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SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Zolpidem 10mg Film-coated Tablets

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

Each film-coated tablet contains 10mg zolpidem tartrate, equivalent to 8.03mg zolpidem.

Excipient with known effect: Each film-coated tablet contains 95.2mg of lactose (as lactose monohydrate).

For the full list of excipients, see section 6.1.

3    PHARMACEUTICAL FORM

Film-coated tablet

White, oblong, biconvex tablet of length 10mm-10.4mm and height of 2.6mm-3.0mm, with a break score

The tablet can be divided into equal halves

4    CLINICAL PARTICULARS

Zolpidem is indicated for short-term treatment of insomnia in adults in situations where the insomnia is debilitating or is causing severe distress for the patient.

4.2    Posology and method of administration

Posology

Treatment should be as short as possible. Generally the duration of treatment varies from a few days to two weeks with a maximum, including the tapering off process, of four weeks. The tapering off process should be tailored to the individual.

In certain cases extension beyond the maximum treatment period may be necessary; if so, it should not take place without re-evaluation of the patient's status.

Adults:

The treatment should be taken in a single intake and not be re-administered during the same night.

The recommended daily dose for adults is 10 mg to be taken immediately at bedtime. The lowest effective daily dose of zolpidem should be used and must not exceed 10 mg.

In elderly or debilitated patients who may be especially sensitive to the effects of zolpidem and in patients with hepatic insufficiency who do not clear the drug as rapidly as normal individuals, a dose of 5mg is recommended. This dose should only be increased to 10mg where the clinical response is inadequate and the drug is well tolerated.

The total dose of zolpidem should not exceed 10mg in any patient.

Paediatric population

Zolpidem is not recommended for use in children and adolescents below 18 years of age, due to a lack of data to support use in this age group. The available evidence from placebo-controlled clinical trials is presented in section 5.1.

Method of administration

The product should be taken with fluid just before going to bed.

4.3 Contraindications

•    Hypersensitivity to the active substance or to any of the excipients listed in section 6.1

•    Severe hepatic insufficiency

•    Sleep apnoea syndrome

•    Myasthenia gravis

•    Severe respiratory insufficiency

•    Children and adolescents under 18 years of age

4.4 Special warnings and precautions for use

General

The cause of insomnia should be identified wherever possible. The underlying factors should be 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, which should be evaluated.

General information relating to effects seen following administration of benzodiazepines or other hypnotic agents which should be taken into account by the prescribing physician is described below.

Tolerance

Some loss of efficacy to the hypnotic effects of short-acting benzodiazepines and benzodiazapine-like agents may develop after repeated use for a few weeks.

Dependence

Use of benzodiazepines or benzodiazapine-like agents may lead to the development of physical and psychic dependence of these products. The risk of dependence increases with dose and duration of treatment and is also greater in patients with a history of alcohol or drug abuse.

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, irritability and insomnia. 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 a benzodiazepine or benzodiazapine-like agent recur in an enhanced form, may occur on withdrawal of the hypnotic agent. 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 being discontinued.

There are indications that, in the case of benzodiazepines and benzodiazapine-like agents with a short duration of action, withdrawal phenomena can become manifest within the dosage interval, especially when the dosage is high.

As the risk of withdrawal symptoms/rebound phenomena are more likely to develop after abrupt discontinuation of treatment, it is recommended to decrease the dose gradually.

Duration of treatment

The duration of treatment should be as short as possible (see section 4.2.), but should not exceed 4 weeks including the tapering off process. Extension beyond these periods should not take place without re-evaluation of the situation.

It may be useful to inform the patient when treatment is started that it will be of limited duration.

Amnesia

Benzodiazepines or benzodiazapine-like agents may induce anterograde amnesia. The condition usually occurs several hours after ingesting the product.

In order to reduce the risk, patients should ensure that they will be able to have an uninterrupted sleep of 8 hours (see section 4.8).

Psychiatric and "paradoxical" reactions

When using benzodiazepines or benzodiazepine-like agents, reactions like restlessness, agitation, irritability, aggressiveness, delusion, rages, nightmares, hallucinations, psychoses, somnambulism, inappropriate behaviour, increased insomnia and other adverse behavioural effects are known to occur. Should this occur, use of the product should be discontinued. These reactions are more likely to occur in the elderly.

Specific patient groups

Elderly or debilitated patients should receive a lower dose: see recommended dosage (section 4.2.).

Due to the myorelaxant effect there is a risk of falls and consequently of hip fractures particularly for elderly patients when they get up at night.

Although dose adjustment is not necessary, caution should be exercised in patients with renal insufficiency (see section 5.2.).

Caution should be observed when prescribing zolpidem to patients with chronic respiratory insufficiency since benzodiazepines have been shown to impair respiratory drive. It should also be taken into consideration that anxiety or agitation have been described as signs of decompensated respiratory insufficiency.

Benzodiazepines and benzodiazapine-like agents are not indicated for the treatment of patients with severe hepatic insufficiency as they may precipitate encephalopathy.

Use in patients with psychotic illness: benzodiazepines and benzodiazapine-like agents are not recommended for the primary treatment.

Use in depression: despite the fact that relevant clinical, pharmacokinetic and pharmacodynamic interactions with SSRI have not been demonstrated, zolpidem should be administered with caution in patients exhibiting symptoms of depression. Suicidal tendencies may be present. Due to the possibility of intentional overdose by the patient, the lowest amount of drug that is feasible should be supplied to these patients.

Benzodiazepines and benzodiazapine-like agents should not be used alone to treat depression or anxiety associated with depression (suicide may be precipitated in such patients).

Use in patients with a history of drug or alcohol abuse: benzodiazepines and benzodiazapine-like agents should be used with extreme caution in patients with a history of alcohol or drug abuse. These patients should be

under careful surveillance when receiving zolpidem since they are at risk of habituation and psychological dependence.

This product contains lactose, patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Next-day psychomotor impairment

The risk of next-day psychomotor impairment, including impaired driving ability, is increased if:

•    zolpidem is taken within less than 8 hours before performing activities that require mental alertness (see section 4.7);

•    a dose higher than the recommended dose is taken;

•    zolpidem is co-administered with other CNS depressants or with other drugs that increase the blood levels of zolpidem, or with alcohol or illicit drugs (see section 4.5).

Zolpidem should be taken in a single intake immediately at bedtime and not be re-administered during the same night.

4.5 Interaction with other medicinal products and other forms of interaction

Concomitant intake with alcohol is not recommended. The sedative effect may be enhanced when the product is used in combination with alcohol. This affects the ability to drive or use machines.

Combination with CNS depressants

Caution should be exercised when Zolpidem is used in combination with other CNS depressants (see section 4.4.).

Enhancement of the central depressive effect may occur in cases of concomitant use with antipsychotics (neuroleptics), hypnotics, anxiolytics/sedatives, antidepressant agents, narcotic analgesics, antiepileptic drugs, anaesthetics and sedative antihistamines. Therefore, concomitant use of zolpidem with these drugs may increase drowsiness and next-day psychomotor impairment, including impaired driving ability (see section 4.4 and section 4.7). Also, isolated cases of visual hallucinations were reported in patients taking zolpidem with antidepressants including bupropion, desipramine, fluoxetine, sertraline and venlafaxine.

Co- administration of fluvoxamine may increase blood levels of zolpidem, concurrent use is not recommended.

In the case of narcotic analgesics enhancement of euphoria may also occur leading to an increase in psychological dependence.

Zolpidem is metabolised by some enzymes of the cytochrome P450-family. The main enzyme is CYP3A4.

Rifampicin induces the metabolism of zolpidem, resulting in approximately 60% reduction in peak plasma concentrations and possibly decreased efficacy. Similar effects might be expected also with other strong inducers of cytochrome P450-enzymes.

Compounds that inhibit hepatic enzymes (particularly CYP3A4) may increase plasma concentrations and enhance the activity of zolpidem. However, when zolpidem is administrated with Itraconazol (CYP3A4 inhibitor), the pharmacokinetic and pharmacodynamic effects are not significantly different. The clinical relevance of these results is unknown.

CYP450 inhibitors and inducers

Co- administration ciprofloxacin may increase blood levels of zolpidem, concurrent use is not recommended.

Other drugs

When zolpidem was administrated with ranitidine, no significant pharmacokinetic interactions were observed.

4.6 Fertility, pregnancy and lactation

Pregnancy

There are insufficient data to permit an assessment of the safety of Zolpidem during pregnancy and lactation. Although animal studies have shown no teratogenic or embryotoxic effects, safety in pregnancy has not been established in humans. Therefore zolpidem should not be used during pregnancy especially in the first trimester.

If the product is prescribed to a woman of childbearing potential, she should be warned to contact her physician regarding discontinuance of the product if she intends to become or suspects that she is pregnant.

If, for compelling medical reason, zolpidem is administered during the late phase of pregnancy, or during labour, effects on the neonate, such as hypothermia, hypotonia and moderate respiratory depression, can be expected due to the pharmacological action of the product.

Infants born to mothers who took benzodiazepines or benzodiazepine-like agents chronically during the latter stages of pregnancy may develop withdrawal symptoms in the postnatal period as a result of physical dependence.

Breast-feeding

Zolpidem passes into breast milk in minimal amounts. Zolpidem should therefore not be used by breast-feeding mothers since effects on the infant are not studied.

4.7 Effects on ability to drive and use machines

Zolpidem has major influence on the ability to drive and use machines.

Vehicle drivers and machine operators should be warned that, as with other hypnotics, there may be a possible risk of drowsiness, prolonged reaction time, dizziness, sleepiness, blurred/double vision and reduced alertness and impaired driving the morning after therapy (see section 4.8). In order to minimise this risk a resting period of at least 8 hours is recommended between taking zolpidem and driving, using machinery and working at heights.

Driving ability impairment and behaviours such as ‘sleep-driving’ have occurred with zolpidem alone at therapeutic doses.

Furthermore, the co-administration of zolpidem with alcohol and other CNS depressants increases the risk of such behaviours (see section 4.4 and 4.5). Patients should be warned not to use alcohol or other psychoactive substances when taking zolpidem.

4.8 Undesirable effects

Nausea may occur commonly. Male sexual dysfunction has been reported in 23 % of the male patients (corrected for placebo) in clinical trials of treatment of social phobias.

In the treatment of social anxiety disorder, sexual dysfunction (ejaculation failure) in men occurred in 14% for sertraline vs 0% in placebo.

The adverse reactions of the medicinal product are dose dependent and often transient in nature when the treatment is continued.

The undesirable effects profile commonly observed in double-blind, placebo-controlled studies in patients with OCD, panic disorder, PTSD and social anxiety disorder was similar to that observed in clinical trials in patients with depression.

Table 1 displays adverse reactions observed from postmarketing experience (frequency not known) and placebo-controlled clinical trials (comprising a total of 2542 patients on sertraline and 2145 on placebo) in depression, OCD, panic disorder, PTSD and social anxiety disorder.

Some adverse drug reactions listed in Table 1 may decrease in intensity and frequency with continued treatment and do not generally lead to cessation of therapy.

Table 1: Adverse Reactions

	(>1/10)	<1/10)	<1/100)	)		(cannot be estimated from the available data)
Blood and lymphatics system disorders			Platelet disorders Prolonged bleeding time$	Leucopenia, Thrombocytopenia, Lymphadenopathy
Immune system disorders			Hypersensitivity	Allergic reactions including anaphylaxis, Anaphylactoid Reaction		, Allergy
Endocrine disorders			Hypothyroidism			Hyperprolactina emia, Syndrome of inappropriate ADH secretion (SIADH)
Metabolis m and nutrition disorders	Anorexia	Increased appetite*, Decreased appetite		Hyponatraemia $$ , Hypercholesterolae mia, Hypoglycaemia, s Diabetes mellitus,		hyperglycaemia
Psychiatric disorders	Insomnia (19%)	Depression*, Depersonalis ation, Nightmare, Agitation* Anxiety* , Nervousness, Libido Decreased*, Bruxism	Mania, Hypomania, Hallucinations*, Apathy, thinking abnormal, Aggression*, Euphoric mood*	Conversion Disorder, Drug Dependence, Confusion Psychotic disorder*, Paranoia, Suicidal Ideation/behaviour* **, Sleep Walking, Premature Ejaculation		Paroniria
Nervous system disorders	Dizzines s (11%) Somnole nce (13%), Headach e (21%)*	Changes in movement patterns**** Paraesthesias * Hypertonia Dysgeusia, Disturbance in Attention, tremor	Migraine*, Convulsion*, Muscle Contractions Involuntary*, Coordination Abnormal, Hyperkinesia, Amnesia, Speech Disorder, Dizziness Postural, Hypoesthesia*, Syncope	Psychomotor restlessness/ akathisia (see section 4.4) Unconsciousness, Signs and symptoms associated with serotonin syndrome or Neuroleptic Malignant Syndrome: Coma*, Choreoathetosis, Dyskinesia, Hyperaesthesia, Sensory Disturbance		Cerebrovascula r Spasm (including reversible cerebral vasconstriction syndrome and call-fleming syndrome).
Eye disorders		Blurred vision, Visual	Mydriasis*	Glaucoma, Lacrimal Disorder, Scotoma,		Vision Abnormal,

		Distubance		Diplopia, Photophobia, Hyphaema		Pupils Unequal
Ear and labyrinth disorders		Tinnitus*	Ear pain
Cardiac disorders		Palpitations*	Tachycardia	Myocardial Infarction, Bradycardia, Cardiac Disorder
Vascular disorders		Vasodilation, Hot flush*	Hypertension*, Flushing	Peripheral Ischaemia, Hematuria		Abnormal Bleeding (such as epistaxis, gastrointestinal bleeding or
Respirator y, thoracic and mediastina l disorders		Yawning*	Bronchospasm*, Dyspnoea, Epistaxis	Laryngospasm, Hyperventilation, Hypoventilation, Stridor, Dysphonia, Hiccups		Interstitial lung disease
Gastrointes tinal disorders	Nausea (24%), Dry mouth (14%), Diarrhoe a /thin stools (18%)	Dyspepsia Abdominal pain* Vomiting* Constipation *, Flatuence	Oesophagitis, Dysphagia, Haemorrhoids, Salivary Hypersecretion, Tongue Disorder, Eructation	Melaena, Haematochezia, Stomatitis, Tongue ulceration, Tooth Disorder, Glossitis, Mouth Ulceration		Pancreatitis
Hepato biliary disorders				Hepatic function abnormal		Serious liver events (including hepatitis Jaundice) and Hepatic failure
Skin and subcutaneo us tissue disorders		Rash*, Hyperhidrosi s	Periorbital Oedema*, Purpura* Alopecia*, Cold sweat, Dry skin, Urticaria* Pruritus Erythema Multiforme	Dermatitis, Dermatitis Bullous, Rash Follicular, Hair Texture Abnormal, Skin Odour Abnormal Photosensitivity Angiooedema Severe dermal exfoliation / severe cutaneous adverse reactions (SCAR) e.g. Stevens-Johnson syndrome, toxic epidermal necrolysis		Skin Reaction
Musculosk eletal, connective		Myalgia, Arthralgia	Osteoarthritis, Muscular Weakness, Back	Bone disorder, Muscle cramps

tissue and bone disorders			Pain, Muscle Twitching
Renal and urinary disorders			Nocturia, Urinary Retention*, Polyuria, Pollakiuria, Micturition disorder, Urinary incontinence*	Oliguria , Urinary Hesitation
Reproducti ve system and breast disorders* *	Ejaculati on Failure (14%)	Erectile Dysfunction	Vaginal Haemorrhage, Sexual Dysfunction, Female Sexual Dysfunction Menstrual Irregularities	Priapism*, Menorrhagia, Atrophic Vulvovaginitis, Balanoposthitis, Genital Discharge, Galactorrhoea*		Gynaecomastia
General disorders and administrat ion site conditions	Fatigue (10%)*	Chest pain*, Diaphoresis, Malaise	Fever* *, Chills, Thirst, Peripheral oedema, Asthenia*	Facial oedema, Hernia, Injection Site Fibrosis, Drug Tolerance Decreased, Gait Disturbance, Unevaluable Event
Investigati ons		Weight loss*	Weight gain*, Asymptomatic elevation of serum transaminases** **** (Alanine Aminotransferas e Increased*, Aspartate Aminotransferas e Increased*) Abnormal laboratory values	Semen Abnormal		Abnormal Clinical Laboratory Results, Altered Platelet Function, Increased Serum Cholesterol
Injury and poisoning				Injury
Infections and Infestation s		Pharyngitis	Upper Respiratory Tract Infection, Rhinitis	Diverticulitis, Gastroenteritis, Otitis Media
Neoplasms benign, malignant (including cysts and polyps)				Neoplasm f
Surgical and medical procedures				Vasodilation procedure

If adverse experience occurred in depression, OCD, panic disorder, PTSD and social anxiety disorder, body term reclassified by depression studies body term.

f One case of neoplasm was reported in one patient receiving sertraline compared with no cases in the placebo arm.

$ Prolonged bleeding time leading to gastrointestinal haemorrhage, epistaxis, ecchymoses, haematuria, vaginal bleeding, etc.).

$$ Hyponatraemia. This remitted on discontinuation of therapy. Isolated cases may have been attributable to syndrome of inappropriate ADH secretion. These undesirable effects have mainly occurred in elderly patients and in patients using diuretics or other medicinal products.

* these adverse reactions also occurred in postmarketing experience

** the denominator uses the number of patients in that sex group-combined:

sertraline (1118 males, 1424females) placebo (926 males, 1219 females)

For OCD, short term, 1-12 week studies only

*** Cases of suicidal ideation and suicidal behaviours have been reported during sertralin therapy or early after treatment discontinuation (see section 4.4).

**** Changes in movement patterns e.g. extrapyramidal symptoms like hyperkinesia, increased muscular tone, dystonia, jaw rigidity, involuntary mouth movements, teeth grinding, or abnormal gait.

***** Signs and symptoms associated with serotonin syndrome agitation, confusion, diaphoresis, diarrhoea, fever, hypertension, rigidity and tachycardia. In some cases, these symptoms occurred in association with the concomitant use of serotonergic agents (see section 4.5 Interaction with other medicinal products and other forms of interaction).

****** Asymptomatic elevation of serum transaminases. Alterations to transaminase levels mainly occurred in the initial 9 weeks of treatment and rapidly disappeared after discontinuation of therapy.

More than 700 elderly patients (aged >65 years) participated in a clinical study to demonstrate the efficacy of sertraline in this patient group. The types and frequency of undesirable effects in the elderly patients were similar to those in younger patients.

Withdrawal symptoms seen on discontinuation of SSRI/sertraline treatment Discontinuation of sertraline (particularly when abrupt) commonly leads to withdrawal symptoms. Dizziness, sensory disturbances (including paraesthesia), sleep disturbances (including insomnia and intense dreams), agitation or anxiety, nausea and/or vomiting, tremor and headache are the most commonly reported reactions. Generally these events are mild to moderate and are self-limiting; however, in some patients they may be severe and/or prolonged. It is therefore advised that when sertraline treatment is no longer required, gradual discontinuation by dose tapering should be carried out (see section 4.2 Posology and Method of Administration and section 4.4 Special Warnings and Special Precautions for use).

Although withdrawal reactions may occur on stopping therapy, the available preclinical and clinical evidence does not suggest that SSRIs cause dependence.

Elderly population

SSRIs or SNRIs including sertraline have been associated with cases of clinically significant hyponatraemia in elderly patients, who may be at greater risk for this adverse event (see section 4.4).

Paediatric population

In over 600 paediatric patients treated with sertraline, the overall profile of adverse reactions was generally similar to that seen in adult studies. The following adverse reactions were reported from controlled trials (n=281 patients treated with sertraline):

Very common 1/10): Headache (22%), insomnia (21%), diarrhoea (11%) and nausea (15%).

Common ^ 1/100 to <1/10): Chest pain, mania, pyrexia, vomiting, anorexia, affect lability, aggression, agitation, nervousness, disturbance in attention, dizziness, hyperkinesia, migraine, somnolence, tremor, visual disturbance, dry mouth, dyspepsia, nightmare, fatigue, urinary incontinence, rash, acne, epistaxis, flatulence. Uncommon ^ 1/1000 to <1/100): ECG QT prolonged, suicide attempt, convulsion, extrapyramidal disorder, paraesthesia, depression, hallucination, purpura, hyperventilation, anaemia, hepatic function abnormal, alanine aminotransferase increased, cystitis, herpes simplex, otitis externa, ear pain, eye pain, mydriasis, malaise, haematuria, rash pustular, rhinitis, injury, weight decreased, muscle twitching, abnormal dreams, apathy, albuminuria, pollakiuria, polyuria, breast pain, menstrual disorder, alopecia, dermatitis, skin disorder, skin odour abnormal, urticaria, bruxism, flushing.

Frequency not known: enuresis

Class effects

Epidemiological studies, mainly conducted in patients 50 years of age and older, show an increased risk of bone fractures in patients receiving SSRIs and TCAs. The mechanism leading to this risk is unknown.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at www.mhra.gov.uk/yellowcard

4.9 Overdose

In reports of overdose with zolpidem alone, impairment of consciousness has ranged from somnolence to light coma.

Individuals have fully recovered from overdoses up to 400mg of zolpidem, 40 times the recommended dose.

General symptomatic and supportive measures should be used. Immediate gastric lavage should be used where appropriate. Intravenous fluids should be administered as needed. If there is no advantage in emptying the stomach, activated charcoal should be given to reduce absorption. Monitoring of respiratory and cardiovascular functions should be considered. Sedating drugs should be withheld even if excitation occurs.

Use of flumazenil may be considered when serious symptoms are observed. In the treatment of overdose with any medicinal product, it should be borne in mind that multiple agents may have been taken.

Due to the high distribution volume and protein binding of zolpidem, haemodialysis and forced diuresis are not effective measures. Hemodialysis studies in patients with renal failure receiving therapeutic doses have demonstrated that zolpidem is not dialyzable.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Hypnotics and Sedatives, Benzodiazepine related drugs

ATC Code: NO5C FO2

Zolpidem, an imidazopyridine is a benzodiazepine-like hypnotic agent. In experimental studies it was shown that it has sedative effects at lower dosages than those required to exert anticonvulsant, myorelaxant or anxiolytic effects. These effects are related to a specific agonist action at central receptors belonging to the |”GABA-omega” (BZ1 & BZ2) macromolecular receptor” complex, modulating the opening of the chloride ion channel. Zolpidem acts primarily upon omega (BZ1) receptor subtypes. The clinical relevance of this is not known.

The randomized trials only showed convincing evidence of efficacy of 10mg zolpidem.

In a randomized double-blind trial in 462 non-elderly healthy volunteers with transient insomnia, zolpidem 10mg decreased the mean time to fall asleep by 10 minutes compared to placebo, while for 5mg zolpidem this was 3 minutes.

In a randomized double-blind trial in 114 non-elderly patients with chronic insomnia, zolpidem 10mg decreased the mean time to fall asleep by 30 minutes compared to placebo, while for 5mg zolpidem this was 15 minutes.

In some patients, a lower dose of 5mg could be effective.

Paediatric population: Safety and efficacy of zolpidem have not been established in children aged less than 18 years. A randomized placebo-controlled study in 201 children aged 6-17 years with insomnia associated with Attention Deficit Hyperactivity Disorder (ADHD) failed to demonstrate efficacy of zolpidem 0.25 mg/kg/day (with a maximum of 10 mg/day) as compared to placebo. Psychiatric and nervous system disorders comprised the most frequent treatment emergent adverse events observed with zolpidem versus placebo and included dizziness (23.5% versus 1.5%), headache (12.5% versus 9.2%), and hallucinations (7.4% versus 0%) (see sections 4.2 and 4.3).

5.2 Pharmacokinetic properties

Absorption

Zolpidem has both a rapid absorption and onset of hypnotic effect. Bioavailability is 70% following oral administration. It demonstrates linear kinetics in the therapeutic dose range. The therapeutic plasma level is between 80 and 200 ng/ml. Peak plasma concentration is reached at between 0.5 and 3 hours after administration.

Distribution

The distribution volume in adults is 0.54 L/kg and decreases to 0.34 L/kg in the elderly.

Protein binding amounts to 92%. First pass metabolism by the liver amounts to approximately 35%. Repeated administration has been shown not to modify protein binding indicating a lack of competition between zolpidem and its metabolites for binding sites.

Elimination

The elimination half-life is short, with a mean of 2.4 hours and a duration of action up to 6 hours.

All metabolites are pharmacologically inactive and are eliminated in the urine (56%) and in the faeces (37%).

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

Special populations

In patients with renal insufficiency, a moderate reduction in clearance is observed (independent of possible dialysis). The other pharmacokinetic parameters remain unaffected.

In elderly patients and in patients with hepatic insufficiency, the bioavailability of zolpidem is increased. Clearance is reduced and the elimination half-life is prolonged (approximately 10 hours).

In patients with liver cirrhosis a 5-fold increase in AUC and a 3-fold increase in half-life was observed.

5.3 Preclinical safety data

Preclinical effects were only observed at dosages well above the maximum human exposure levels and are therefore of little significance for clinical use.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Tablet core:

Magnesium stearate Microcrystalline cellulose Lactose monohydrate

Silica, colloidal anhydrous

Sodium starch glycollate (Type A) Succinic acid

Tablet coating:

Lactose monohydrate

Macrogol 4000 Hypromellose

Titanium dioxide (colouring agent E 171)

6.2 Incompatibilities

Not applicable

6.3 Shelf life

3 years

6.4    Special precautions for storage

No special precautions for storage.

6.5    Nature and contents of container

The film-coated tablets are packed in polyvinylchloride/aluminium blisters and inserted into a carton.

The packages contain 10, 20, 28, 30, 50, 98, 100 film-coated tablets.

Not all pack sizes may be marketed.

6.6    Special precautions for disposal and other handling

No special requirements for disposal.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.