digoxin 0.25 mg in healthy volunteers did
not show any alteration of the pharmacokinetic or pharmacodynamic profile of digoxin.

H2-antagonist
Simultaneous administration of zolpidem 20 mg and cimetidine 200 mg tds and 400 mg at night or ranitidine
150 mg bd did not cause any significant change in psychometric tests from those produced by zolpidem
alone. No change in the pharmacokinetics of zolpidem was caused by concomitant administration of either
cimetidine or ranitidine.

Hepatic Enzyme Inhibitors and Inducers

Zolpidem is metabolised via several hepatic cytochrome P450 enzymes: the main enzyme being CYP3A4
with the contribution of CYP1A2. Compounds which inhibit or enhance certain hepatic enzymes
(particularly cytochrome P450) may increase or decrease the activity of some hypnotics. The
pharmacodynamic effect of zolpidem is decreased when it is administered with a CYP3A4 inducer such as

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rifampicin and St John’s wort. Co- administration of St John’s wort may decrease blood levels of zolpidem
therefore concurrent use is not recommended.

Ketoconazole has a significant but only quantitatively modest reduction in zolpidem clearance, with an
increase in its pharmacodynamic effects.

Patients should be advised that use of zolpidem with ketoconazole may enhance the sedative effects of
zolpidem.

However, when zolpidem is administered with itraconazole (a CYP3A4 inhibitor) its pharmacokinetics and
pharmacodynamics were not significantly modified. The clinical relevance of these results is unknown.

Fluvoxamine is a strong inhibitor of CYP1A2 and a moderate to weak inhibitor of CYP2C9 and CYP3A4.
Co-administration of fluvoxamine may increase blood levels of zolpidem, concurrent use is not
recommended.

Ciprofloxacin has been shown to be a moderate inhibitor of CYP1A2 and CYP3A4. Co-administration of
ciprofloxacin may increase blood levels of zolpidem, concurrent use is not recommended.

ADVERSE EFFECTS
Clinical Trials Data
There is evidence of a dose-relationship for adverse effects associated with Zolpidem use, particularly for
certain CNS events. These occur most frequently in elderly patients.

Associated with Discontinuation of Treatment

Approximately 4% of 1,701 patients who received zolpidem at all doses (1.25 to 90 mg) in US premarketing
clinical trials discontinued treatment because of an adverse clinical event. Events most commonly
associated with discontinuation from US trials were daytime drowsiness (0.5%), dizziness (0.4%),
headache (0.5%), nausea (0.6%) and vomiting (0.5%).

Approximately 6% of 1,320 patients who received zolpidem at all doses (5 to 50 mg) in similar European
trials discontinued treatment because of an adverse event. Events most commonly associated with
discontinuation from these trials were daytime drowsiness (1.6%), amnesia (0.6%), dizziness (0.6%),
headache (0.6%) and nausea (0.6%).

Incidence in Controlled Clinical Trials

Most Commonly Observed Adverse Events in Controlled Trials
During short-term treatment (up to 10 nights) with zolpidem at doses up to 10 mg, the most commonly
observed adverse events associated with the use of Zolpidem and seen at statistically significant
differences from placebo treated patients were drowsiness (reported by 2% of zolpidem patients), dizziness
(1 %) and diarrhoea (1 %). During longer-term treatment (28 to 35 nights) with zolpidem at doses up to 10
mg, the most commonly observed adverse events associated with the use of zolpidem and seen at
statistically significant differences from placebo treated patients were dizziness (5%) and drugged feelings
(3%).

Adverse Events Observed at an Incidence of ≥ 1% in Controlled Trials

Tables 1 and 2 enumerate treatment emergent adverse event frequencies that were observed at an
incidence equal to 1 % or greater among patients with insomnia who received zolpidem in US placebo
controlled trials. Events reported by investigators were classified utilising a modified World Health
Organization (WHO) dictionary of preferred terms for the purpose of establishing event frequencies.

Table 1 was derived from a pool of 11 placebo-controlled short-term US efficacy trials involving zolpidem
in doses ranging from 1.25 to 20 mg. The table is limited to data from doses up to and including 10 mg, the
highest dose recommended for use.

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Table 1

Incidence of Treatment Emergent Adverse Experiences in Short-Term Placebo Controlled

Clinical Trials (Percentage of Patients Reporting)

ZOLPIDEM (< 10 mg) PLACEBO

BODY SYSTEM / ADVERSE EVENT *
(n = 685) (n = 473)
Central & Peripheral Nervous System
Headache 7 6
Drowsiness 2 -
Dizziness 1 -
Gastrointestinal System
Nausea 2 3
Diarrhoea 1 -
Musculoskeletal system
Myalgia 1 2
* Events reported by at least 1 % of zolpidem patients are included

Table 2 was derived from a pool of three placebo controlled long-term efficacy trials involving zolpidem
(zolpidem tartrate). These trials involved patients with chronic insomnia who were treated for 28 to
35 nights with zolpidem at doses of 5, 10 or 15 mg. The table is limited to data from doses up to and
including 10 mg, the highest dose recommended for use. The table includes only adverse events occurring
at an incidence of at least 1 % for zolpidem patients.

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Table 2

Incidence of Treatment Emergent Adverse Experiences in Long-Term Placebo Controlled

Clinical Trials (Percentage of Patients Reporting)

ZOLPIDEM (< 10 mg) PLACEBO

BODY SYSTEM / ADVERSE EVENT *
(n = 152) (n = 161)
Autonomic Nervous System
Dry mouth 3 1
Body as a Whole
Allergy 4 1
Back pain 3 2
Influenza-like symptoms 2 -
Chest pain 1 -
Fatigue 1 2
Cardiovascular System
Palpitation 2 -
Central & Peripheral Nervous System
Headache 19 22
Drowsiness 8 5
Dizziness 5 1
Lethargy 3 1
Drugged feeling 3 -
Lightheadedness 2 1
Depression 2 1
Abnormal dreams 1 -
Amnesia 1 -
Anxiety 1 1
Nervousness 1 3
Sleep disorder 1 -
Gastrointestinal System
Nausea 6 6
Dyspepsia 5 6
Diarrhoea 3 2
Abdominal pain 2 2
Constipation 2 1
Anorexia 1 1
Vomiting 1 1
Immunologic System
Infection 1 1
Musculoskeletal System
Myalgia 7 7
Arthralgia 4 4
Respiratory system
Upper respiratory infection 5 6
Sinusitis 4 2
Pharyngitis 3 1
Rhinitis 1 3
Skin & Appendages
Rash 2 1
Urogenital System
Urinary tract infection 2 2
* Events reported by at least 1 % of patients treated with zolpidem.

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Post-Marketing Data
Gastrointestinal
Common: Diarrhoea, nausea, vomiting, abdominal pain.

Metabolism and nutritional disorders

Uncommon: Appetite disorder

Neurological
Common: Dizziness, somnolence, headache, exacerbated insomnia, anterograde amnesia
(amnestic effects may be associated with inappropriate behaviour).
Uncommon Paraesthesia, tremor.
Rare: Ataxia, dysarthria, depressed level of consciousness.

Visual
Rare: Diplopia, vision blurred.
Visual impairment has been reported.

Psychiatric
Common: Drowsiness, hallucinations, agitation, nightmare.
Uncommon: Confusion, memory disturbances, reduced alertness, irritability.

Rare: Nightmares, perceptual disturbances, restlessness, aggravated insomnia, change in

libido, aggressiveness, delusion, rages, inappropriate behaviour, somnambulism (see
PRECAUTIONS, Somnambulism and Associated Behaviours), dependence
(withdrawal symptoms, or rebound effects may occur after treatment discontinuation),
other adverse behavioural effects, depression, euphoric mood.
Anger and abnormal behaviour have been reported.

Immune system
Rare: Angioneurotic oedema.

Respiratory, thoracic and mediastinal

Respiratory depression has been reported.

Skin and subcutaneous tissue

Rare: Hyperhydrosis, rash, pruritus, urticarial.

Musculoskeletal and connective tissue

Common Back pain
Uncommon Arthralgia, myalgia, muscle spasms, neck pain
Rare: Muscular weakness.

Hepatobiliary
Elevated liver enzymes, hepatocellular, cholestatic and mixed liver injury have been reported.

Infections and infestations

Common: Upper respiratory tract infection, lower respiratory tract infection

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 Product Information – Australia

General disorders and administration site conditions

Common: Fatigue.
Rare: Fall, ataxia/gait disturbances, drug tolerance.

DOSAGE AND ADMINISTRATION

Zolpidem acts rapidly and should therefore be taken immediately before retiring, or in bed. Zolpidem should
be taken in a single intake and not be re-administered during the same night. As with all hypnotics, long-
term use is not recommended and a course of treatment should not exceed four weeks.

For oral use only.

Discontinuation of Treatment: see ADVERSE EFFECTS section.

Withdrawal Effects: see PRECAUTIONS.

Recommended Dosage
Adults
10 mg to be taken at night. The lowest effective daily dose of zolpidem should be used and must not exceed
10 mg.

Elderly or Debilitated Patients

5 mg to be taken at night. This dose should not be exceeded.

Hepatic Impairment
5 mg to be taken at night.

In adults less than 65 years the dosage may be increased if the clinical response is inadequate and the
drug is well tolerated.

Renal Impairment
No dosage adjustment is necessary in these patients, although they should be closely monitored.

Children
The use of zolpidem in children under 18 years is contraindicated.

OVERDOSAGE
Symptoms
In reports of overdose with zolpidem alone, or with other CNS depressant agents (including alcohol),
impairment of consciousness has ranged from somnolescence to coma and more severe symptomology,
including fatal outcomes have been reported. Fatalities have occurred when overdoses of multiple CNS
depressants were taken.

Treatment
General symptomatic and supportive measures should be used, along with immediate gastric lavage where
appropriate. Intravenous fluids should be administered as needed. Sedative drugs should be withheld, even
if excitation occurs.

Zolpidem has been shown in trials to be non-dialysable.

Use of flumazenil may be considered when serious symptoms are observed. However, flumazenil
administration may contribute to the appearance of neurological symptoms, such as convulsions, since
zolpidem does not exhibit the anticonvulsant effects of benzodiazepines.

For information on the management of overdose, contact the Poisons Information Centre on
13 11 26 (Australia).

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 Product Information – Australia

PRESENTATION AND STORAGE CONDITIONS

Apo-Zolpidem tablets are intended for oral administration

Each tablet contains 5 mg or 10 mg of zolpidem tartrate as the active ingredient.

APO-Zolpidem 5 mg tablets
Pink, capsule-shaped, film-coated tablets, imprinted “APO” on one side and “ZOL 5” on the other side

Blister Pack (Aluminium silver foil) of 7 tablets (AUST R 127151)

Blister Pack (Aluminium silver foil) of 14 tablets (AUST R 127151)

Bottle (white, round HDPE bottle with blue PP child-resistant cap) of 7 tablets (AUST R 127167)
Bottle (white, round HDPE bottle with blue PP child-resistant cap) of 14 tablets (AUST R 127167)

APO-Zolpidem 10 mg tablets
White, modified oval, scored tablets, imprinted “APO” on one side and “1” European bisect “0” on the
other side

Blister Pack (Aluminium silver foil) of 7 tablets (AUST R 127174)

Blister Pack (Aluminium silver foil) of 14 tablets (AUST R 127174)

Bottle (white, round HDPE bottle with blue PP child-resistant cap) of 7 tablets (AUST R 127178)
Bottle (white, round HDPE bottle with blue PP child-resistant cap) of 14 tablets (AUST R 127178)

* Not all strengths, pack types and/or pack sizes may be available.

Storage
Store below 30°C. Store in original package.

NAME AND ADDRESS OF SPONSOR

Apotex Pty Ltd
16 Giffnock Avenue
Macquarie Park NSW 2113

Apotex Pty Ltd is the licensee of the registered trade marks APO and APOTEX from the registered
proprietor, Apotex Inc.

POISONS SCHEDULE OF THE MEDICINE

S4: Prescription Only Medicine.

Date of first inclusion in the ARTG: 11 July 2007

Date of most recent amendment: 23 February 2017

APO- Zolpidem Tablets Page 14