Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2019 Publisher: Aventis Pharma Limited, 410 Thames Valley Park Drive, Reading, Berkshire, RG6 1PTUK Trading as: Sanofi, 410 Thames Valley Park Drive, Reading, Berkshire, RG6 1PTUK
In the absence of data, zolpidem tartrate should not be prescribed for children or patients with psychotic illness.
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.
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 should be taken in a single intake immediately at bedtime and not be re-administered during the same night.
As hypnotics have the capacity to depress respiratory drive, precautions should be observed if Stilnoct is prescribed to patients with compromised respiratory function.
See section 4.2.
See section 4.2 for dose recommendations.
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.
If a decision is made to prescribe Stilnoct concomitantly with opioids, the lowest effective dose should be used, and the duration of treatment should be as short as possible (see also general dose recommendation in section 4.2).
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 (see section 4.5).
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.
Hypnotics such as Stilnoct are not recommended for the primary treatment of psychotic illness.
Some epidemiological studies suggest an increased incidence of suicidal ideation, suicide attempt and suicide in patients with or without depression, and treated with benzodiazepines and other hypnotics, including zolpidem. However, a causal relationship has not been established.
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.
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.
Use of zolpidem may lead to the development of abuse and/or physical and psychological dependence. The risk of dependence increases with dose and duration of treatment. The risk of abuse and dependence is also greater in patients with a history of psychiatric disorders and/or alcohol, substance or drug abuse. Zolpidem should be used with extreme caution in patients with current or a history of alcohol, substance or drug abuse or dependence.
If physical dependence is developed, a sudden discontinuation of treatment will be accompanied by withdrawal symptoms. These may consist of headaches, muscle pain, extreme anxiety, 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.
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.
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 (see section 4.8).
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.
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 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 (see sections 4.5 and 4.8).
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.
The sedative effect may be enhanced when the product is used in combination with alcohol. This affects the ability to drive or use machines.
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 Stilnoct with these drugs may increase drowsiness and next-day psychomotor impairment, including impaired driving ability (see sections 4.4 and 4.7). Also, isolated cases of visual hallucinations were reported in patients taking Stilnoct with antidepressants including bupropion, desipramine, fluoxetine, sertraline and venlafaxine.
Co-administration of fluvoxamine may increase blood levels of zolpidem tartrate, concurrent use is not recommended.
In the case of narcotic analgesics enhancement of euphoria may also occur leading to an increase in psychological dependence.
The concomitant use of sedative medicines such as benzodiazepines or related drugs such as Stilnoct with opioids increases the risk of sedation, respiratory depression, coma and death because of additive CNS depressant effect. The dosage and duration of concomitant use should be limited (see section 4.4).
Co-administration of ciprofloxacin may increase blood levels of zolpidem tartrate, concurrent use is not recommended.
Compounds which inhibit certain hepatic enzymes (particularly cytochrome P450) may enhance the activity of benzodiazepines and benzodiazepine-like agents.
Zolpidem tartrate is metabolised via several hepatic cytochrome P450 enzymes, the main enzyme being CYP3A4 with the contribution of CYP1A2. The pharmacodynamic effect of zolpidem tartrate is decreased when it is administered with a CYP3A4 inducer such as rifampicin and St. John’s Wort. St. John’s Wort has been shown to have a pharmacokinetic interaction with zolpidem. Mean Cmax and AUC were decreased (33.7 and 30.0% lower, respectively) for zolpidem administered with St. John’s Wort compared to zolpidem administered alone. Co-administration of St. John’s Wort may decrease blood levels of zolpidem, concurrent use is not recommended.
However when zolpidem tartrate 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 Stilnoct with ketoconazole (200 mg twice daily), a potent CYP3A4 inhibitor, prolonged Stilnoct elimination half-life, increased total AUC, and decreased apparent oral clearance when compared to Stilnoct plus placebo. The total AUC for Stilnoct, when co-administered with ketoconazole, increased by a factor of 1.83 when compared to Stilnoct alone. A routine dosage adjustment of Stilnoct is not considered necessary, but patients, should be advised that use of Stilnoct with ketoconazole may enhance the sedative effects.
Since CYP3A4 plays an important role in zolpidem tartrate metabolism, possible interactions with drugs that are substrates or inducers of CYP3A4 should be considered.
When zolpidem tartrate was administered with ranitidine, no significant pharmacokinetic interactions were observed.
The use of zolpidem is not recommended during pregnancy.
Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity.
Zolpidem crosses the placenta.
A large amount of data on pregnant women (more than 1000 pregnancy outcomes) collected from cohort studies has not demonstrated evidence of the occurrence of malformations following exposure to benzodiazepines or benzodiazepine-like substances during the first trimester of pregnancy. However, certain case-control studies reported an increased incidence of cleft lip and palate associated with use of benzodiazepines during pregnancy.
Cases of reduced fetal movement and fetal heart rate variability have been described after administration of benzodiazepines or benzodiazepine-like substances during the second and/or third trimester of pregnancy.
Administration of zolpidem during the late phase of pregnancy or during labour has been associated with effects on the neonate, such as hypothermia, hypotonia, feeding difficulties (‘floppy infant syndrome’) and respiratory depression due to the pharmacological action of the product. Cases of severe neonatal respiratory depression have been reported.
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 risk of developing withdrawal symptoms in the postnatal period. Appropriate monitoring of the newborn in the postnatal period is recommended.
If Stilnoct 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.
Small quantities of zolpidem tartrate appear in breast milk. The use of zolpidem tartrate in nursing mothers is therefore not recommended.
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 (see section 4.8). 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 (see sections 4.4 and 4.5). Patients should be warned not to use alcohol or other psychoactive substances when taking zolpidem tartrate.
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. As recommended in section 4.2, they should in theory be less if zolpidem tartrate is taken immediately before retiring, or in bed. They occur most frequently in elderly patients.
Not known: angioneurotic oedema
Common: hallucination, agitation, nightmare, depression (see section 4.4)
Uncommon: confusional state, irritability, restlessness, aggression, somnambulism (see section 4.4), 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
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
Uncommon: diplopia, vision blurred
Very rare: visual impairment
Very rare: respiratory depression (see section 4.4)
Common: diarrhea, nausea, vomiting, abdominal pain
Uncommon: liver enzymes elevated
Rare: hepatocellular, cholestatic or mixed liver injury (see sections 4.2, 4.3 and 4.4)
Uncommon: appetite disorder
Uncommon: rash, pruritus, hyperhidrosis
Rare: urticaria
Common: back pain
Uncommon: myalgia, muscle spasms, muscular weakness
Common: upper respiratory tract infection, lower respiratory tract infection
Common: fatigue
Rare: gait disturbance, fall (predominantly in elderly patients and when zolpidem was not taken in accordance with prescribing recommendation) (see section 4.4).
Not known: drug tolerance
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.
None known.
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