A white, capsule-shaped film coated tablet; imprinted with "122" on one side and breakline on the other side.
Each tablet contains: Zolpidem hemitartrate 10 mg.
ATC code: N05CF02.
Pharmacology: Pharmacodynamics: (GABA-A receptor modulator selective for omega-1 receptor subtype hypnotic agent).
Zolpidem hemitartrate 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 hemitartrate. These effects are reversed by the benzodiazepine antagonist flumazenil.
Zolpidem hemitartrate 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 hemitartrate has generally been shown to preserve sleep stages. At the recommended dose, zolpidem hemitartrate 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 hemitartrate. All identified effects of zolpidem hemitartrate are reversed by the benzodiazepine antagonist flumazenil.
Pharmacokinetics: Zolpidem hemitartrate 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 hemitartrate 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/Lg in the very elderly.
All metabolites are pharmacologically inactive and are eliminated in the urine (56%) and in the faeces (37%).
Zolpidem hemitartrate 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 hemitartrate 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 hemitartrate metabolism, possible interactions with drugs that are substrates or inducers of CYP3A4 should be considered.
Indications are limited to treatment of severe sleep disorders in the following cases: Occasional insomnia; Transient insomnia.
Route of administration: Oral.
The treatment should always be implemented at the lowest effective dose and maximum dosage never exceeded. The usual dose for adults is one 10-mg tablet daily. The medicinal product should always be taken just before going to bed.
In elderly subjects or subjects presenting with hepatic insufficiency: dosage should be halved, i.e. 5 mg. Dosage must never exceed 10 mg per day.
Safety and effectiveness of Zolpidem in paediatric patients under the age of 18 years have not been established. Therefore, Zolpidem hemitartrate should not be prescribed in this population.
Zolpidem hemitartrate can be prescribed either continuously or on demand, depending on the patient's symptoms.
Treatment duration: The treatment period should be as short as possible, from a few days to four weeks, including the tapering period (see Precautions).
The patient should be advised to take the treatment as follows: 2 to 5 days for occasional insomnia (e.g. during a trip); 2 to 3 weeks for transient insomnia (e.g. during a troubled period).
Very short treatment periods do not require any gradual treatment discontinuation. For certain patients, it may be necessary to continue treatment for longer than four weeks, in which case careful and repeated reassessment of the patient's condition is necessary.
Signs and Symptoms: In cases of overdose involving zolpidem hemitartrate alone or with other CNS-depressant agents (including alcohol), impairment of consciousness ranging from somnolence to coma and 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 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).
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.
Zolpidem hemitartrate is contraindicated in patients with a hypersensitivity to zolpidem hemitartrate or any of the inactive ingredients, obstructive sleep apnoea, myasthenia gravis, severe hepatic insufficiency, acute and/or severe respiratory depression. In the absence of data, zolpidem hemitartrate should not be prescribed for children or patients with psychotic illness.
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.
Depression: As with other sedative/hypnotic drugs, zolpidem hemitartrate 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.
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 hemitartrate or any other hypnotic, since they are at risk of habituation and psychological dependence.
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 as follows.
Tolerance: Some loss of efficacy to the hypnotic effects of short-acting benzodiazepines and benzodiazepine-like agents like zolpidem may develop after repeated use for a few weeks.
Dependence: Use of benzodiazepines or benzodiazepine-like 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 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 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.
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: Complex sleep-related behaviours which may include sleep driving, making phone calls, preparing and eating food while asleep.
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 patients and others (see Interactions and Adverse Reactions).
Anaphylaxis (severe allergic reaction) and angioedema (severe facial swelling) which can occur as early as the first time the product is taken.
Effects on 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 the morning after therapy. In order to minimise this risk a resting period of 7 to 8 hours is recommended between taking zolpidem hemitartrate and driving.
Hepatic Insufficiency: 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 to 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.
Use in Children: Safety and effectiveness of zolpidem have not been established in patients below the age of 18 years.
Although animal studies have shown no teratogenic or embryotoxic effects, safety in pregnancy has not been established. As with all drugs zolpidem hemitartrate should be avoided in pregnancy particularly during the first trimester.
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, for compelling medical reasons, zolpidem hemitartrate 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 hemitartrate 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 have developed physical dependence and may be at some risk of developing withdrawal symptoms in the postnatal period.
Small quantities of zolpidem hemitartrate appear in breast milk. The use of zolpidem hemitartrate in nursing mothers is therefore not recommended.
The following CIOMS frequency rating is used when applicable: Very common, Common, Uncommon, Rare, Very rare, Not known: cannot be estimated based on available data.
There is evidence of a dose-relationship for adverse effects associated with zolpidem hemitartrate use, particularly for certain CNS and gastrointestinal events. As recommended in Dosage & Administration, they should in theory be less if zolpidem hemitartrate is taken immediately before retiring, or in bed. They occur most frequently in elderly patients.
Immune system disorders: Not known: angioneurotic oedema.
Psychiatric disorders: Common: hallucination. agitation, nightmare. Uncommon: confusional state, irritability. Not known: restlessness, aggression, delusion, anger, psychosis, abnormal behaviour, somnambulism (see Precautions), dependence (withdrawal symptoms, or rebound effects may occur after treatment discontinuation), libido disorder.
Most of these psychiatric undesirable effects are related to paradoxical reactions.
Nervous system disorders: Common: somnolence, headache, dizziness, exacerbated insomnia, anterograde amnesia: (amnestic effects may be associated with inappropriate behaviour). Not known: depressed level of consciousness.
Eye disorders: Uncommon: diplopia.
Gastrointestinal Disorders: Common: diarrhea.
Hepatobiliary disorders: Not known: Liver enzymes elevated.
Skin and subcutaneous tissue disorders: Not known: rash, pruritus, urticaria.
Musculoskeletal and connective tissue disorders: Not known: muscular weakness.
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).
Not recommended: Concomitant intake with alcohol.
The sedative effect may be enhanced when the product is used in combination with alcohol. This affects the ability to drive or use machines.
Take into account: Combination with 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.
Zolpidem hemitartrate appears to interact with sertraline. This interaction may cause increased drowsiness. Also, isolated cases of visual hallucinations were reported.
In the case of narcotic analgesics enhancement of euphoria may also occur leading to an increase in psychological dependence.
CYP450 Inhibitors: Compounds which inhibit certain hepatic enzymes (particularly cytochrome P450) may enhance the activity of benzodiazepines and benzodiazepine-like agents.
Zolpidem hemitartrate is metabolised via several hepatic cytochrome P450 enzymes, the main enzyme being CYP3A4 with the contribution of CYP lA2. The pharmacodynamic effect of zolpidem hemitartrate is decreased when it is administered with rifampicin (a CYP3A4 inducer). However when zolpidem hemitartrate 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 (200 mg 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 when co-administered with ketoconazole, increased by a factor of 1.83 when compared with 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.
Since CYP3A4 plays an important role in zolpidem hemitartrate metabolism possible interactions with drugs that are substrates or inducers of CYP3A4 should be considered.
Other drugs: When zolpidem hemitartrate was administered with ranitidine or cimetidine, no significant pharmacokinetic interactions were observed.
Store below 30°C. Protect from light and moisture.
N05CF02 - zolpidem ; Belongs to the class of benzodiazepine related agents. Used as hypnotics and sedatives.
Avonox FC tab 10 mg
10 × 10's
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