Consumer medicine information

Zolpidem AN Tablets

Zolpidem tartrate

BRAND INFORMATION

Brand name

Zolpidem AN Tablets

Active ingredient

Zolpidem tartrate

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Zolpidem AN Tablets.

What is in this leaflet

This leaflet answers common questions about ZOLPIDEM AN. It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risk of taking ZOLPIDEM AN against the benefits it is expected to have for you.

If you have any concerns about taking this medicine, ask your doctor or pharmacist.

Keep this leaflet with the medicine.

You may need to read it again.

What ZOLPIDEM AN is used for

ZOLPIDEM AN is a prescription medicine that your doctor has prescribed for you. Do not share it with anyone.

ZOLPIDEM AN is the brand name of a medicine called Zolpidem tartrate.

ZOLPIDEM AN is used to initiate sleep in those with sleeping difficulties, also called insomnia. The cause of sleeping problems should be known, if possible. The causes should be treated before ZOLPIDEM AN, or any hypnotic is prescribed.

It should not be used for more than 4 weeks at a time.

Continuous long term use is not recommended unless advised by your doctor.

The use of ZOLPIDEM AN may lead to dependence on the medicine.

ZOLPIDEM AN has a different chemical structure to any other sleeping tablet that is currently available in Australia.

ZOLPIDEM AN works by binding to special sites in the brain which produce sleep.

Your doctor will have explained why you are being treated with ZOLPIDEM AN and told you what dose to take. Follow these instructions carefully. They may differ from the information contained in this leaflet.

Before you take Zolpidem AN

When you must not take it

Do not take ZOLPIDEM AN if:

  • You are allergic to the active ingredient or any of the inactive ingredients mentioned at the end of this leaflet. Some of the symptoms of an allergic reaction may include shortness of breath, wheezing or difficulty breathing; swelling of the face, lips, tongue or other parts of the body; rash, itching or hives on the skin
  • It is past its expiry date or the packaging appears to have been tampered with
  • You are pregnant or breastfeeding, unless permitted by your doctor
  • You suffer from severe muscle weakness known as myasthenia gravis
  • You suffer from a sleeping disorder known as obstructive sleep apnoea
  • You have severe liver problems
  • You have acute or severe lung problems
  • You have taken alcohol

Do not give Zolpidem AN to children and adolescents under 18 years of age unless advised by your child’s doctor. The safety and effectiveness of Zopidem AN in this age group has not been established.

Before you start to take it

Tell your doctor if you have allergies to:

  • Any other medicines, especially if they are in the same medicine class as Zolpidem AN.
  • Any other substances, including foods, preservatives or dyes.

Tell your doctor if you plan on becoming pregnant or will be breastfeeding while you are using Zolpidem AN.

Tell your doctor if you have or have had any other medical conditions, especially the following:

  • Kidney problems
  • Liver problems
  • Lung disease
  • Fits or convulsions
  • Depression, psychosis or schizophrenia
  • Drug and/or alcohol addiction
  • If you have any problems with your breathing or if you often snore while you are asleep

Taking other medicines

Tell your doctor if you are taking any other medicines, including medicines that you buy without a prescription from your pharmacy, supermarket or health food shop.

Some medicines may affect the way other medicines work.

In particular, tell your doctor if you take any of the following:

  • Other sleeping tablets, sedatives or tranquilizers
  • Medicines for depression including imipramine
  • Medicines to treat anxiety and mental illness
  • Medicines to treat bacterial infections such as rifampicin, erythromycin and clarithromycin
  • Medicines to treat fungal infections such as ketoconazole
  • Pain relievers

These medicines may be affected by Zopidem AN or may affect how well it works. You may need to use different amounts of your medicine, or you may need to take different medicines. Your doctor will advise you.

Let your doctor know if you have used Zolpidem AN before and if you had any problems with it.

Some medicines can cause dependence, especially when they are used regularly for longer than a few weeks.

People who have been dependant on alcohol or other drugs in the past may have a higher chance of becoming addicted to sleep medicines.

If you have been addicted to alcohol or drugs in the past, it is important to tell your doctor before starting ZOLPIDEM AN.

Use with caution in the elderly or debilitated patient.

How to take ZOLPIDEM-PS

Follow all directions given to you by your doctor or pharmacist carefully.

They may differ from the information contained in this leaflet.

If you do not understand the instructions on the box, ask your doctor or pharmacist for help.

How much to take

The usual adult dose of ZOLPIDEM AN is 10 mg.

If you are over 65 years of age the dose is 5 mg (half of the 10 mg) ZOLPIDEM AN at night.

If you have a liver problem, you should start with 5 mg (half of the 10 mg) ZOLPIDEM AN, taken at night. If necessary, this can be increased to 10 mg.

How to take it

ZOLPIDEM AN should be taken just before you go to bed because it puts you to sleep quite quickly. It works more quickly if you take it on an empty stomach.

How long to take it

It should not be used for more than 4 weeks at a time.

Continuous long term use is not recommended unless advised by your doctor.

If you forget to take your dose

If you forget to take ZOLPIDEM-PS before you go to bed and you wake up late in the night or early morning, do not take any ZOLPIDEM AN as you may have trouble waking in the morning.

Do not take a double dose to make up for the dose you missed.

This may increase the chance of you getting an unwanted side effect.

If you are not sure what to do or have any questions, ask your doctor or pharmacist.

If you take too much (overdosage)

Some signs and symptoms of taking too much ZOLPIDEM AN include severe drowsiness, clumsiness or unsteadiness, mental or mood changes, unusual tiredness or weakness and unconsciousness.

If you or someone else has taken too much ZOLPIDEM AN, immediately telephone your doctor or the Poisons Information Centre (13 11 26), or go to Accident and Emergency at your nearest hospital. Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

While you are taking ZOLPIDEM AN

Things you must do

Always follow your doctors instructions carefully.

Tell your doctor if you become pregnant while taking Zolpidem AN.

If you are about to start taking a new medicine, tell your doctor and pharmacist that you are taking ZOLPIDEM AN.

ZOLPIDEM AN will add to the effects of alcohol and other central nervous system (CNS) depressant medicines that cause drowsiness. Some examples of CNS depressants are:

  • Sedating antihistamines or medicine for hay fever, other allergies or colds
  • Sedative tranquilisers or sleeping medicines
  • Prescription pain medicines or narcotics
  • Barbiturates
  • Medicines for seizures
  • Muscle relaxants
  • Anaesthetics including some dental anaesthetics

Check with your doctor or pharmacist before taking any of the above or any other medicines with or without a prescription while you are using Zolpidem AN.

Keep all your doctor’s appointments so that your progress can be monitored.

Discuss with your doctor any problems or difficulties during or after taking ZOLPIDEM AN.

After taking ZOLPIDEM AN for insomnia, you may have difficulty sleeping (rebound insomnia) for the first few nights after you stop taking it.

Tell your doctor if, for any reason, you have not taken your medicine exactly as prescribed.

Otherwise your doctor may think it was not effective and change your treatment unnecessarily.

If you develop any unusual and strange thoughts or abnormal behaviour while you are taking ZOLPIDEM AN, be sure to discuss it with your doctor. Some changes that have occurred in people taking this medicine are like those seen in people who drink alcohol and then act in a manner that is not normal. Other changes may be more unusual and extreme, such as aggression, hallucinations (seeing, hearing, or feeling things that are not there), and unusual excitement, nervousness, or irritability.

When sleep medicines are used every night for more than a few weeks, they may lose their effectiveness to help you sleep.

Sleep medicines should in most cases, be used only for short periods of time. If your sleep problems continue, consult your doctor.

Things you must not do

Do not stop taking Zolpidem AN or lower the dose without checking with your doctor.

Stopping this medicine suddenly, especially when you are on a high dose or have been taking it for a long time, may cause some unwanted side effects such as mood changes, anxiety and restlessness.

Your doctor will advise you to slowly reduce your dose of ZOLPIDEM AN before you can stop taking it completely.

Do not use ZOLPIDEM AN to treat any other complaint unless your doctor says so.

Do not give this medication to anyone else, even if their symptoms seem similar to yours.

Do not take ZOLPIDEM AN for a longer time than your doctor has prescribed.

ZOLPIDEM AN should be taken for short periods only (maximum 4 weeks), unless advised by your doctor.

ZOLPIDEM AN will make you sleepy, dizzy or light-headed and may therefore affect alertness. Do not drive motor vehicles or operate dangerous machinery for 8 hours after you take it.

You should also be careful the next morning when you wake up. Even if you take Zolpidem AN at night, you may still be drowsy or dizzy early the next day.

Do not take Zolpidem AN with alcohol, as combining Zolpidem AN and alcohol can increase the risk of sleep walking and other associated behaviours (see Side Effects).

Things to be careful of

Be careful if you are elderly, unwell or taking other medicines.

Some people may experience side effects such as drowsiness, confusion, dizziness and unsteadiness, which may increase the risk of a fall.

Side Effects

All medicines can have unwanted effects. Sometimes they are serious, most of the time they are not. Your doctor or pharmacist has weighed the risk of using this medicine against the benefits they expect it will have for you.

Do not be alarmed by this list of possible side effects.

You may not experience any of them.

Tell your doctor if you notice any of the following and they worry you:

  • Drowsiness, dizziness or light-headedness
  • Headache
  • Nausea and vomiting
  • Diarrhea
  • Muscle weakness

These are more common side effects of Zolpidem AN. Mostly, these are mild and short-lived.

Some sleep medicines may cause a special type of memory loss “anterograde amnesia”.

When this occurs, a person may not remember what has happened for several hours after taking the medicine. This is usually not a problem since most people fall asleep after taking the medicine. To reduce this risk, ensure that you are able to get a full night’s sleep (7 to 8 hours) before you need to be active again.

Less common side effects include:

  • Unexpected changes in behavior. These have included rage reactions, worsened insomnia, confusion, agitation, hallucinations and other forms of unwanted behaviour
  • Sleep walking, driving motor vehicles and other unusual and on some occasions, dangerous behaviours whilst apparently asleep. These have also included preparing and eating food, making phone calls or having sexual intercourse. People experiencing these effects have had no memory of the events.
    Alcohol can increase the risk of sleep walking and other related behaviours. These side effects can also occur without the presence of alcohol.
    Although these side effects can occur at the usual recommended doses, the risk of these behaviours occurring may also be increased if you take more than the recommended dose.
    If any of the following happen stop taking Zolpidem AN and tell your doctor immediately, or go to Accident and Emergency at your nearest hospital.
  • Skin rashes or hives
  • Excessive sweating
  • Swelling of the face, lips, mouth or throat which may cause difficulty in swallowing or breathing
  • Fainting

These are very serious side effects. If you have them, you may have had a serious allergic reaction to Zolpidem AN. You may need urgent medical attention or hospitalization.

All of these side effects are very rare.

Other side effects not listed above may also occur in some people.

Tell your doctor if you notice any other effects and they worry you.

After taking Zolpidem AN

Storage

Keep your tablets in the blister pack until it is time to take them.

If you take the tablets out of the blister pack they may not keep well.

Keep your tablets in a cool dry place where the temperature stays below 25°C and protect from light.

Do not store it or any other medicine in the bathroom or near a sink.

Do not leave it in the car or on window sills.

Heat and dampness can destroy some medicines.

Keep it where children cannot reach it.

A locked cupboard at least one-and-a-half meters above the ground is a good place to store medicines.

Disposal

If your doctor tells you to stop taking this medicine, or the tablets have passed their expiry date, ask your pharmacist what to do with any that are left over.

Product Description

What it looks like

ZOLPIDEM AN 10 mg tablets (AUST R 131917) are white, oval, biconvex, film-coated tablets, scored on both sides and embossed with "ZIM" and "10" on one side.

ZOLPIDEM AN tablets are available in pack sizes of 14 tablets.

Ingredients

Active Ingredient:
Zolpidem tartrate.

Other Ingredients:

  • lactose
  • microcrystalline cellulose
  • hypromellose
  • sodium starch glycollate
  • magnesium stearate.

The coating contains:

  • hypromellose
  • titanium dioxide
  • macrogol 400

Name and Address of the Sponsor

Amneal Pharma Australia Pty Ltd
12 River Street
South Yarra,
VIC - 3141
Australia

Date of Preparation
September 2014

BRAND INFORMATION

Brand name

Zolpidem AN Tablets

Active ingredient

Zolpidem tartrate

Schedule

S4

 

Name of the medicine

Zolpidem tartrate.

Excipients.

Lactose, microcrystalline cellulose, hypromellose, sodium starch glycollate and magnesium stearate. The coating on the tablets consists of hypromellose, titanium dioxide and macrogol 400.

Description

Chemical name: 2-(4-methylphenyl)-N,N,6- trimethylimidazo [1,2,a] pyridine-3-acetamide hemitartrate. Molecular formula: C42H48N6O8. MW: 764.9. CAS: 99294-93-6 (zolpidem tartrate) and 82626-48-0 (zolpidem base). Zolpidem tartrate is a white to off white colourless, crystalline powder, sparingly soluble in water.

Pharmacology

Pharmacodynamics.

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. Whereas benzodiazepines nonselectively 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 tartrate, i.e. the preservation of deep sleep (stage 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 tartrate 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 tartrate 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 tartrate plasma binding.

Effect of food.

A food effect study in 30 healthy male volunteers compared the pharmacokinetics of zolpidem tartrate 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 hr). The half-life remained unchanged. These results suggest that, for faster sleep onset, zolpidem tartrate should not be administered with or immediately after a meal.

Special populations.

Zolpidem tartrate did not accumulate in young adults following nightly dosing with 20 mg zolpidem tartrate tablets for 2 weeks.
In the elderly, the recommended dose for Zolpidem AN is 5 mg (see Precautions and 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 tartrate did not accumulate in elderly subjects following nightly oral dosing of 10 mg for 1 week.
The pharmacokinetics of zolpidem tartrate in eight patients with chronic hepatic insufficiency were compared to results in healthy subjects. Following a single 20 mg oral zolpidem tartrate dose, mean Cmax and AUC were found to be two times (250 vs 499 nanogram/mL) and five times (788 vs 4,203 nanogram.hr/mL) higher, respectively, in hepatically compromised patients. Tmax did not change. The mean half-life in cirrhotic patients of 9.9 hr (range: 4.1 to 25.8 hr) was greater than that observed in normals of 2.2 hr (range: 1.6 to 2.4 hr). 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 tartrate has been shown to be nondialysable.

Clinical Trials

Insomnia in nonelderly adults.

Short-term (1 to 2 nights) placebo controlled studies in 620 volunteers showed that zolpidem tartrate 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 tartrate 40 mg.
The efficacy of zolpidem tartrate 2.5-20 mg was investigated in 11 placebo controlled studies in 1606 (513 received zolpidem tartrate 10 mg) nonelderly insomniacs over a period of 2-35 nights. Zolpidem tartrate 10 mg was superior to placebo using both objective (polysomnography) and subjective methods of assessment. Zolpidem tartrate 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 tartrate 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 tartrate 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 MSLT 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 tartrate. 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 tartrate. There was subjective evidence from adverse event data for anterograde amnesia occurring in association with the administration of zolpidem tartrate, 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 tartrate 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 rapid eye movement (REM) (paradoxical) sleep at the recommended dose.
The hypnotic efficacy and safety of zolpidem tartrate have not been assessed in children and pregnant women.

Indications

Zolpidem tartrate is indicated for the short-term treatment of insomnia in adults (see Dosage and Administration).

Contraindications

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

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 7-14 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 AN 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 AN 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.

CNS effects.

As with all patients taking CNS depressant medications, patients receiving Zolpidem AN 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 AN 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 AN. Prior or concomitant intake with alcohol is contraindicated (see Contraindications).

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 AN at doses exceeding the maximum recommended dose. Discontinuation of Zolpidem AN 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.

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.

Interactions with alcohol.

Prior or concomitant intake with alcohol is contraindicated (see Contraindications). Patients should be advised that there 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).

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 AN. Drowsiness may continue the following day. After ingesting the medicine, patients should be cautioned against engaging in hazardous occupations requiring complete mental alertness or motor coordination 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 AN.

Respiratory function.

Both animal and human pharmacology studies performed with zolpidem tartrate 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 AN is administered to patients with respiratory insufficiency. (See Contraindications.)

Use in the elderly or debilitated patient.

As with other sedatives/ hypnotics, caution is advised when zolpidem tartrate is used in these patients. Elderly and debilitated patients may be particularly sensitive to the effects of zolpidem tartrate, therefore 5 mg dose is recommended. This dose should not be exceeded in these patients. (See Dosage and Administration.) 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.

Hepatic impairment.

As clearance and metabolism of zolpidem tartrate 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 medicine is well tolerated. (See Use in elderly and Dosage and Administration.)

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 7-8 hours.

Depression, psychosis and schizophrenia.

Zolpidem AN 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 AN. 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 smallest quantity of the medicine that is feasible should be prescribed for the patient at any one time.
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 AN. Should such reactions occur, Zolpidem AN should be discontinued. These reactions are more likely to occur in the elderly.

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 AN is used in these patients.

Abuse.

Caution must be exercised in administering Zolpidem AN 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.

Carcinogenicity, mutagenicity, impairment of fertility.

Mutagenic potential.

Zolpidem tartrate 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 tartrate and/or its metabolites was equivocal in a Chinese hamster V79/HRPT gene mutation assay in the presence of metabolic activation.

Carcinogenic potential.

Two year dietary carcinogenicity studies on zolpidem tartrate were conducted in rats and mice. No evidence of carcinogenic potential was observed in mice at plasma concentrations (AUC) of zolpidem tartrate 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)
This drug has 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 foetus having been observed. Studies in animals have shown evidence of an increased occurrence of foetal damage, the significance of which is 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 postimplantation survival index and postpartum viability of the offspring were significantly reduced. In rats, delayed ossification of foetal skull bones occurred at zolpidem tartrate and metabolite exposure levels of 8 and 3 times, respectively, the anticipated clinical exposure.
Rabbits treated with oral zolpidem tartrate with estimated exposure to zolpidem tartrate of 0.6-2.6 times the anticipated clinical exposure did not exhibit teratogenic effects, but there was increased postimplantation loss.
Although animal studies have not shown any teratogenic effects with zolpidem tartrate, the safety of zolpidem tartrate in human pregnancy has not been established.

Nonteratogenic effects.

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.
However, no cases of withdrawal phenomena were reported to date in newborn of women treated with zolpidem tartrate during the late phase of pregnancy.

Use in lactation.

The use of zolpidem tartrate in breastfeeding women is not recommended as small quantities of zolpidem tartrate are excreted into breast milk.

Interactions

CNS depressants.

Coadministration of Zolpidem AN 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. 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 tartrate 20 mg were shown to be additive when the two compounds were given concomitantly in healthy volunteers. No pharmacokinetic interaction was shown between zolpidem tartrate and imipramine or its metabolite, desipramine.

Chlorpromazine.

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

Haloperidol.

No evidence of pharmacokinetic interaction between zolpidem tartrate 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 300 mg caffeine was given in the evening 45 minutes before administration of zolpidem tartrate 20 mg to 8 healthy volunteers.

Warfarin.

Prothrombin times were not prolonged in healthy adults when zolpidem tartrate 20 mg was administered for 4 consecutive nights concomitantly with warfarin. Warfarin had been given for at least 10 days previously to produce a 1.5 times prolongation of baseline prothrombin time in the volunteers. Zolpidem tartrate does not appear to modify the anticoagulant activity of warfarin.

Digoxin.

The concurrent administration of zolpidem tartrate 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-antagonists.

Simultaneous administration of zolpidem tartrate 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 tartrate alone. No change in the pharmacokinetics of zolpidem tartrate were caused by concomitant administration of either cimetidine or ranitidine.

Hepatic enzyme inhibitors and inducers.

Zolpidem tartrate 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 rifampicin (a CYP3A4 inducer).
Ketoconazole has a significant but only quantitatively modest reduction in zolpidem tartrate 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 tartrate is administered with itraconazole (a CYP3A4 inhibitor) its pharmacokinetics and pharmacodynamics were not significantly modified. The clinical relevance of these results is unknown.

Adverse Effects

Clinical trials data.

There is evidence of a dose relationship for adverse effects associated with zolpidem tartrate 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 tartrate 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 tartrate 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 tartrate at doses up to 10 mg, the most commonly observed adverse events associated with the use of zolpidem tartrate and seen at statistically significant differences from placebo treated patients were drowsiness (reported by 2% of zolpidem tartrate patients), dizziness (1%) and diarrhoea (1%). During longer-term treatment (28 to 35 nights) with zolpidem tartrate at doses up to 10 mg, the most commonly observed adverse events associated with the use of zolpidem tartrate and seen at statistically significant differences from placebo treated patients were dizziness (5%) and drugged feelings (3%).

Adverse events observed at an incidence of greater than or equal to 1% in controlled trials.

The following tables enumerate treatment emergent adverse event frequencies that were observed at an incidence equal to 1% or greater among patients with insomnia who received zolpidem tartrate 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 tartrate 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.
Table 2 was derived from a pool of three placebo controlled long-term efficacy trials involving zolpidem tartrate. These trials involved patients with chronic insomnia who were treated for 28 to 35 nights with zolpidem tartrate 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 tartrate patients.

Postmarketing data.

Gastrointestinal.

Common: diarrhoea.

Neurological.

Common: dizziness. Uncommon: headache. Rare: ataxia, dysarthria.

Visual.

Rare: diplopia.

Psychiatric.

Common: drowsiness. Uncommon: confusion, hallucinations*, memory disturbances, reduced alertness. Rare: nightmares, perceptual disturbances, restlessness, aggravated insomnia, change in libido, agitation, irritability, aggressiveness, delusion, rages, inappropriate behaviour, somnambulism (see Precautions, Somnambulism and associated behaviours), other adverse behavioural effects.

Skin.

Rare: angioneurotic oedema, hyperhidrosis.

Miscellaneous.

Rare: fatigue, muscle weakness, fall, ataxia/ gait disturbances.
Elevated liver enzymes, rash, pruritus and urticaria have also been reported.

Dosage and Administration

Zolpidem AN acts rapidly and should therefore be taken immediately before retiring. As with all hypnotics, long-term use of zolpidem is not recommended and a course of treatment should not exceed four weeks.

Discontinuation of treatment.

See Adverse Effects.

Withdrawal effects.

See Precautions.

Recommended dosage.

Adults.

10 mg to be taken at night.

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 of age, 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 AN in children and adolescents under 18 years of age is contraindicated as the safety and efficacy of zolpidem tartrate has not yet been established in this age group.

Overdosage

In reports of overdose with zolpidem tartrate alone, impairment of consciousness has ranged from somnolescence to coma. Fatalities have occurred when overdoses of multi CNS depressants were taken.
General symptomatic and supportive measures should be used, where appropriate. Intravenous fluids should be administered as needed. Sedative drugs should be withheld, even if excitation occurs.
Zolpidem tartrate has been shown in trials to be nondialysable.
Use of flumazenil (Anexate), a benzodiazepine antagonist, may be considered when serious symptoms are observed. However, flumazenil administration may contribute to the appearance of neurological symptoms, such as convulsions, since zolpidem tartrate does not exhibit the anticonvulsant effects of benzodiazepines. Flumazenil should only be administered under closely monitored conditions. It has a short half-life (about an hour), therefore patients administered flumazenil will require monitoring after its effects have worn off. Flumazenil may precipitate seizures and is contraindicated in the presence of medicines that reduce seizure threshold (e.g. tricyclic antidepressants) and epileptic patients who have been treated with benzodiazepines. See the prescribing information for flumazenil (Anexate), for further information on the correct use of this medicine.
Contact the Poisons Information Centre (telephone no: 131 126) for advice on management of overdosage.

Presentation

Tablets (white, oval, biconvex, film coated, scored, marked ZIM 10 on one side), 10 mg: 14's (PVC/ PE/ PVDC/ Al blister pack; AUST R 131917).

Storage

Store below 25°C. Protect from light and moisture.

Poison Schedule

S4.