Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2018 Publisher: Athlone laboratories Limited, Ballymurray, Co. Roscommon, Ireland
Chlordiazepoxide should not be used alone in depression or anxiety with depression (may precipitate suicidal tendencies).
Loss of efficacy to the hypnotic effects of benzodiazepines may develop after repeated use for a few weeks.
The dependent potential of the benzodiazepines is low, particularly when limited to short-term use. The risk of dependence (physical or psychological) increases when high doses are used, especially when given over long periods and is greater in patients with a history of alcoholism 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 routine repeat prescriptions should be avoided treatment should be withdrawn gradually.
The duration of treatment should be as short as possible (see section 4.2). If physical dependence has developed, abrupt termination of treatment results in withdrawal symptoms. These include headache, muscle pain, extreme anxiety, tension, restlessness, nervousness, sweating, confusion and irritability; sleep disturbance, diarrhoea, depression, rebound insomnia and mood changes. In severe cases the following may occur: a feeling of unreality or of being separated from the body, depersonalisation, hyperacusis, 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.
The duration of treatment should be as short as possible (see section 4.2) depending on the indication, but should not exceed 4 weeks, including tapering-off process. Routine repeat prescriptions should be avoided.
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.
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.
This is a transient syndrome whereby the symptoms that led to treatment with a benzodiazepine recur in an enhanced form, may occur on withdrawal of treatment. Symptoms including mood changes, insomnia, restlessness and anxiety may occur on withdrawal of treatment. Since the risk of withdrawal phenomena/rebound phenomena is greater after abrupt discontinuation, the dose should be decreased gradually (see section 4.2).
Benzodiazepines may induce anterograde amnesia, occurring 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).
Reactions such as restlessness, agitation, irritability, aggressiveness, excitement, confusion, delusion, rages, nightmares, hallucinations, psychoses, inappropriate behaviour and other adverse behavioural effects can occur when using benzodiazepines. 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.
Elderly patients should be given a reduced dose (see section 4.2). A lower dose is also recommended for patients with chronic respiratory insufficiency due to the risk of respiratory depression. Benzodiazepines are contraindicated to treat patients with severe hepatic insufficiency as they may precipitate encephalopathy and reduced doses should be given to patients with renal or hepatic disease. Benzodiazepines are not recommended for the primary treatment of psychotic illness.
Chlordiazepoxide should not be used alone to treat depression or anxiety associated with depression as depression with suicidal tendencies may be precipitated in such patients. Extreme caution should be used in prescribing benzodiazepines to patients with personality disorders. Benzodiazepines should be used with extreme caution in patients with a history of alcohol or drug abuse (risk of abuse/dependence).
In cases of loss or bereavement, psychological adjustment may be inhibited by benzodiazepines.
Due to the myorelaxant effect there is a risk of falls and consequently fractures in the elderly.
Patients with rare hereditary problems of galactose intolerance, the Lapp lactose deficiency or glucose-galactose malabsorption should not take chlordiazepoxide.
Concomitant intake of chlordiazepoxide with alcohol should be avoided as the enhanced sedative effect adversely affects the ability to drive or operate machinery.
Enhancement of central depressive effects 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.
Enhancement of the euphoria may also occur, leading to an increase in psychological dependence.
When used concurrently, side effects and toxicity may be more evident, particularly with hydantoins (e.g. phenytoin) or barbiturates or combinations including them. This requires extra care in adjusting dosage in the initial stages of treatment.
Cisapride, lofexidine, nabilone and the muscle relaxants baclofen and tizanidine.
Known inhibitors (e.g. cimetidine, omeprazole and disulfram) reduce the clearance of benzodiazepines and may potentiate their action. The same applies to the use of contraceptive agents. Known inducers (e.g. rifampicin) may increase clearance of benzodiazepines.
Enhanced hypotensive effect in patients receiving long-term treatment 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.
In patients receiving long-term treatment with other medicines (such as anticoagulant agents and cardiac glycosides) the nature and extent of interactions cannot safely be foreseen.
Benzodiazepines possibly antagonise of the effect of levodopa.
Sedative effects are possibly increased when benzodiazepines are given with monoxidine.
Effects of benzodiazepines are possibly reduced by theophylline.
Avoid concomitant use (enhanced effects of sodium oxybate).
Chlordiazepoxide crosses the placenta.
There is a limited amount of data from the use of chlordiazepoxide in pregnant women.
Studies in animals have shown reproductive toxicity (see section 5.3).
There is no evidence as to drug safety in human pregnancy. Do not use during pregnancy, especially during the first and last trimesters, unless there are compelling reasons (e.g. no alternative or 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.
The administration of high doses or prolonged administration of low doses of benzodiazepines during the late phase of pregnancy or during labour has been reported to produces hypothermia, irregularities in fetal heart rate, hypotonia, poor-sucking and moderate respiratory depression, in the neonate. Infants born to mothers who took benzodiazepines chronically during the later stages of pregnancy may have developed physical dependence and may be at some risk for developing withdrawal symptoms in the postnatal period.
Use during lactation should be avoided as chlordiazepoxide is found in breast milk.
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. Patients should further be advised that alcohol may intensify any impairment, and should therefore be avoided during treatment. Other concurrent medication may increase effects (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:
Common adverse effects include light-headedness and drowsiness, sedation, dizziness, somnolence, fatigue, balance disorder, unsteadiness and ataxia; these are usually dose related but, even after a single dose, may persist into the following day. However, these phenomena occur predominantly at the start of therapy and usually disappear with repeated administration. 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).
Evaluation of undesirable effects is based on the following frequency information: 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 (frequency cannot be estimated from available data).
Rare: Bone marrow depression (e.g. thrombocytopenia, leukopenia, agranulocytosis, pancytopenia)
Not known: Blood dyscrasias.
Very rare: Anaphylactic reaction, angioedema
Frequency not known: Hypersensitivity
Frequency not known: Increased appetite
Frequency not known: Amnesia, hallucinations, dependence, depression, depressed level of consciousness, restlessness, agitation, irritability, aggression, delusion, nightmares, psychotic disorder, abnormal behaviour, emotional disturbances, paradoxical drug reaction (e.g. anxiety, sleep disorders, insomnia, suicide attempt, suicidal ideation) aggressive outbursts and inappropriate behaviour.
Rare: numbed emotions
Common: Sedation, dizziness, confusional states, unsteadiness, somnolence, ataxia, balance disorder, Rare: Headache, vertigo, reduced alertness
Frequency not known: Dysarthria, gait disturbance, extrapyramidal disorder (e.g. tremor, dyskinesia)
Rare: Visual impairment including diplopia and blurred vision.
Rare: Hypotension
Frequency not known: Respiratory depression
Rare: Gastrointestinal upsets
Frequency not known: Saliva altered
Frequency not known: Jaundice, blood bilirubin increased, transaminases increased, blood alkaline phosphatase increased
Rare: Skin reaction (e.g. rash)
Due to the myorelaxant effect there is a risk of falls and consequently fractures in the elderly.
Frequency not known: Muscle weakness
Rare: Urinary retention, incontinence
Rare: Libido disorders, erectile dysfunction, menstrual disorder
Common: Fatigue
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).
Pre-existing depression may be unmasked by benzodiazepines.
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.
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).
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.
There are no known incompatibilities.
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