This information is intended for use by health professionals

1. Name of the medicinal product

Chlordiazepoxide 10mg Capsules

2. Qualitative and quantitative composition

Chlordiazepoxide Hydrochloride Ph. Eur. 10 mg

3. Pharmaceutical form

Capsule

4. Clinical particulars
4.1 Therapeutic indications

For short term use (2 – 4 weeks only)

• Symptomatic relief of anxiety that is severe, disabling or subjecting the individual to unacceptable distress occurring alone or in association with insomnia or short-term psychosomatic, organic or psychotic illness

• Muscle spasm of varied aetiology

• Symptomatic relief of acute alcohol withdrawal

Chlordiazepoxide is not recommended; for long term use (i.e. longer than 4 weeks), mild anxiety or for use in children.

4.2 Posology and method of administration

Posology:

Anxiety

Adults

Starting dose 5mg daily: usual dose up to 30mg in divided doses. For severe symptoms 20mg, 2-4 times a day. Maximum dose up to 100mg daily, in divided doses, adjusted on an individual basis.

Treatment should not continue as full dose for more than 4 weeks including 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 2 to 4hrs

Special populations

Elderly or debilitated patients, patients with organic brain damage, respiratory impairmentshould normally not exceed half of the doses normally recommended.

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)

Paediatric patients

Chlordiazepoxide Capsules are not for paediatric use.

Treatment should be given at the lowest effective dose. The dosage and duration of treatment should be determined on an individual basis dependent by the patient's response and severity of the disorder. Given that chlordiazepoxide is a long-acting benzodiazepine, the patient should be monitored regularly at the start of the treatment to decrease, if necessary, the dose or frequency of administration to prevent overdose due to accumulation.

Treatment should be as short as possible duration (not exceeding 4 weeks) and given under close medical supervision. The patient should be reassessed regularly and the need for continued treatment should be evaluated, especially in case the patient is symptom free. Extension of use should not take place without further clinical evaluation. Chronic use is 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 the treatment will be of limited duration, the dosage will be progressively decreased and that there is a possibility of rebound phenomena (see section 4.4). Treatment should be tapered off gradually. Patients who have taken benzodiazepines for a prolonged time may require a longer period of dosage reduction and specialist help may be appropriate.

Method of administration:

Chlordiazepoxide capsules are for oral administration and must be taken with water and not be chewed.

4.3 Contraindications

• Hypersensitivity to benzodiazepines or to any of the excipients listed in section 6.1

• Severe pulmonary insufficiency, respiratory depression, sleep apnoea syndrome (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

• Spinal or cerebral ataxia

Chlordiazepoxide should not be used alone in depression or anxiety with depression (may precipitate suicidal tendencies)

4.4 Special warnings and precautions for use

Tolerance

Loss of efficacy to the hypnotic effects of benzodiazepines may develop after repeated use for a few weeks.

Dependence

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.

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 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.

Duration of treatment

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.

Rebound insomnia and anxiety

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).

Amnesia

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).Psychiatric and 'paradoxical' reactions

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.

Specific patient groups

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.

4.5 Interaction with other medicinal products and other forms of interaction

Alcohol: Concomitant intake of chlordiazepoxide with alcohol should be avoided as the enhanced sedative effect adversely affects the ability to drive or operate machinery.

Centrally acting drugs: 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.

Narcotic analgesics: Enhancement of the euphoria may also occur, leading to an increase in psychological dependence.

Anti-epileptic drugs: 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.

Other drugs enhancing the sedative effect of chlordiazepoxide: cisapride, lofexidine, nabilone and the muscle relaxants baclofen and tizanidine.

Compounds that affect hepatic enzymes (particularly cytochrome P450):

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

Antihypertensives, vasodilators & diuretics: 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.

Dopaminergics: 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.

Sodium oxybate: avoid concomitant use (enhanced effects of sodium oxybate)

4.6 Fertility, pregnancy and lactation

Pregnancy

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.

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. 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:

• 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

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).

Blood and lymphatic system disorders:

Rare: Bone marrow depression (e.g. thrombocytopenia, leukopenia, agranulocytosis, pancytopenia)

Not known: Blood dyscrasias.

Immune system disorders:

Very rare: Anaphylactic reaction, angioedema

Frequency not known: Hypersensitivity

Metabolism and nutrition disorders:

Frequency not known: Increased appetite

Psychiatric disorders:

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 andinappropriate behaviour.

.

Rare: numbed emotions.

Nervous system disorders:

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)

Eye disorders:

Rare: Visual impairment including diplopia and blurred vision.

Vascular disorders:

Rare: Hypotension

Respiratory, thoracic and mediastinal disorders:

Frequency not known: Respiratory depression

Gastrointestinal disorders:

Rare: Gastrointestinal upsets

Frequency not known: Saliva altered.

Hepatobiliary disorders:

Frequency not known: Jaundice, blood bilirubin increased, transaminases increased, blood alkaline phosphatase increased

Skin and subcutaneous tissue disorders:

Rare: Skin reaction (e.g. rash)

Musculoskeletal and connective tissue disorders:

Due to the myorelaxant effect there is a risk of falls and consequently fractures in the elderly Frequency not known: Muscle weakness.

Renal and urinary disorders:

Rare: Urinary retention, incontinence

Reproductive system and breast disorders:

Rare: Libido disorders, erectile dysfunction, menstrual disorder

General disorders and administration site conditions:

Common: Fatigue

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).

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.

4.9 Overdose

When taken alone in overdosage, Chlordiazepoxide presents few problems in management. 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.

Symptoms

Overdose of benzodiazepines is usually manifested by degrees of central nervous system depression ranging from drowsiness to coma. In mild cases, symptoms include drowsiness, mental confusion and lethargy, in more serious cases, symptoms may include ataxia, dysarthria, hypotonia, nystagmus, hypotension, respiratory depression, rarely coma and very rarely deathComa usually lasts a few hours but in the elderly may be more contracted and cyclical. Respiratory depression is more serious in those with severe obstructive airways disease. If excitation occurs, barbiturates should not be used. Patients who are asymptomatic at 4 hours are unlikely to develop symptoms.

Management

In the management of overdose with any medicinal product, it should be borne in mind that multiple agents may have been taken.

Treatment is symptomatic.

• Maintain clear airways and adequate ventilation, if indicated

• The value of gastric decontaminants is uncertain. Consider activated charcoal (50g for an adult: 1g/kg for a child) within 1 hour of ingestion if more than 1mg/kg has been taken provided the patient is not too drowsy.

• Gastric lavage – unnecessary if only benzodiazepine taken

• Supportive measures as indicated by the patients clinical condition

• The value of dialysis has not been determined. Flumazenil, a benzodiazepine antagonist, is available but should rarely be required. It may be required in children who are naïve to benzodiazepines or patients with COPD as alternative to ventilation. Flumazenil may be used as an antidote; however it has a short half-life (about 1 hour) and in this situation an infusion may therefore be required. Flumazenil should not normally be used in patients with mixed overdoses, a history of seizures, head injury, chronic benzodiazepine use, co-ingestion of a benzodiazepine and tricyclic antidepressant or other proconvulsantor as a “diagnostic test”.

If excitation occurs, barbiturates should not be used.

5. Pharmacological properties
5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Psycholeptics, anxiolytics, benzodiazepine derivatives.

ATC code: N05BA02

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

.

Absorption:

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.

Distribution:

Chlordiazepoxide is extensively metabolised in the liver by hepatic microsomal enzymes and exhibits capacity limited, protein binding sensitive, hepatic clearance.

Chlordiazepoxide is metabolised to desmethyl-chlordiazepoxide. Pharmacologically active metabolites of chlordiazepoxide include desmethylchlordiazepoxide, demoxepam, desmethyldiazepam and oxazepam.

Demoxepam and desmethyldiazepam are also found in the plasma of patients on continuous treatment. The active metabolite desmethylchlordiazepoxide has an accumulation half-life of 10-18 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.

Elimination:

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.

Pharmacokinetic / pharmacodynamic relationship:

No clear correlation has been demonstrated between the blood levels of Chlordiazepoxide and its clinical effects.

5.3 Preclinical safety data

Reproductive effects:

Oral

Man

TDLo: 286 ug/kg (1D male)

Paternal effects (impotence)

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)

Mutagenic and tumourigenic potential:

In in-vivo and in-vitro studies with chlordiazepoxide, there are indications for a mutagenic effect. Nevertheless, in similar test systems results are negative. The relevance of the positive findings is currently unclear.

In carcinogenicity studies in mice an increase of liver tumours was seen at high doses, especially in males, whereas no increase of tumour incidence was seen in rats.

Reproductive toxicity:

In animal studies increased resorption rates, increased incidence of stillbirth and neonatal death, malformation of the scull (exencephaly, cleft palate), lung anomalies and changes in the urogenital tract as well as behavioural disorders and neurochemical changes have been observed in the offspring.

6. Pharmaceutical particulars
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 250µm / 40 gsm film and 20µm aluminium foil

Pack sizes: 28, 30 and 100 capsules

6.6 Special precautions for disposal and other handling

None

Administrative Data

7. Marketing authorisation holder

Athlone laboratories Limited

Ballymurray

Co. Roscommon

Ireland

8. Marketing authorisation number(s)

PL 06453/0003

9. Date of first authorisation/renewal of the authorisation

19th March 2003

10. Date of revision of the text

16th August 2018