Zolpi

Zolpidem Tartrate 10 mg Tablets

Each tablet contains 10 mg zolpidem tartrate.

Film-coated tablet.

White to off-white, film-coated oblong tablet, scored and engraved SN10 on one side.

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

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 should be used and must not exceed 10 mg.

As with all hypnotics, long-term use is not recommended and a course of treatment should not exceed four weeks. 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. In certain cases extension beyond the maximal treatment period may be necessary; if so, this should not take place without re-evaluation of the patient's status.

Special populations

Paediatric population

Zolpidem 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 therefore a 5 mg dose is recommended. These recommended doses should not be exceeded.

Hepatic impairment

As clearance and metabolism of zolpidem 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.

-

- Obstructive sleep apnoea.

- Myasthenia gravis.

- Severe hepatic insufficiency.

- Acute and/or severe respiratory depression.

In the absence of data, zolpidem 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.

Next-day psychomotor impairment

Like other sedative/hypnotic drugs, zolpidem has CNS-depressant effects. The risk of next-day psychomotor impairment, including impaired driving ability, is increased if:

- zolpidem is taken within less than 8 hours before performing activities that require mental alertness ;

- a dose higher than the recommended dose is taken;

- zolpidem is co-administered with other CNS depressants or with other drugs that increase the blood levels of zolpidem, or with alcohol or illicit drugs.

Zolpidem 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 zolpidem is prescribed to patients with compromised respiratory function.

Hepatic insufficiency:

Elderly:

Risks from concomitant use with opioids:

Concomitant use of zolpidem 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 zolpidem 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 zolpidem are not recommended for the primary treatment of psychotic illness.

Depression:

As with other sedative/hypnotic drugs, zolpidem 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 overdose 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.

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 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 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 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 behaviour, 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 behaviour (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.

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, 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.

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 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

Gastro-intestinal disorders

Common: diarrhoea, 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 the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

Signs and symptoms:

In cases of overdose, involving zolpidem 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 has 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.

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

Zolpidem 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 modulation of the chloride anion channel via this receptor leads to the specific sedative effects demonstrated by zolpidem. These effects are reversed by the benzodiazepine antagonist flumazenil.

The randomized trials only showed convincing evidence of efficacy of 10 mg zolpidem. In a randomized 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 randomized 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.

In animals: The selective binding of zolpidem 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. All identified effects of zolpidem are reversed by the benzodiazepine antagonist flumazenil.

Paediatric populations

Safety and efficacy of zolpidem have hot 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 0.25 mg/kg/day (with 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%), hallucinations (7.4% versus 0%).

Zolpidem 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 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 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 metabolism, possible interactions with drugs that are substrates or inducers of CYP3A4 should be considered.

Preclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction.

Tablet core:

- Lactose monohydrate

- Microcrystalline cellulose

- Hypromellose

- Sodium starch glycollate

- Magnesium stearate

Film coating:

- Hypromellose

- Titanium dioxide (E171)

- Macrogol 400

Not applicable

3 years.

No special precautions.

Cartons of 4 or 28 tablets in PVC/foil blister strips.

Not all pack sizes may be marketed.

Not applicable.

Winthrop Pharmaceuticals UK Limited

One Onslow Street

Guildford

Surrey

GU1 4YS

United Kingdom

Trading as: Winthrop Pharmaceuticals, PO Box 611, Guildford, Surrey, GU1 4YS

or

Trading as: Zentiva, One Onslow Street, Guildford, Surrey, GU1 4YS, UK

PL 17780/0018

15 May 2002

21/05/2018