Chlordiazepoxide 5mg Capsules
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Chlordiazepoxide 5mg Capsules
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Chlordiazepoxide Hydrochloride 5 mg
3 PHARMACEUTICAL FORM
Capsule.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
FOR SHORT TERM (2 - 4 weeks only) USE
• Symptomatic relief of anxiety that is severe, disabling or subjecting the individual to unacceptable distress occurring alone or in association with insomnia or shortterm psychosomatic, organic or psychotic illness
• Muscle spasm of varied aetiology
• Symptomatic relief of acute alcohol withdrawal
NOT FOR USE
• Long term (ie longer than 4 weeks)
• For mild anxiety
• In children
4.2
Posology and method of administration
Route of administration: oral
Treatment to be given
• Under close medical supervision
• At the lowest effective dose
• For the shortest possible duration (not exceeding 4 weeks)
Extension of use should not take place without further clinical evaluation
Chronic use not recommended (little is known of the long term safety and efficacy: potential for dependence - see section 4.4).
When treatment is started the patient should be informed that
• Treatment will be of limited duration
• The dosage will be progressively decreased
• There is a possibility of rebound phenomena
Anxiety
Adults
• Starting dose 5mg daily: usual dose up to 30mg in divided doses increasing to a maximum of 100mg daily, in divided doses, adjusted on an individual basis.
• Treatment should not continue as full dose for more than 2 weeks with a 2 week tapering off process
Insomnia associated with anxiety Adults
• 10 - 30 mg at bedtime
• Treatment would normally vary from a few days to two weeks with a maximum of four weeks, including two weeks tapering off.
Muscle Spasm Adults
10mg to 30mg daily in divided doses
Symptomatic relief of acute alcohol withdrawal Adults
25 to 100mg, repeated if necessary, in 2hrs to 4hrs.
Special populations
Elderly and/or debilitated patients Dosage should not exceed half the adult dose
Children
Chlordiazepoxide Capsules are not for paediatric use
Patients with impaired hepatic or renal function
• Dosage should not exceed half the adult dose and steps should be taken to ensure that there is no accumulation of plasma chlordiazepoxide
• Contraindicated in severe hepatic insufficiency (see section 4.3)
Patients who have taken benzodiazepines for a prolonged time may require a longer period of dosage reduction and specialist help may be appropriate.
4.3 Contraindications
• Hypersensitivity to benzodiazepines or to any of the other ingredients
• Acute pulmonary insufficiency: respiratory depression: sleep apnoea (risk of further respiratory depression)
• Phobic and obsessional states (inadequate evidence of safety and efficacy).
• Chronic psychosis
• Severe hepatic insufficiency (may precipitate encephalopathy)
• Planning a pregnancy (see section 4.6)
• Pregnancy (unless there are compelling reasons - see section 4.6)
• Myasthenia gravis
Chlordiazepoxide should not be used alone in depression or anxiety with depression (may precipitate suicide)
4.4 Special warnings and precautions for use Tolerance
Loss of efficacy to the hypnotic effects may develop after repeated use for a few weeks.
Dependence
The risk of dependence (physical or psychological) increases with dose and duration of treatment and is greater in patients with a history of alcohol or drug abuse, or in patients with a marked personality disorder. Therefore
• regular monitoring of such patients is essential
• routine repeat prescriptions should be avoided
• treatment should be withdrawn gradually
Withdrawal effects
The duration of treatment should be as short as possible (see section 4.2). If physical dependence has developed, abrupt termination of treatment results is withdrawal symptoms. These include headache, muscle pain, extreme anxiety, tension, restlessness, nervousness, sweating, confusion and irritability, sleep disturbance, diarrhoea and mood changes. In severe cases the following may occur: a feeling of unreality or of being separated from the body, depersonalisation, confusional states, numbness and tingling of the extremities, hypersensitivity to light, noise and physical contact, psychotic manifestations including hallucinations or epileptic seizures. Withdrawal symptoms will be worse in patients who have been dependent on alcohol or other narcotic drugs in the past, but can occur following abrupt cessation of treatment in patients receiving normal therapeutic doses for a short period of time.
It may be useful to inform the patient when treatment commences that it will be of limited duration and to explain precisely how the dosage will be progressively decreased. Moreover, it is important that the patient should be aware of the possibility of rebound phenomena, thereby minimising anxiety over such symptoms should they occur while the medicinal product is being discontinued.
There are indications that, in the case of benzodiazepines with a short duration of action, withdrawal phenomena can become manifest within the dosage interval, especially when the dosage is high.
When benzodiazepines with a long duration of action are being used, e.g. chlordiazepoxide, it is important to warn against changing to a benzodiazepine with a short duration of action, as withdrawal symptoms may develop.
Rebound symptoms
Symptoms including insomnia and anxiety may occur on withdrawal of treatment. As this is greater after abrupt discontinuation, the dose should be decreased gradually (see section 4.2).
Amnesia
Anterograde amnesia may occur, most often several hours after ingestion. To reduce the risk, patients should ensure that they will be able to have an uninterrupted sleep of 7 - 8 hours (see also section 4.8).
Bereavement / loss
Psychological adjustment may be inhibited by benzodiazepines
Psychiatric and ‘paradoxical’ reactions
Reactions such as restlessness, agitation, irritability, aggressiveness, excitement, confusion, delusions, rage, nightmares, hallucinations, psychoses, inappropriate behaviour and other adverse behavioural effects can occur. These reactions are more likely in children and the elderly, and extreme caution should be used in prescribing benzodiazepines to patients with personality disorders. Should they occur, treatment should be discontinued.
Specific patient groups
Intolerance to sugars
WARNING: Chlordiazepoxide should not be given to patients with rare hereditary problems of galactose intolerance, the Lapp lactose deficiency or glucose-galactose malabsorption. [DN - if appropriate]
Patients with depression
Chlordiazepoxide should not be used alone to treat depression or anxiety associated with depression as suicide may be precipitated in such patients.
Patients with a history of alcohol & drug abuse
Chlordiazepoxide should be used with extreme caution in patients with a history of alcohol or drug abuse (risk of abuse / dependence),
Patients with phobias and/or chronic psychoses
Chlordiazepoxide is not recommended (inadequate evidence of efficacy and safety)
4.5 Interaction with other medicinal products and other forms of interaction Not recommended
Alcohol: Chlordiazepoxide should not be used together with alcohol (enhanced sedative effects: effect the ability to drive or operate machinery).
Sodium oxybate: avoid concomitant use (enhanced effects of sodium oxybate) Take into account
Centrally acting drugs: Enhancement of the central depressive effect may occur if chlordiazepoxide is combined with drugs such as neuroleptics, antipsychotics, tranquillisers, antidepressants, hypnotics, analgesics, anaesthetics, barbiturates and sedative antihistamines. The elderly may require special supervision.
Anti-epileptic drugs: When used concurrently, side effects and toxicity may be more evident, particularly with hydantoins (e.g. phenytoin) and/or barbiturates. This requires extra care in adjusting dosage in the initial stages of treatment.
Narcotic analgesics: Enhancement of the euphoria may lead to increased psychological dependence.
Other drugs enhancing the sedative effect of chlordiazepoxide: cisapride, lofexidine, nabilone, disulfiram and the muscle relaxants baclofen and tizanidine.
Compounds that affect hepatic enzymes (particularly cytochrome P450):
• Inhibitors (e.g. cimetidine) reduce clearance and may potentiate the action of benzodiazepines.
• Inducers (e.g. rifampicin) may increase clearance of benzodiazepines
Antihypertensives, vasodilators & diuretics: enhanced hypotensive effect with ACE inhibitors, alpha-blockers, angiotensin-II receptor antagonists, calcium channel blockers adrenergic neurone blockers, beta-blockers, moxonidine, nitrates, hydralazine, minoxidil, sodium nitroprusside and diuretics
Dopaminergics: possible antagonism of the effect of levodopa
4.6 Fertility, pregnancy and lactation
Pregnancy
Chlordiazepoxide should only be used during pregnancy if there are compelling reasons (e.g. no alternative: benefit outweighs risk).
An increased risk of congenital malformations in humans has been associated with its use, particularly in the first and second trimesters. If the product is prescribed to a woman of childbearing potential, she should be warned to contact her physician regarding stopping if she intends to become or suspects she may be pregnant.
If the product is administered at high doses during the late phase of pregnancy or during labour, effects on the neonate such as hypothermia, irregularities in fetal heart rate and hypotonia, poor-sucking and moderate respiratory depression, can be expected. Infants born to mothers who took benzodiazepines chronically during the later stages of pregnancy may have physical dependence and may be at some risk for withdrawal symptoms in the postnatal period.
Lactation
Use during lactation should be avoided as chlordiazepoxide is found in breast milk.
4.7 Effects on ability to drive and use machines
Patients should be advised that sedation, amnesia, impaired concentration, dizziness, blurred vision and impaired muscular function may occur and that, if affected, they should not drive or use machines, or take part in other activities where this would put themselves or others at risk. If insufficient sleep duration occurs, the likelihood of impaired alertness may be increased. Concurrent medication may increase there effects (see section 4.5).
If insufficient sleep occurs, the likelihood of impaired alertness may be increased.
4.8 Undesirable effects
Common adverse effects include light-headedness and drowsiness, sedation, unsteadiness and ataxia; these are usually dose related but, even after a single dose, may persist into the following day. The elderly are particularly sensitive to the effects of central depressant drugs and may experience confusion, especially if organic brain changes are present; the dosage of chlordiazepoxide should not exceed one-half that recommended for other adults (see section 4.2).
Other adverse effects include dependence, confusion, restlessness, agitation, irritability, aggressive outbursts, delusion, nightmares, hallucinations, inappropriate behaviour, tremor, dysarthria, salivation changes, incontinence, and thrombocytopenia / other blood disorders. Depressions and amnesia can result from high doses (see also below).
Rare adverse effects include numbed emotions, reduced alertness, fatigue, headache, dizziness, muscle weakness, vertigo, blurred vision, hypotension, gastrointestinal upsets, skin rashes, visual disturbances, changes in libido, and urinary retention.
Isolated cases of blood dyscrasias and jaundice have also been reported.
Amnesia
Anterograde amnesia may occur at the therapeutic doses, with increasing risk at higher doses. This may be associated with inappropriate behaviour (see section 4.4).
Depression
Pre-existing depression may be unmasked by benzodiazepines.
Psychiatric and paradoxical reactions
Reactions like restlessness, agitation, irritability, aggressiveness, delusion, rages, nightmares, hallucinations, psychoses, inappropriate behaviour and other adverse behavioural effects are known to occur when using benzodiazepine-like agents. They may be quite severe with this product. They are more likely to occur in children and the elderly.
Dependence
Use (even therapeutic doses) may lead to the development of physical dependence: discontinuation of the therapy may result in the withdrawal or rebound phenomena. Psychological dependence may occur. Abuse of benzodiazepines has been reported (see section 4.2 & 4.4).
4.9 Overdose
Benzodiazepines potentiate the effects of other CNS depressants including alcohol. When taken with centrally-acting drugs, especially alcohol, effects of overdose are likely to be more severe and in absence of supportive measures, may prove fatal.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Chlordiazepoxide has anxiolytic and central muscle relaxant properties. It has little autonomic activity.
Chlordiazepoxide acts as depressant of the central nervous system producing all levels of CNS depression, from mild sedation to hypnosis, to coma depending on the dose. The precise sites and mechanisms of action have not been fully established but various mechanisms have been proposed. It is believed that chlordiazepoxide enhances or facilitates the inhibitory neurotransmitter action of gama-aminobutyric acid (GABA) which mediates both pre- and post synaptic inhibition in all regions of the CNS following interaction between chlordiazepoxide and a specific neuronal membrane receptor. Anti-anxiety action of chlordiazepoxide is believed to result from stimulation of GABA receptors in the ascending reticular activating system, since GABA in inhibitory receptor stimulation increases inhibition and blocks both cortical and limbic arousal following stimulation of the brainstem reticular formation.
The exact mechanism of action of chlordiazepoxide is not fully established. Skeletal muscle relaxation primarily occurs by inhibiting spinal polysynaptic afferent pathways but it may also inhibit monosynaptic afferent pathways.
5.2 Pharmacokinetic properties
Chlordiazepoxide is well absorbed with peak blood levels being achieved one or two hours after administration. Rate of absorption is age-related and tends to be delayed in the elderly. After absorption it is highly bound to plasma proteins. The drug has a half-life of 6-30 hours. Steady state levels are usually reached within 3 days.
Chlordiazepoxide is extensively metabolised in the liver by hepatic microsomal enzymes and exhibits capacity limited, protein binding sensitive, hepatic clearance.
Pharmacologically active metabolites of chlordiazepoxide include desmethylchlordiazepoxide, demoxepam ,desmethyldiazepam and oxazepam.
The active metabolite desmethylchlordiazepoxide has an accumulation half-life of 1018 hours and Demoxepam has an accumulation half-life of approximately 21-78 hours.
Steady state levels of these active metabolites are reached after 10-15 days with metabolite concentrations which are similar to those of the parent drug.
Chlordiazepoxide is distributed in the CSF corresponding to the free fraction of chlordiazepoxide. It enters the brain following a rapid distribution phase in grey matter with its high blood flow, followed by a longer accumulation phase of chlordiazepoxide and its metabolites in the white matter. The accumulation is more marked following repeated dosage. Chlordiazepoxide has a high affinity for lipids.
Chlordiazepoxide is excreted mainly in the urine mainly in the form of its metabolites; only a small percent of this is in free form most being excreted as conjugates with glucuronide or sulphate. There is no biliary excretion.
5.3 Preclinical safety data
Reproductive effects:
|
Oral Man |
TDLo: 286 ug/kg (1D male) | |
|
Toxicity data: | ||
|
Oral Human |
TDlo: 857 ug/kg |
Behavioural (sleep) |
|
Oral Human |
TDlo: 2 mg/kg/2D |
Behavioural (sleep, ataxia) |
|
Oral Female |
TDlo: 4 mg/kg |
Behavioural (Euphoria, |
somnolence, antianxiety)
(Registry of Toxic Effects of Chemical Substances 1985-86)
PHARMACEUTICAL PROPERTIES
6.
6.1. List of Excipients
Lactose monohydrate Maize Starch Magnesium Stearate
Capsule Shell Composition: Indigo Carmine (E132) Titanium dioxide (E171) Erythrosine (E127) Quinoline yellow (E104) Gelatin
Printing Ink Composition: Shellac
Dehydrated alcohol Isopropyl alcohol Butyl alcohol Propylene glycol Strong Ammonia Solution Purified water Potassium hydroxide Titanium dioxide (E171)
6.2 Incompatibilities
There are no known incompatibilities.
6.3 Shelf life
24 months.
6.4 Special precautions for storage
Store below 25 °C.
6.5. Nature and Contents of Container
Polypropylene tablet containers with low density polyethylene caps Pack sizes: 28, 30, 56, 60, 100 and 500 capsules.
White opaque PVC/PVdC 250pm / 40 gsm film and 20pm aluminium foil
Pack sizes: 28, 30 and 100 capsules
Special precautions for disposal
None.
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18/07/2013