Zolpidem Tartrate 5mg Film-Coated Tablets
Out of date information, search anotherSUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Zolpidem Tartrate 5 mg Filmcoated Tablets
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
One film-coated tablet contains:
5 mg zolpidem tartrate
Excipients: 43 mg lactose/film-coated tablet
For a full list of excipients, see section 6.1.
3 PHARMACEUTICAL FORM
Film-coated tablet.
White, oval, biconvex, film-coated tablet, embossed with ‘ZIM’ and ‘5’ on one side.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Short term treatment of insomnia.
Benzodiazepines or benzodiazepine-like agents are only indicated when the disorder is severe, disabling or subjecting the individual to extreme distress.
4.2 Posology and method of administration
Treatment should be as short as possible. Generally the duration of treatment varies from a few days to two weeks with a maximum, including the tapering off process, of four weeks. The tapering off process should be tailored to the individual.
In certain cases extension beyond the maximum treatment period may be necessary; if so, it should not take place without re-evaluation of the patient's status.
The product should be taken with fluid just before going to bed.
Adults
The recommended daily dose for adults is 10 mg immediately before going to bed. Elderly
In elderly or debilitated patients who may be especially sensitive to the effects of zolpidem a dose of 5 mg is recommended. This dose should only be increased to 10 mg where the clinical response is inadequate and the drug is well tolerated.
Patients with hepatic insufficiency
Patients with hepatic insufficiency who do not clear the drug as rapidly as normal individuals, a dose of 5 mg is recommended. This dose should only be increased to 10 mg where the clinical response is inadequate and the drug is well tolerated.
The total dose of zolpidem should not exceed 10 mg in any patient.
Children and adolescents under 18 years of age
Zolpidemtartrate 5 mg filmcoated tablets is contraindicated in children and adolescents under 18 years of age.
4.3 Contraindications
Hypersensitivity to zolpidem or to any of the excipients
Severe hepatic insufficiency
Sleep apnoea syndrome
Myasthenia gravis
Severe respiratory insufficiency
Children and adolescents under 18 years of age
4.4 Special warnings and precautions for use
General
The cause of insomnia should be identified wherever possible. The underlying factors should be 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, which should be evaluated.
General information relating to effects seen following administration of benzodiazepines or 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 may develop after repeated use for a few weeks.
Dependence
Use of benzodiazepines or benzodiazepine-like agents may lead to the development of physical and psychological dependence on these products.
The risk of dependence increases with dose and duration of treatment and is also greater in patients with a history of psychiatric disorders and/or alcohol or drug abuse. These patients should be monitored carefully when receiving benzodiazepines or benzodiazepine-like agents.
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 benzodiazepines or benzodiazepine-like agent recur in an enhanced form, may occur on withdrawal of hypnotic agent. 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 being discontinued.
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.
As the risk of withdrawal symptoms/rebound phenomena are more likely to develop after abrupt discontinuation of treatment, it is recommended to decrease the dose gradually.
Duration of treatment
The duration of treatment should be as short as possible (see section 4.2), but should not exceed 4 weeks including the tapering off process. Extension beyond these periods should not take place without re-evaluation of the situation.
It may be useful to inform the patient when treatment is started that it will be of limited duration.
Amnesia
Benzodiazepines or benzodiazepine-like agents may induce anterograde amnesia. The condition usually occurs 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 7-8 hours (see section 4.8).
Psychiatric and ‘paradoxical’ reactions
When using benzodiazepines or benzodiazepine-like agents, reactions like restlessness, agitation, irritability, aggressiveness, delusion, rages, nightmares, hallucinations, phychoses, somnambulism, inappropriate behaviour, increased insomnia and other adverse behavioural effects are known to occur. Should this occur, use of the product should be discontinued. These reactions are more likely to occur in the elderly.
Somnambulism and associated behaviour:
Sleep walking and other associated behaviour such as “sleep driving”, preparing and eating food, or making phone calls and having sex, with amnesia for the event, have been reported in patients who have taken zolpidem and were not fully awake. 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 of whom such behaviours are reported (see section 4.5 and section 4.8).
Specific patient groups
Elderly or debilitated patients should receive a lower dose: see recommended dosage (section 4.2).
Due to the myorelaxant effect there is risk of falls and consequently of hip fractures particularly for elderly patients when they get up at night.
Patients with renal insufficiency (see section 5.2)
Although dose adjustment is not necessary, caution should be exercised.
Patients with chronic respiratory insufficiency.
Caution should be observed when prescribing zolpidem since benzodiazepines have been shown to impair respiratory drive.. It should also be taken into consideration that anxiety or agitation have been described as signs of decompensated respiratory insufficiency.
Patients with severe hepatic insufficiency.
Benzodiazepines and benzodiazepine-like agents are not indicated for the treatment of patients with severe hepatic insufficiency as they may precipitate encephalopathy.
Use in patients with phychotic illness.
Benzodiazepines and benzodiazepine-like agents are not recommended for the primary treatment.
Use in depression.
Despite the fact that relevant clinical, pharmacokinetic and pharamcoydnamic interactions with SSRI have not been demonstrated, zolpidem should be administered with caution in patients exhibiting symptoms of depression. Suicidal tendencies may be present. Due to the possibility of intentional overdose by the patient, the lowest amount of drug that is feasible should be supplied to these patients.
Benzodiazepines and benzodiazepine-like agents should not be used alone to treat depression or anxiety associated with depression (suicide may be precipitated in such patients).
Pre-existing depression may be disclosed during use of zolpidem. Since insomnia is a symptom of depression, the patient should be re-evaluated if insomnia persists.
Use in patients with a history of drug or alcohol abuse.
Benzodiazepines and benzodiazepine-like agents should be used with extreme caution in patients with a history of alcohol or drug abuse. These patients should be under careful surveillance when receiving zolpidem since they are at risk of habituation and psychological dependence.
Zolpidem tartrate 5 mg tablets contains lactose. Patients with rare hereditary problems of galactose intolerance, the lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
4.5 Interaction with other medicinal products and other forms of interaction
Concomitant intake with alcohol is not recommended. The sedative effect may be enhanced when the product is used in combination with alcohol. This affects the ability to drive or use machines.
Caution should be exercised when zolpidem is used in combination with other CNS depressants (see section 4.4).
Enhancement of the central depressive effect may occur in cases of concomitant use with antipsychotics (neuroleptics), hypnotics, anxiolytics/sedatives,muscle relaxants, antidepressant agents, narcotic analgesics, antiepileptic drugs, anaesthetics and sedative antihistamines (see sections 4.8 and 5.1).
In the case of narcotic analgesics enhancement of euphoria may also occur leading to an increase in psychological dependence.
Zolpidem is metabolised by some enzymes of the cytocrome P45 0-family in-vitro. The main enzyme is CYP3A4 with partial contribution of CYP1A2.
Rifampicin induces the metabolism of zolpidem, resulting in approximately 60%, reduction in peak plasma concentrations and possibly decreased efficacy. Similar effects might be expected also with other strong inducers of cytochrome P450-enzymes.
Compounds that inhibit hepatic enzymes (particularly CYP3A4) may increase plasma concentrations and enhance the activity of zolpidem.
However, when zolpidem is administered with Itraconazole (CYP3A4 inhibitor), the pharmacokinetic and pharmacodynamic effects are not significantly different. The clinical relevance of these results is unknown.
Concomitant administration of zolpidem and ketoconazole, which is a potent CYP3A4 inhibitor, prolonged the half-life of zolpidem. The total exposure of zolpidem increased by 83 % and the apparent oral clearance was decreased. It is not necessary to perform a routine dose adjustment, but the patient should be informed about the potential increase in the sedative effect when ketoconazole and zolpidem are used concomitantly. Dose reduction of zolpidem may be considered when treatment with ketoconazole is introduced.
There is clinical evidence that sertraline, a CYP3A4 inhibitor, may interact with zolpidem leading to increased drowsiness. Also, isolated cases of visual hallucinations have been reported.
When zolpidem was administered with warfarin, haloperidol, chlorpromazine, digoxin, ranitidine or cimetidine, no significant pharmacokinetic interactions were observed.
4.6 Pregnancy and lactation
There are insufficient data to permit an assessment of the safety of Zolpidem during pregnancy and lactation. 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 the product is prescribed to a woman of childbearing potential, she should be warned to contact her physician regarding discontinuance of the product if she intends to become or suspects 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.
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.
Zolpidem is excreted in breast milk in minimal amounts. Zolpidem should therefore not be used during breast-feeding since effects on the infant are not studied.
4.7 Effects on ability to drive and use machines
The ability to drive or to use machines may be adversely affected by sedation, amnesia, impaired concentration and impaired muscular function. If insufficient sleep duration occurs, the likelihood of impaired alertness may be increased (see section 4.5).
This medicine can impair cognitive function and can affect a patient’s ability to drive safely. This class of medicine is in the list of drugs included in
regulations under 5a of the Road Traffic Act 1988. When prescribing this medicine, patients should be told:
The medicine is likely to affect your ability to drive,
• Do not drive until you know how the medicine affects you
• It is an offence to drive while under the influence of this medicine
However, you would not be committing an offence (called ‘statutory defence’) if:
• The medicine has been prescribed to treat a medical or dental problem and
• You have taken it according to the instructions given by the prescriber and in the information provided with the medicine and
• It was not affecting your ability to drive safely.
4.8 Undesirable effects
The following frequency data is the basis for the evaluation of undesirable effects:
Very common (> 1/10)
Common (> 1/100 to < 1/10)
Uncommon (> 1/1,000 to < 1/100)
Rare (> 1/10,000 to < 1/1,000)
Very rare (< 1/10,000)
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.
These undesirable effects occur most frequently in elderly patients.
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 (see section 4.2).
Immune system disorders
Not known: Angioneurotic oedema
Psychiatric disorders
Common: Hallucination, agitation, nightmare.
Uncommon: Confusional state, irritability
Not known: Restlessness, aggression, delusions, anger, psychosis, sleep walking (see section 4.4), inappropriate behaviour and other adverse behavioural effects (such reactions are more likely to occur in the elderly, see section 4.4).
Pre-existing depression may become manifest during use of benzodiazepines or benzodiazepine-like agents (see section 4.4).
Use (even at therapeutic dosages) may lead to physical dependence: Discontinuation of the therapy may result in withdrawal or rebound phenomena (see section 4.4).
Psychological dependence may occur. Abuse has been reported in polydrug abusers.
Decreased libido.
Nervous system disorders
Common: Somnolence, drowsiness during the following day, numbed emotions, reduced alertness, headache, dizziness, Anterograde amnesia, which may be associated with inappropriate behaviour, ataxia, exacerbated insomnia.
Not known: Depressed level of consciousness.
Eye disorders
Uncommon: Double vision.
Ear and labyrinth disorders Common: Vertigo.
Gastrointestinal disorders
Common : Gastrointestinal disturbances (diarrhoea, nausea , vomiting, abdominal pain).
Hepatobiliary disorders
Not known: Liver enzymes elevated.
Skin and subcutaneous tissue disorders
Not known: rash, pruritus, urticaria, hyperhidrosis.
Musculoskeletal, connective tissue and bone disorders Not known: Muscle weakness.
General disorders and administration site conditions Common: Fatigue.
Not known: Gait disturbance, drug tolerance, falls (predominantly in elderly patients and when zolpidem tartrate was not taken in accordance with prescribing recommendation).
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.
4.9 Overdose
In reports of overdose with zolpidem alone, impairment of consciousness has ranged from somnolence to light coma.
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 drugs should be withheld even if excitation occurs.
Use of flumazenil may be considered when serious symptoms are observed. 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. Haemodialysis studies in patients with renal failure receiving therapeutic doses have demonstrated that zolpidem is not dialysable.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Hypnotics and Sedatives, Benzodiazepine related drugs ATC code: N05CF02
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 clinical relevance of this is not known
5.2 Pharmacokinetic properties
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, a moderate reduction in clearance is observed (independent of possible dialysis). 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 halflife was observed.
5.3 Preclinical safety data
Preclinical effects were only observed at dosages well above the maximum human exposure levels and are therefore of little significance for clinical use.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Tablet core:
Lactose monohydrate Microcrystalline cellulose Sodium starch glycollate (Type A)
Magnesium stearate Hypromellose
Tablet coating:
Hypromellose Macrogol 400
Titanium dioxide (colouring agent E 171)
6.2 Incompatibilities
Not applicable
6.3 Shelf life
3 years.
6.4 Special precautions for storage
Store in the original packaging.
6.5 Nature and contents of container
Carton boxes containing 4, 5, 7, 10, 14, 15, 20, 28, 30, 50, 100, 500 tablets packed in PVC/PVDC/Al blisters.
30, 100 or 500 tablets packed in HDPE tablet containers sealed with a childproof PP closure.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
No special requirements.
7 MARKETING AUTHORISATION HOLDER
Ratiopharm GmbH,
Graf-Arco-Strasse 3 D-89079Ulm Germany
8 MARKETING AUTHORISATION NUMBER(S)
PL 15773/0064
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
26/07/2006
10 DATE OF REVISION OF THE TEXT
24/09/2014