SANOFI

Stilnoct 10mg Film-coated Tablets

Each tablet contains:

Zolpidem tartrate 10mg

Also contains Lactose 90.4mg.

For a full list of excipients, see section 6.1.

Film-coated tablet.

Oblong, white, scored tablet engraved SN10.

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

For oral use.

Zolpidem tartrate acts rapidly and therefore should be taken immediately before retiring, or in bed.

The recommended daily dose for adults is 10 mg.

As with all hypnotics, long-term use of zolpidem is not recommended and a course of treatment should not exceed four weeks.

In certain cases extension beyond the maximal treatment period may be necessary; if so, this should not take place without revaluation of the patients status.

The duration of treatment should usually vary from a few days to two weeks with a maximum of four weeks including tapering off where clinically appropriate.

Special Populations

Children:

Safety and effectiveness of zolpidem in paediatric patients under the age of 18 years have not been established. Therefore, zolpidem should not be prescribed in this population (see Precautions: Paediatric Patients)

Elderly:

Elderly or debilitated patients may be especially sensitive to the effects of zolpidem , in these subjects a 5mg dose is recommended. The zolpidem dose should not exceed 10mg in this population.

Hepatic Impairment:

As clearance and metabolism of zolpidem tartrate is reduced in hepatic impairment, dosage should begin at 5mg in these patients, with particular caution being exercised in elderly patients. In adults (under 65 years) dosage may be increased to 10mg only where the clinical response is inadequate and the drug is well tolerated.

Zolpidem tartrate is contraindicated in patients with a hypersensitivity to zolpidem or any of the inactive ingredients, severe hepatic insufficiency, acute and/or severe respiratory insufficiency.

Warnings:

Zolpidem should be used with caution in patients with sleep apnoea syndrome, and myasthenia gravis.

Respiratory Insufficiency:

As hypnotics have the capacity to depress respiratory drive precautions should be observed if zolpidem is prescribed to patients with compromised respiratory function.

Hepatic Insufficiency:

See dose recommendations.

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.

4.4.1 Specific patient groups

Elderly: See dose recommendations. Due to the myorelaxant effect, there is a risk of falls and consequent injury, particularly for elderly patients when they get up at night.

Psychotic illness:

Hypnotics such as zolpidem are not recommended for the primary treatment of psychotic illness.

Paediatric Patients:

Safety and effectiveness of zolpidem have not been established in patients below the age of 18 years. In an 8-week study in paediatric patients (aged 6-17 years) with insomnia associated with attention-deficit/hyperactivity disorder (ADHD), psychiatric and nervous system disorders comprised the most frequent treatment emergent adverse events observed with zolpidem versus placebo and included dizziness (23.5% vs 1.5%), headache (12.5% vs 9.2%), and hallucinations (7.4% vs. 0%). (See section 4.2 Posology and method of Administration).

Use in patients with a history of drug or alcohol abuse:

Extreme caution should be exercised when prescribing for patients with a history of drug or alcohol abuse. These patients should be under careful surveillance when receiving zolpidem tartrate or any other hypnotic, since they are at risk of habituation and psychological dependence.

Amnesia:

Sedative/hypnotic agents such as zolpidem 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: Although no clinically significant pharmacokinetic and pharmacodynamic interactions with SSRIs have been demonstrated (see section 4.5 Interactions with other medicinal products and other forms of interactions), as with other sedative/hypnotic drugs, zolpidem tartrate should be administered with caution in patients exhibiting symptoms of depression. Suicidal tendencies may be present therefore the least amount of zolpidem that is feasible should be supplied to these patients to avoid the possibility of intentional overdosage by the patient. Pre-existing depression may be unmasked during use of zolpidem. Since insomnia may be a symptom of depression, the patient should be re-evaluated if insomnia persists.

4.4.2 General information

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

Tolerance:

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

Dependence:

Use of sedative/hypnotic agents like zolpidem 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 a 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. Since the risk of withdrawal phenomena or rebound has been shown to be greater after abrupt discontinuation of treatment, it is recommended that the dosage is decreased gradually where clinically appropriate.

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.

In the case of sedative/hypnotic agents with a short duration of action, withdrawal phenomena can become manifest within the dosage interval.

Other Psychiatric and "paradoxical" reactions:

Other Psychiatric and “paradoxical” reactions like restlessness, insomnia exacerbated, agitation, irritability, aggression, delusion, anger, nightmares, hallucinations, abnormal behaviour and other adverse behavioural effects are known to occur when using sedative/hypnotic agents like zolpidem. Should this occur, use of the product should be discontinued. These reactions are more likely to occur in the elderly.

Somambulism 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 section 4.5 Interactions with other medicinal products and other forms of interaction and section 4.8 Undesirable effects).

Intolerance:

Patients with rare hereditary problems of galactose intolerance, the lapp lactose deficiency or glucose-galactose malabsorption should not take this medicine.

Alcohol: 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.

CNS depressants.

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. However, in the case of SSRI antidepressant agents (fluoxetine and sertraline), no clinically significant pharmacokinetic or pharmacodynamic interactions have been observed.

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

CYP450 inhibitors and inducers:

Compounds which inhibit certain hepatic enzymes (particularly cytochrome P450) may enhance the activity of some hypnotics like zolpidem.

Zolpidem is metabolised via several hepatic cytochrome P450 enzymes, the main enzyme being CYP3A4 with the contribution of CYP1A2. The pharmacodynamic effect of zolpidem is decreased when it is administered with rifampicin (a CYP3A4 inducer).

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

Co-administration of zolpidem with ketoconazole (200mg twice daily), a potent CYP3A4 inhibitor, prolonged zolpidem elimination half-life, increased total AUC, and decreased apparent oral clearance when compared to zolpidem plus placebo. The total AUC for zolpidem was increased modestly, when co-administered with ketoconazole, it increased by a factor of 1.83 when compared to zolpidem alone. A routine dosage adjustment of zolpidem is not considered necessary, but patients should be advised that use of zolpidem with ketoconazole may enhance the sedative effects.

Other drugs: When zolpidem was administered with warfarin, digoxin, ranitidine or cimetidine, no significant pharmacokinetic interactions were observed.

Pregnancy

As a precautionary measure, it is preferable to avoid the use of zolpidem in pregnancy.

For zolpidem, no or very limited amount of data on pregnant patients are available. Animal studies do not indicate direct harmful effects with respect to reproduction toxicity development.

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

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

Moreover, infants born to mothers who took sedative/hypnotic agents chronically during the latter stages of pregnancy may have developed physical dependence and may be at some risk of developing withdrawal symptoms in the postnatal period.

Lactation

Small quantities of zolpidem tartrate appear in breast milk. The use of zolpidem in nursing mothers is therefore not recommended.

Vehicle drivers and machine operators should be warned that, as with other hypnotics, there may be a possible risk of drowsiness the morning after therapy. In order to minimise this risk a full night sleep (7-8 hours) is recommended.

The following CIOMS frequency rating is used, when applicable: Very common > 10%; common > 1 and < 10%; Uncommon > 0.1 and < 1%; Rare > 0.01 and < 0.1%; Very rare <0.01%.

Not known: Cannot be estimated based on available data.

There is evidence of a dose-relationship for adverse effects associated with zolpidem use, particularly for certain CNS events. As recommended in section 4.2 Posology and method of administration, they should in theory, be less if zolpidem is taken immediately before retiring, or in bed. They occur most frequently in elderly patients.

Nervous System disorders:

Common: somnolence, headache, dizziness, exacerbated insomnia, anterograde amnesia: (amnestic effects may be associated with inappropriate behaviour)

Not know: depressed level of consciousness.

Psychiatric disorders:

Common: Hallucination, agitation, nightmare.

Uncommon: confusional state, irritability.

Not Known: restlessness, aggression, delusion, anger, abnormal behaviour, somnambulism, (See section 4.4 Special warnings and precautions for use: Somnambulism and associated behaviours),dependence (drug withdrawal syndrome, or rebound effects may occur after treatment discontinuation), libido disorder, depression (see section 4.4).

Most of these psychiatric undesirable effects are related to paradoxical reactions.

General Disorders and administration site conditions

Common: fatigue

Not known: gait disturbance, drug tolerance, fall (predominantly in elderly patients and when zolpidem was not taken in accordance with prescribing recommendation.

Eye Disorders

Uncommon: diplopia

Respiratory, thoracic and mediastinal disorders

Not Known: respiratory depression (see section 4.4)

Gastro-intestinal Disorders:

Common: diarrhoea, nausea, vomiting, abdominal pain.

Musculoskeletal and connective tissue disorder

Not known: muscular weakness.

Infections and infestations

Common: upper respiratory tract infection, lower respiratory tract infection

Skin and subcutaneous tissue disorders

Not known: rash, pruritus, urticariam hyperhidrosis.

Hepatobiliary disorders

Not known: liver enzymes elevated.

Immune system disorders: Not known: angioneurotic oedema.

Signs & Symptoms:

In cases of overdose involving zolpidem alone or with other CNS-depressant agents (including alcohol), impairment of consciousness up to coma, and more severe symptomatology, including fatal outcomes have been reported.

Management:

General symptomatic and supportive measures should be used. If there is no advantage in emptying the stomach, activated charcoal should be given to reduce absorption. Special attention should be paid to respiratory and cardiovascular functions in intensive care. Sedating drugs should be withheld even if excitation occurs. Use of flumazenil may be considered where serious symptoms are observed. However, flumazenil administration may contribute to the appearance of neurological symptoms (convulsions).

Zolpidem is not dialyzable.

(GABA-A receptor agonist selective for omega-1-type sub-unit hypnotic agent).

Zolpidem tartrate is an imidazopyridine which 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 non-selectively bind all three omega receptor subtypes, zolpidem preferentially binds the omega-1 subtype. The clinical relevance is not known. The modulation of the chloride anion channel via this receptor leads to the specific sedative effects demonstrated by zolpidem tartrate. These effects are reversed by the benzodiazepine antagonist flumazenil.

In animals: The selective binding of zolpidem tartrate to omega-1 receptors may explain the virtual absence at hypnotic doses of myorelaxant and anti-convulsant 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 tartrate. All identified effects of zolpidem tartrate are reversed by the benzodiazepine antagonist flumazenil.

Preliminary single dose studies did not reveal respiratory depressant effects in normal subjects or in mild or moderate COPD.

Zolpidem tartrate has both a rapid absorption and onset of hypnotic action. Bioavailability is 70% following oral administration and demonstrates linear kinetics in the therapeutic dose range. Peak plasma concentration is reached at between 0.5 and 3 hours.

The elimination half-life is short, with a mean of 2.4 hours (0.7-3.5) and a duration of action of up to 6 hours.

Protein binding amounts to 92.5% ± 0.1%. 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.

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.

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

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

Plasma concentrations in elderly subjects and those with hepatic impairment are increased. In patients with renal insufficiency, whether dialysed or not, there is a moderate reduction in clearance. The other pharmacokinetic parameters are unaffected.

No data of therapeutic relevance.

Tablet core:

Lactose

Microcrystalline cellulose

Hypromellose

Sodium starch glycollate (Type A)

Magnesium stearate.

Film coating:

Hypromellose

Titanium dioxide (E171)

Macrogol 400.

Not applicable

4 years.

No special precautions for storage.

Cartons of 28 tablets in PVC/foil blister strips.

No special requirements

sanofi-aventis Ireland Ltd T/A SANOFI.

Citywest Business Campus

Dublin 24

Ireland

PA540/160/2

25 February 1993/9 June 2007

22 February 2013.