In reports of overdose with zolpidem alone or with other CNS-depressant agents (including alcohol), impairment of consciousness has ranged from somnolence to coma and fatal outcomes have been reported.
Individuals have fully recovered from overdoses up to 400 mg 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 medicinal products should be withheld even if excitation occurs.
Use of flumazenil may be considered when serious symptoms are observed. Flumazenil is reported to have an elimination half-life of about 40 to 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).
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.
2 years
Not applicable.
Tablet core
Lactose monohydrate
Microcrystalline cellulose
Maize starch, pregelatinised
Magnesium stearate.
Film-coating
Hypromellose
Titanium dioxide (E l71)
Polysorbate 80 (E 433)
Macrogol 400
These effects seem to be related with individual sensitivity and to appear more often within the hour following the drug intake if the patient does not go to bed or does not sleep immediately.
The adverse drug reactions are stated in the table below using the following convention:
Very common (>1/10); common (>1/100; <1/10); uncommon (>1/1,000; <1/100); rare (>1/10,000; <1/1,000); very rare (<1/10,000) including isolated reports; not known (cannot be estimated from available data).
There is evidence for a dose connection for reactions associated with use of zolpidem, especially certain CNS reactions and gastrointestinal events. Theoretically they should be less if zolpidem is taken immediately before bedtime. They occur most frequently in elderly patients.
|
SOC |
Frequency | |||
|
Common |
Uncommon |
Rare |
Not known | |
|
Infections and infestations |
Upper respiratory tract infection, lower respiratory tract infection | |||
|
Immune system disorders |
Angioneurotic oedema | |||
|
Psychiatric disorders |
Hallucination, agitation, nightmare, numbed emotions |
Irritability, confusion |
Restlessness, aggression, delusion, anger, psychosis, abnormal behaviour, sleep walking , dependence (withdrawal symptoms, or rebound effects may occur after treatment discontinuation), depression, decreased libido | |
|
Nervous system disorders |
Somnolence, headache, dizziness, increased insomnia, cognitive disorders such as anterograde amnesia: (amnestic effects may be associated with inappropriate behaviour), drowsiness during the following day, reduced alertness |
Ataxia |
Depressed level of consciousness | |
|
Eye disorders |
Double vision | |||
|
Ear and labyrinth disorders |
Vertigo | |||
|
Respiratory, thoracic and mediastinal disorders |
Respiratory depression | |||
|
Gastrointestinal disorders |
Diarrhoea, nausea, vomiting, abdominal pain | |||
|
Hepatobiliary disorders |
Elevated liver enzymes, hepatocellular, cholestatic or mixed liver injury | |||
|
Skin and subcutaneous tissue disorders |
Skin reactions |
Rash, pruritus, urticaria, hyperhidrosis | ||
|
Musculoskeletal and connective tissue disorders |
Back pain |
Muscle weakness | ||
|
General disorders and administration site conditions |
Fatigue |
Paradoxical reactions |
Gait disturbance, drug tolerance, falls (predominantly in elderly patients and when zolpidem was not taken in accordance with prescribing recommendation) | |
These phenomena occur predominantly at the start of the therapy or in elderly patients and usually disappear with repeated administration.
Amnesia
Anterograde amnesia may occur during therapeutic dosages, the risk increasing at higher dosages. In order to reduce the risk, patients should ensure that they will be able to have an uninterrupted sleep of 8 hours. Amnestic effects may be associated with inappropriate behaviour.
Depression
Pre-existing depression may become manifest during use of benzodiazepines or benzodiazepine-like agents.
Psychiatric and “paradoxical†reactions
Reactions like restlessness, agitation, irritability, aggressiveness, delusions, rage, nightmares, increased insomnia, hallucinations, psychoses, inappropriate behaviour and other adverse behavioural effects may occur when using benzodiazepines and benzodiazepine-like agents. Such reactions are more likely to occur in the elderly.
Dependence
Use (even at therapeutic dosages) may lead to physical dependence: discontinuation of the therapy may result in withdrawal or rebound phenomena.
Psychological dependence may occur. Abuse has been reported in polydrug abusers.
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.
Preclinical effects were only observed at dosages well above the maximum human exposure levels and are therefore of little significance for clinical use.
Pharmacotherapeutic group: Hypnotics and Sedatives, Benzodiazepine related drugs
ATC Code: N05C F02
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 randomised trials only showed convincing evidence of efficacy of 10 mg zolpidem.
In a randomised double-blind trial in 462 non-elderly healthy volunteers with transient insomnia, zolpidem 10 mg decreased the mean time to fall asleep by 10 minutes compared to placebo, while for 5 mg zolpidem this was 3 minutes.
In a randomised double-blind trial in 114 non-elderly patients with chronic insomnia, zolpidem 10 mg decreased the mean time to fall asleep by 30 minutes compared to placebo, while for 5 mg zolpidem this was 15 minutes.
In some patients, a lower dose of 5 mg could be effective.
Paediatric population: Safety and efficacy of zolpidem have not been established in children aged less than 18 years. A randomised 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%).
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, including patients on dialysis a moderate reduction in clearance is observed. The other pharmacokinetic parameters remain unaffected.
In elderly patients and in patients with hepatic insufficiency, the bio-availability 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.
July 2016
Generics [UK] Ltd t/a Mylan
Station Close
Potters Bar
Hertfordshire
EN6 1TL
United Kingdom
Do not store above 25°C. Store in the original package.
4, 7, 10, 14, 20, 28, 30, 50, 100 or 250 film-coated tablets in PVC/aluminium blisters or Polypropylene tablet containers with polyethylene caps.
Not all packs sizes may be marketed.
PL 04569/0604
Pregnancy
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 zolpidem is prescribed to a woman of childbearing potential, she should be encouraged to contact her physician regarding discontinuance of the product if she intends to become or suspect 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. Cases of severe neonatal respiratory depression have been reported when zolpidem tartrate was used with other CNS depressants at the end of pregnancy.
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
There are insufficient data to evaluate the safety of using zolpidem while breast-feeding. Zolpidem passes into breast milk in small amounts. Zolpidem should therefore not be used by breast-feeding mothers since effects on the infant are not studied.
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. 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. Patients should be warned not to use alcohol or other psychoactive substances when taking zolpidem.
No special requirements
Date of first authorisation: 09/07/2003
Date of latest renewal: 20/09/2007
