Zolpidem Tartrate 10mg Tablets
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Zolpidem Tartrate 10mg tablets
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
One film-coated tablet contains 10mg zolpidem tartrate.
Excipient with known effect: 90 mg lactose monohydrate /film-coated tablet For the full list of excipients, see section 6.1.
3 PHARMACEUTICAL FORM
Film-coated tablet
White, oval, biconvex, film-coated tablet with a break score on both sides and embossed ”ZIM” on one side and ”10” on the other side. The tablet can be divided into equal doses.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Zolpidem is indicated for short-term treatment of insomnia in adults in situations where the insomnia is debilitating or is causing severe distress for the patient.
4.2 Posology and method of administration
Posology
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.
Adults
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.
Elderly
In elderly or debilitated patients who may be especially sensitive to the effects of zolpidem tartrate 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 tartrate should not exceed 10 mg in any patient.
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. The available evidence from placebo-controlled clinical trials is presented in section 5.1.
Method of administration
The product should be taken with fluid just before going to bed.
4.3 Contraindications
Severe hepatic insufficiency.
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
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 of 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.
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, insomnia, 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 the 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 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, psychoses, 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.
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 a 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 tartrate 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 psychotic illness:
Benzodiazepines and benzodiazepine-like agents are not recommended for the primary treatment.
Use in depression:
Despite the fact that relevant clinical, pharmacokinetic and pharmacodynamic interactions with SSRI have not been demonstrated, zolpidem tartrate 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).
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 tartrate since they are at risk of habituation and psychological dependence.
Zolpidem tartrate 10 mg 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 tartrate 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 tartrate is metabolised by some enzymes of the cytochrome P450-family. The main enzyme is CYP3A4.
Rifampicin induces the metabolism of zolpidem tartrate, 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 such as carbamazepine and phenytoin.
Compounds that inhibit hepatic enzymes (particularly CYP3A4) may increase plasma concentrations and enhance the activity of zolpidem tartrate. However, when zolpidem tartrate is administered with Itraconazol (CYP3A4 inhibitor), the pharmacokinetic and pharmacodynamic effects are not significantly different. The clinical relevance of these results is unknown.
4.6 Fertility, pregnancy and lactation
Pregnancy
There are insufficient data to permit an assessment of the safety of zolpidem tartrate 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 tartrate 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 suspect that she is pregnant.
If, for compelling medical reasons, zolpidem tartrate 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.
Breastfeeding
Zolpidem tartrate is excreted in breast milk in minimal amounts. Zolpidem tartrate 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).
4.8 Undesirable effects
Frequencies are defined as:
Very common (>1/10)
Common (>1/100 to <1/10)
Uncommon (>1/1000 to <1/100)
Rare (>1/10000 to <1/1000)
Very rare (<1/10000) not known (cannot be estimated from the 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.
Infections and infestations
Common: upper respiratory tract infection, lower respiratory tract infection.
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, abuse, somnambulism (See Section 4.4), dependence (withdrawal symptoms, or rebound effects may occur after treatment discontinuation), libido disorder, depression (See Section 4.4)
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, ataxia
Eye disorders
Uncommon: diplopia
Respiratory, thoracic and mediastinal disorders
Not Known: respiratory depression (see section 4.4)
Gastro-intestinal disorders
Common: diarrhoea, nausea, vomiting, abdominal pain
Hepatobiliary disorders
Not known: Liver enzymes elevated
Skin and subcutaneous tissue disorders
Not known: rash, pruritus, urticaria, hyperhidrosis
Musculoskeletal and connective tissue disorders
Not known: muscular weakness
General disorders and administration site conditions
Common: fatigue
Not known: gait disturbance, drug tolerance.
Injury, poisoning and procedural complications
Not known: fall (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 website: www.mhra.gov.uk/yellowcard.
4.9 Overdose
In reports of overdose with zolpidem tartrate alone, impairment of consciousness has ranged from somnolence to light coma.
Individuals have fully recovered from overdoses up to 400 mg of zolpidem tartrate, 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. 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 tartrate, haemodialysis and forced diuresis are not effective measures. Haemodialysis studies in patients with renal failure receiving therapeutic doses have demonstrated that zolpidem tartrate is not dialyzable.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Hypnotics and Sedatives, Benzodiazepine related drugs.
ATC code: N05C F02 Mechanism of action
Zolpidem tartrate, an imidazopyridine is a benzodiazepine-like hypnotic agent. Pharmacodynamic effects
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 tartrate acts primarily upon omega (BZ1) receptor subtypes. The clinical relevance of this is not known.
Clinical efficacy and safety
The randomized trials only showed convincing evidence of efficacy of 10mg zolpidem.
In a randomized double-blind trial in 462 non-elderly healthy volunteers with transient insomnia, zolpidem 10mg decreased the mean time to fall asleep by 10 minutes compared to placebo, while for 5mg zolpidem this was 3 minutes.
In a randomized double-blind trial in 114 non-elderly patients with chronic insomnia, zolpidem 10mg decreased the mean time to fall asleep by 30 minutes compared to placebo, while for 5mg zolpidem this was 15 minutes.
In some patients, a lower dose of 5mg could be effective.
Paediatric population
Safety and efficacy of zolpidem have not 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 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%) (see section 4.2).
5.2 Pharmacokinetic properties Absorption
Zolpidem tartrate 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 tartrate 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 tartrate 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 is observed.
5.3 Preclinical safety data
Effects in non-clinical studies were observed only at exposures considered sufficiently in excess of the maximum human exposure indicating little relevance to clinical use.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Core:
Lactose monohydrate Microcrystalline cellulose Sodium starch glycolate (type A)
Hydroxypropyl methylcellulose Magnesium stearate.
Coating
Hydroxypropyl methylcellulose Titanium dioxide (colouring agent E171)
Polyethylene glycol 400.
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
3 years.
6.4 Special precautions for storage
No special precautions for storage.
6.5 Nature and contents of container
The film-coated tablets are packed in PVC/PE/PVDC/Al blisters inserted into a carton and in HDPE containers with a child-resistant PP closure.
The blister packages contain 7, 8, 10, 14, 15, 20, 28, 30, 50, 56, 60 and 100 film-coated tablets.
The HDPE containers contain 30, 100, 500 and 1000 film-coated tablets.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
No special requirements.
7 MARKETING AUTHORISATION HOLDER
Actavis UK Limited (Trading style: Actavis)
Whiddon Valley Barnstaple North Devon EX32 8NS
8 MARKETING AUTHORISATION NUMBER
PL 00142/0537
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
04/07/2013
10 DATE OF REVISION OF THE TEXT
10/06/2015