Signs and symptoms:
In cases of overdose involving zolpidem tartrate alone or with other CNS-depressant agents (including alcohol), impairment of consciousness ranging from somnolence 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. Sedating drugs should be withheld even if excitation occurs.
Use of flumazenil may be considered where serious symptoms are observed. Flumazenil is reported to have an elimination half-life of about 40 - 80 minutes. Patients should be kept under close observation because of this short duration of action; further doses of flumazenil may be necessary. However, flumazenil administration may contribute to the appearance of neurological symptoms (convulsions).
Zolpidem is not dialyzable. The value of dialysis in the treatment of an overdose has not been determined. Dialysis in patients with renal failure receiving therapeutic doses of zolpidem have demonstrated no reduction in levels of zolpidem.
In the management of overdose with any medicinal product, it should be borne in mind that multiple agents may have been taken.
3 years.
-
- Obstructive sleep apnoea.
- Myasthenia gravis.
- Severe hepatic insufficiency.
- Acute and/or severe respiratory depression.
In the absence of data, zolpidem tartrate should not be prescribed for children or patients with psychotic illness.
None known
Tablet core:
- Lactose monohydrate
- Microcrystalline cellulose
- Hypromellose
- Sodium starch glycollate
- Magnesium stearate
Film coating:
- Hypromellose
- Titanium dioxide (E171)
- Polyethylene glycol 400
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 tartrate use, particularly for certain CNS and gastrointestinal events. They occur most frequently in elderly patients.
Immune system disorders
Not known: angioneurotic oedema
Psychiatric disorders
Common: hallucination, agitation, nightmare, depression
Uncommon: confusional state, irritability, restlessness, aggression, somnambulism , euphoric mood
Rare: libido disorder
Very rare: delusion, dependence (withdrawal symptoms, or rebound effects may occur after treatment discontinuation)
Not known: anger, psychosis, abnormal behaviour
Most of these psychiatric undesirable effects are related to paradoxical reactions
Nervous system disorders
Common: somnolence, headache, dizziness, exacerbated insomnia, cognitive disorders such as anterograde amnesia (amnestic effects may be associated with inappropriate behaviour)
Uncommon: paraesthesia, tremor, disturbance in attention, speech disorder
Rare: depressed level of consciousness
Eye disorders
Uncommon: diplopia, vision blurred
Very rare: visual impairment
Respiratory, thoracic and mediastinal disorders
Very rare: respiratory depression
Gastrointestinal disorders
Common: diarrhea, nausea, vomiting, abdominal pain
Hepatobiliary disorders
Uncommon: liver enzymes elevated
Rare: hepatocellular, cholestatic or mixed liver injury
Metabolism and nutrition disorders
Uncommon: appetite disorder
Skin and subcutaneous tissue disorders
Uncommon: rash, pruritus, hyperhidrosis
Rare: urticaria
Musculoskeletal and connective tissue disorders
Common: back pain
Uncommon: myalgia, muscle spasms, muscular weakness
Infections and infestations
Common: upper respiratory tract infection, lower respiratory tract infection
General disorders and administration site conditions
Common: fatigue
Rare: gait disturbance, fall (predominantly in elderly patients and when zolpidem was not taken in accordance with prescribing recommendation).
Not known: drug tolerance
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 Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.
No data of therapeutic relevance.
(GABA-A receptor modulator selective for omega-1 receptor subtype hypnotic agent).
Zolpidem tartrate is an imidazopyridine which preferentially binds the omega-1 receptor subtype (also known as the benzodiazepine-1 subtype) which corresponds to GABA-A receptors containing the alpha-1 sub-unit, whereas benzodiazepines non-selectively bind both omega-1 and omega-2 subtypes. 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 man: zolpidem tartrate decreases sleep latency and the number of awakenings, and increases sleep duration and sleep quality. These effects are associated with a characteristic EEG profile, different from that of the benzodiazepines. In studies that measured the percentage of time spent in each sleep stage, zolpidem tartrate has generally been shown to preserve sleep stages. At the recommended dose, zolpidem tartrate has no influence on the paradoxical sleep duration (REM). 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.
The randomized trials only showed convincing evidence of efficacy of 10 mg zolpidem tartrate.
In a randomized double-blind trial in 462 non-elderly healthy volunteers with transient insomnia, zolpidem tartrate 10 mg decreased the mean time to fall asleep by 10 minutes compared to placebo, while for 5 mg zolpidem tartrate this was 3 minutes.
In a randomized double-blind trial in 114 non-elderly patients with chronic insomnia, zolpidem tartrate 10 mg decreased the mean time to fall asleep by 30 minutes compared to placebo, while for 5 mg zolpidem tartrate this was 15 minutes.
In some patients, a lower dose of 5 mg could be effective.
Paediatric population
Safety and efficacy of zolpidem tartrate 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 tartrate 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 tartrate versus placebo and included dizziness (23.5% versus 1.5%), headache (12.5% versus 9.2%), and hallucinations (7.4% versus 0%).
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 (± 0.2 h) 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 tartrate 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.
Zolpidem tartrate is metabolised via several hepatic cytochrome P450 enzymes, the main enzyme being CYP3A4 with the contribution of CYP1A2. Since CYP3A4 plays an important role in zolpidem tartrate metabolism, possible interactions with drugs that are substrates or inducers of CYP3A4 should be considered.
21/05/2018
Aventis Pharma Limited
One Onslow Street
Guildford
Surrey
GU1 4YS
UK
or trading as
Sanofi-aventis or Sanofi
One Onslow Street
Guildford
Surrey
GU1 4YS
UK
Store in a dry place below 30°C
Cartons of 4, 14, 28 or 56 tablets in PVC/foil blister strips of 7 or 14 tablets.
PL 04425/0618
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.
Next-day psychomotor impairment
Like other sedative/hypnotic drugs, Stilnoct has CNS-depressant effects. The risk of next-day psychomotor impairment, including impaired driving ability, is increased if:
- zolpidem tartrate is taken within less than 8 hours before performing activities that require mental alertness ;
- a dose higher than the recommended dose is taken;
- zolpidem tartrate is co-administered with other CNS depressants or with other drugs that increase the blood levels of zolpidem tartrate, or with alcohol or illicit drugs.
Zolpidem tartrate should be taken in a single intake immediately at bedtime and not be re-administered during the same night.
Specific patient groups
Respiratory insufficiency:
As hypnotics have the capacity to depress respiratory drive, precautions should be observed if Stilnoct is prescribed to patients with compromised respiratory function.
Hepatic insufficiency:
Elderly:
Risk from concomitant use of opioids:
Concomitant use of Stilnoct and opioids may result in sedation, respiratory depression, coma and death. Because of these risks, concomitant prescribing of sedative medicines such as benzodiazepines or related drugs such as Stilnoct with opioids should be reserved for patients for whom alternative treatment options are not possible.
The patients should be followed closely for signs and symptoms of respiratory depression and sedation. In this respect, it is strongly recommended to inform patients and their environment to be aware of these symptoms.
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.
Psychotic illness:
Hypnotics such as Stilnoct are not recommended for the primary treatment of psychotic illness.
Depression:
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 Stilnoct that is feasible should be supplied to these patients to avoid the possibility of intentional overdose by the patient. Pre-existing depression may be unmasked during use of Stilnoct. Since insomnia may be a symptom of depression, the patient should be re-evaluated if insomnia persists.
General information relating to effects seen following administration of benzodiazepines and other 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 short-acting benzodiazepines and benzodiazepine-like agents like Stilnoct may develop after repeated use for a few weeks.
Dependence:
Use of benzodiazepines or benzodiazepine-like agents like Stilnoct 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 benzodiazepine or benzodiazepine-like agent 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. 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.
There are indications that, in the case of benzodiazepines and benzodiazepine-like agents with a short duration of action, withdrawal phenomena can become manifest within the dosage interval, especially when the dosage is high.
Amnesia:
Benzodiazepines or benzodiazepine-like agents such as Stilnoct may induce anterograde amnesia. The condition occurs most often 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.
Other psychiatric and “paradoxical†reactions:
Other psychiatric and paradoxical reactions like restlessness, exacerbated insomnia, agitation, irritability, aggression, delusion, anger, nightmares, hallucinations, psychosis, abnormal behaviour and other adverse behavioural effects are known to occur when using benzodiazepines or benzodiazepine-like agents. Should this occur, use of the product should be discontinued. These reactions are more likely to occur in the elderly.
Somnambulism and associated behaviours:
Sleep walking and other associated behaviours such as “sleep drivingâ€, preparing and eating food, making phone calls or having sex, with amnesia for the event, have been reported in patients who had taken Stilnoct and were not fully awake. The use of alcohol and other CNS-depressants with Stilnoct appears to increase the risk of such behaviours, as does the use of Stilnoct at doses exceeding the maximum recommended dose. Discontinuation of Stilnoct should be strongly considered for patients who report such behaviours (for example, sleep driving), due to the risk to the patient and others.
Severe injuries:
Due to its pharmacological properties, zolpidem can cause drowsiness and a decreased level of consciousness, which may lead to falls and consequently to severe injuries.
Stilnoct 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. In order to minimise this risk a resting period of at least 8 hours is recommended between taking zolpidem tartrate and driving, using machinery and working at heights.
Driving ability impairment and behaviours such as 'sleep-driving' have occurred with zolpidem tartrate alone at therapeutic doses.
Furthermore, the co-administration of zolpidem tartrate with alcohol and other CNS depressants increases the risk of such behaviours. Patients should be warned not to use alcohol or other psychoactive substances when taking zolpidem tartrate.
Posology
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 tartrate should be used and must not exceed 10 mg.
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.
As with all hypnotics, long-term use is not recommended and a course of treatment should not exceed four weeks.
Special populations
Paediatric population
Stilnoct 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.
Elderly
Elderly or debilitated patients may be especially sensitive to the effects of zolpidem tartrate therefore a 5 mg dose is recommended. These recommended doses should not be exceeded.
Hepatic impairment
As clearance and metabolism of zolpidem tartrate is reduced in hepatic impairment, dosage should begin at 5 mg in these patients with particular caution being exercised in elderly patients. In adults (under 65 years) dosage may be increased to 10 mg only where the clinical response is inadequate and the drug is well tolerated.
Zolpidem must not be used in patients with severe hepatic impairment as it may contribute to encephalopathy.
Method of administration
Oral administration.
Please consult the package insert before use. Do not use after the stated expiry date on the carton and blister.
KEEP OUT OF THE REACH OF CHILDREN
03 December 2009
