SUMMARY OF PRODUCT CHARACTERISTICS 1 NAME OF THE MEDICINAL PRODUCT

Chlordiazepoxide Capsules 10 mg Tropium Capsules 10mg

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Chlordiazepoxide hydrochloride BP 10 mg

3    PHARMACEUTICAL FORM

Capsule

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Adults:

Benzodiazepines are indicated for the short-term relief (2-4 weeks only) 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.

The use of benzodiazepines to treat short-term 'mild' anxiety is considered to be inappropriate and unsuitable.

Muscle spasm of varied aetiology.

Symptomatic relief of acute alcohol withdrawal. Children:

Not recommended for use in children.

4.2 Posology and method of administration

Route of administration: oral

When treatment is started it may be useful to inform the patient that treatment 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 has been discontinued.

Anxiety

Adults:

The starting dose should be 5 mg daily increasing to a maximum of 100 mg daily, in divided doses adjusted on an individual basis. Treatment should always be as short as possible and should not normally exceed 8-12 weeks including tapering off process. Extension should not take place without reevaluation of the situation.

Elderly and debilitated patients:

Dosage should not exceed half the adult dose. The same applies to patients with impaired liver or renal function and steps should be taken to ensure that there is no accumulation of plasma chlordiazepoxide in these patients.

Insomnia associated with anxiety

Adults:

10-30 mg at bed time. Treatment should be as short as possible and would normally vary from a few days to two weeks with a maximum, including tapering off of four weeks. Where extension beyond the maximum treatment period may be necessary it should not take place without re-evaluation of the patients status.

Elderly and debilitated patients:

Dosage should not exceed half the adult dose. The same applies to patients with impaired liver or renal function and steps should be taken to ensure that there is no accumulation of plasma chlordiazepoxide in these patients.

Muscle Spasm

Adults:

10 mg to 30 mg daily in divided doses. Symptomatic relief of acute alcohol withdrawal

Adults:

25 to 100 mg, repeated if necessary in 2hrs to 4hrs.

4.3 Contraindications

Myasthenia gravis Hypersensitivity to benzodiazepines Acute pulmonary insufficiency Severe respiratory depression Sleep apnoea syndrome Severe hepatic insufficiency

4.4 Special warnings and precautions for use Tolerance

Some loss of efficacy to the hypnotic effects of chlordiazepoxide may develop after repeated use for a few weeks.

Dependence

The risk of dependence increases with dose and duration of treatment; it is also greater in patients with a history of alcohol or drug abuse. Dependence may be physical or psychic.

Once physical dependence has developed, abrupt termination of treatment will be accompanied by withdrawal symptoms. These may consist of headache, muscle pain, extreme anxiety, 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 and anxiety: a transient syndrome whereby the symptoms that led to treatment with a benzodiazepine recur in an enhanced form, may occur on withdrawal of treatment. It may be accompanied by other reactions including mood changes, anxiety or sleep disturbances and restlessness. Since the risk of withdrawal phenomena/rebound phenomena is greater after abrupt discontinuation of treatment, it is recommended that the dosage is decreased gradually.

Duration of treatment

The duration of treatment should be as short as possible (see Posology) and should not exceed four weeks for insomnia and 8-12 weeks in case of anxiety, including 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 and to explain precisely how the dosage will be progressively decreased. Patients should be made aware of the possibility of rebound phenomena; thereby minimising anxiety other symptoms should they occur while the product is being discontinued.

There are indications that, in the case of benzodiazepines with a short duration of action, withdrawal phenomena can become manifest with the dosage interval, especially when the dosage is high.

When chlordiazepoxide is being used it is important to warn against changing to a benzodiazepine with a short duration of action, as withdrawal symptoms may develop.

Amnesia

Chlordiazepoxide may induce anterograde amnesia. The condition occurs most often several hours after ingesting the product and therefore to reduce the risk patients should ensure that they will be able to have an uninterrupted sleep of 7-8 hours (see also Undesirable Effects).

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 benzodiazepines. Should this occur, treatment with the product should be discontinued.

They are more likely to occur in children and the elderly.

Specific Patient Groups

Chlordiazepoxide is not recommended for the primary treatment of psychotic illness.

Chlordiazepoxide should not be used alone to treat depression or anxiety associated with depression because suicide may be precipitated in such patients.

Chlordiazepoxide should be used with extreme caution in patients with a history of alcohol or drug abuse.

Not for use in phobic or obsessional states (inadequate evidence of efficiency and safety)

Chlordiazepoxide should not be given to children without careful assessment, and the duration of treatment must be kept to the minimum. The elderly should be given a reduced dose (see Posology). A lower dose is also recommended for patients with chronic respiratory insufficiency due to the risk of respiratory depression. Benzodiazepines are not indicated to treat patients with severe hepatic insufficiency as they may precipitate encephalopathy.

4.5 Interaction with other medicinal products and other forms of interaction

Not recommended: Concomitant intake with alcohol

Chlordiazepoxide should not be used together with alcohol as this may enhance the sedative effects and affect the ability to drive or operate machinery.

Take into account: Combination with CNS depressants

Enhancement of the central depressive effect may occur if chlordiazepoxide is combined with centrally acting drugs such as neuroleptics, tranquillisers, antidepressants, hypnotics, analgesics, anaesthetics and sedative antihistamines. The elderly may require special supervision.

When chlordiazepoxide is used in conjunction with anti-epileptic drugs, side effects and toxicity may be more evident, particularly with hydantoins or barbiturates or combinations including them. This requires extra care in adjusting dosage in the initial stages of treatment.

In the case of narcotic analgesics enhancement of the euphoria may also occur leading to an increase in psychic dependence.

Compounds that inhibit certain hepatic enzymes (particularly cytochrome P450) may enhance the activity of benzodiazepines. To a lesser degree this also applies to benzodiazepines that are metabolised only by conjugation.

Drugs which enhance the sedation effect of chlordiazepoxide are: cisapride, lofexidine, nabilone, and the muscle-relaxants baclofen and tizanidine. Cimetidine inhibits the metabolism of chlordiazepoxide resulting in increased plasma concentration.

4.6 Pregnancy and lactation

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 reasons, the product is administered during the late phase of pregnancy, or during labour at high doses, effects on the neonate, such as hypothermia, hypotonia and moderate respiratory depression, can be expected, due to the pharmacological action of the compound.

Moreover, infants born to mothers who took benzodiazepines chronically during the latter stages of pregnancy may have developed physical dependence and may be at some risk for developing withdrawal symptoms in the postnatal period.

Since benzodiazepines are found in breast milk, benzodiazepines should not be given to breast-feeding mothers.

4.7 Effects on ability to drive and use machines

Sedation, amnesia, impaired concentration and impaired muscular function may adversely affect the ability to drive or to use machines. If insufficient sleep duration occurs, the likelihood of impaired alertness may be increased (see also Interactions).

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 drowsiness, sedation, unsteadiness and ataxia; these are dose related and may persist into the following day even after a single dose. 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.

Other adverse effects are rare and include numbed emotions, reduced alertness, fatigue, headache dizziness, muscle weakness, vertigo, 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 using therapeutic dosages, the risk increasing at higher dosages. Amnestic effects may be associated with inappropriate behaviour. (See warnings and precautions).

Depression

Pre-existing depression may be unmasked during benzodiazepine use.

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 benzodiazepines or 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 (see warnings and precautions). Psychic dependence may occur. Abuse of benzodiazepines has been reported.

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 [www.mhra.gov.uk/yellowcard].

4.9 Overdose

As with other benzodiazepines, overdosage should not present a threat to life unless combined with other CNS depressants (including alcohol).

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

Following overdose with oral benzodiazepines, vomiting, should be induced (within one hour) if the patient is conscious or gastric lavage is undertaken with the airway protected if the patient is unconscious. If there is no advantage in emptying the stomach, activated charcoal should be given to reduce absorption. Special attention should be paid to respiratory and cardiovascular functions in intensive care.

Overdose is usually manifested by varying degrees of depression of the central nervous system, ranging from drowsiness to coma; jaundice. Symptoms in mild cases include drowsiness, mental confusion and lethargy; in more serious cases symptoms may include ataxia, hypotonia, hypotension, respiratory depression, rarely coma, and very rarely death.

Flumazenil may be useful as an antidote.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Chlordiazepoxide acts as an anxiolytic, sedative and hypnotic depending on the dose. It also has a muscle relaxant function in cases of muscular spasticity and is an anti-convulsant.

5.2 Pharmacokinetic properties

Oral absorption Pre-systemic metabolism Plasma half-life Volume of distribution Plasma protein binding

Chlordiazepoxide is metabolized by demethylation and hydroxylation to active metabolites.

5.3 Preclinical safety data

Not applicable.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Lactose Maize starch Sodium starch glycollate Magnesium stearate Titanium dioxide (E171)

Gelatin

Quinoline yellow (E104)

Indigotine (E132)

6.2 Incompatibilities

None known.

6.3 Shelf life

36 months for containers, 24 months for blister packs.

6.4 Special precautions for storage

Store in a dry place below 25°C. Keep container well closed.

6.5 Nature and contents of container

A.    High density polystyrene

B.    Polypropylene 'Securitainer' or 'Snap Secure' type containers. Polythene

bellows

and/or polyurethane sponge wads.

Pack sizes: 28, 30, 50, 56, 60, 84, 100, 250, 500 & 1000

PVC/Aluminium blister packs.

Pack sizes: 28, 30,50, 56, 60, 84, 100, 250, 500 & 1000

6.6 Special precautions for disposal

No special instructions

7    MARKETING AUTHORISATION HOLDER

Chelonia Healthcare Limited 11 Boumpoulinas Street,

3^rd floor, 1060 Nicosia Cyprus

8 MARKETING AUTHORISATION NUMBER(S)

PL 33414/0019

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

29 December 1983 / 28 November 2008

10 DATE OF REVISION OF THE TEXT

23/01/2015