SUMMARY OF PRODUCT CHARACTERISTICS

1. NAME OF THE MEDICINAL PRODUCT

Chlordiazepoxide 5 mg Film-coated Tablets

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Chlordiazepoxide hydrochloride equivalent to 5mg chlordiazepoxide. For a full list of excipients, see section 6.1

3. PHARMACEUTICAL FORM

Film-coated tablet

Plain, biconvex, mid-green film-coated tablets

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 short-term 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

Posology:

Treatment to be given

•    under close medical supervision

•    at the lowest effective dose

•    for the shortest possible duration (not exceeding 4 weeks)

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.

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 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 the possibility of rebound phenomena

Anxiety

Adults

•    Starting dose 5 mg daily: usual dose up to 30mg in divided doses increasing to a maximum of 100 mg daily, in divided doses adjusted on an individual basis.

•    Treatment should not continue at full dose for more than 2 weeks with a 2 week tapering off process

Insomnia associated with anxiety

Adults

•    10-30mg at bed time.

•    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

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.

Special populations

Elderley and/or debilitated patients

Dosage should not exceed half the adult dose

Children

Chlordiazepoxide Film-coated Tablets are not for paediatric use

Patients with organic brain damage, respiratory impairment and/or hepatic or renal dysfunction

•    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 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)

•    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

•    Chronic psychosis.

Chlordiazepoxide should not be used alone in depression or anxiety with depression (may precipitate suicide).

4.4 Special warnings and precautions for use Tolerance:

Some 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 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 in withdrawal symptoms. These include headache, muscle pain, extreme anxiety, tension, restlessness, confusion, depression, nervousness, rebound insomnia, irritability, sweating and diarrhoea, sleep disturbance and mood changes following abrupt cessation of treatment in patients receiving even normal therapeutic doses for short periods of time. In severe cases the following may occur: a feeling of unreality or of being separated from the body (derealisation), depersonalisation, hyperacusis, confusional state, 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.

When chlordiazepoxide is being used it is important not to change to a benzodiazepine with a short duration of action, as withdrawal symptoms may be precipitated.

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. 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 (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 to occur 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 lactase deficiency or glucose-galactose malabsorption.

Elderly patients

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.

Due to the myorelaxant effect there is a risk of falls and consequently fractures in the elderly.

Patients with hepatic insufficiency

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.

Patients with depression

Chlordiazepoxide should not be used alone to treat depression or anxiety associated with depression because 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). Patients with psychotic illness

Benzodiazepines are not recommended for the primary treatment of psychotic illness.

Patients with personality disorders

Extreme caution should be used in prescribing benzodiazepines to patients with personality disorders.

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: affect 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 centrally acting 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 (eg phenytoin) and/or barbiturates. This requires extra care in adjusting dosage in the initial stages of treatment.

Narcotic analgesics: Enhancement of the euphoria may also occur leading 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, omeprazole and disulfiram) reduce clearance and may potentiate the action of benzodiazepines. The same applies to the use of contraceptive agents

•    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. In patients receiving long-term treatment with other medicines (such as centrally acting antihypertensive agents, beta receptor blockers, anticoagulant agents and cardiac glycosides), nature and extent of interactions cannot safely be foreseen

Sedative effects are possibly increased when benzodiazepines are given with moxonidine

Dopaminergics: possible antagonism of the effect of levodopa Effects of benzodiazepines are possibly reduced by theophylline.

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).

Chlordiazepoxide should not be used during pregnancy, especially during the first and last trimester unless the clinical condition of the woman requires treatment with chlordiazepoxide.

If the product is prescribed to a woman of childbearing potential, she should be warned to contact her physician to discuss discontinuation of Chlordiazepoxide if she intends to become or suspects that she is pregnant.

The administration of high doses or prolonged administration of low doses of benzodiazepines in the last trimester of pregnancy or during labour have been reported to produce irregularities in the foetal heart rate, moderate respiratory depression, hypotonia, poor sucking and hypothermia in the neonate. Moreover, infants born to mothers who chronically took benzodiazepines 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.

Breast-feeding

Chlordiazepoxide may appear in breast milk. If possible the use of Chlordiazepoxide should be avoided during breast-feeding.

4.7 Effects on ability to drive and use machines

Patients should be advised that sedation, amnesia, impaired concentration, dizziness, blurred vision and impaired muscle 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 these effects (see section 4.5).

Patients should further be advised that alcohol may intensify any impairment, and should, therefore, be avoided during treatment.

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, unsteadiness and ataxia; these are 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)

Immune system disorders:

Very rare: Anaphylactic reaction, angioedema Frequency not known: Hypersensitivity

Psychiatric disorders:

Frequency not known: Amnesia, hallucinations, dependence, depression, restlessness, agitation, irritability, depressed level of consciousness, aggression, delusion, nightmares, psychotic disorder, abnormal behaviour, emotional disturbances, paradoxical drug reaction (e.g. anxiety, sleep disorders, insomnia, suicide attempt, suicidal ideation)

Nervous system disorders:

Common: Sedation, dizziness, unsteadiness, somnolence, ataxia, balance disorder, confusional states Rare: Headache, vertigo

Frequency not known: Dysarthria, gait disturbance, extrapyramidal disorder (e.g. tremor, dyskinesia)

Eye disorders:

Rare: Visual impairment including diplopia

Vascular disorders:

Rare: Hypotension

Respiratory, thoracic and mediastinal disorders:

Frequency not known: Respiratory depression

Gastrointestinal disorders:

Rare: Gastrointestinal upsets

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

Frequency not known: Changes in salivation Amnesia

Anterograde amnesia may occur at the therapeutic doses, with increasing risk at higher doses. This may be associated with inappropriate behavior (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 behavior and other adverse behavioural effects are known to occur when using benzodiazepinelike 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

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.

4.9 Overdose

Benzodiazepines potentiate the effects of other CNS depressants including alcohol.

Features

Benzodiazepines commonly cause drowsiness, ataxia, dysathria and nystagmus. Coma, hypotension and respiratory depression occasionally occur but are seldom serious if these drugs are taken alone. Coma usually lasts a few hours but in the elderly may be more protracted and cyclical. Respiratory depression is more serious in those with severe obstructive airways disease. Patients who are asymptomatic at 4 hours are unlikely to develop symptoms.

Management

•    Maintain clear airway and adequate ventilation, if indicated

•    The value of gastric decontaminants is uncertain. Consider activated charcoal (50g for an adult: 1g/Kg for a child) in adults or children who have taken

more than a potentially toxic amount within 1 hour provided the airway can be protected.

•    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 an alternative to ventilation. Flumazenil has a short half-life (about an hour) and in this situation an infusion may therefore be required. Flumazenil should not normally be used in patients with a history of seizures, head injury, chronic benzodiazepine use, co-ingestion of a benzodiazepine and tricyclic antidepressant or other proconvulsant or as a “diagnostic test”.

If excitation occurs, barbiturates should not be used.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeiutic group: Psycholeptics, anxiolytics, benzodiazepine derivatives. ATC code: N05BA02

Chlordiazepoxide is a psychotropic substance from the class of 1, 4-benzodiazepines with tension, excitement, anxiety attenuating properties and sedative and hypnotic effects. Chlordiazepoxide shows muscle relaxant and anticonvulsant effects.

Chlordiazepoxide has a low affinity as an agonist at specific benzodiazepine receptors, located on GABA-ergic neurones. Stimulation of benzodiazepine receptors potentiates the actions of GABA, which in turn controls the flow of chloride ions across neuronal membranes. An endogenous benzodiazepine has been postulated, but not as yet demonstrated. GABA-ergic neurones are inhibitory in the nervous system. This results in diminuation of some 5-HT, dopamine and noradrenergic neurotransmitter system effects.

5.2 Pharmacokinetic properties

Absorption:

Chlordiazepoxide is completely absorbed after oral administration and peak plasma concentrations are seen between one and two hours after administration.

Steady-state levels are usually reached within three days.

Distribution:

Chlordiazepoxide is metabolised to desmethyl-chlordiazepoxide. Demoxepam and desmethyldiazepam are also found in the plasma of patients on continuous treatment. The active metabolite desmethyl-chlordiazepoxide has an accumulation half-life of 10 - 18 hours; that of demoxepam has been recorded as 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.

Elimination

The drug has a half-life of 6 - 30 hours.

In the elderly the rate of metabolism and excretion of chlordiazepoxide and its active metabolytes is significantly reduced.

Pharmacokinetic/pharmacodynamic relationship:

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

5.3 Preclinical safety data

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

Tablet core:

Maize starch Magnesium stearate Lactose monohydrate Pregelatinised maize starch

Film coating: Hypromellose Ethylcellulose Diethylphthalate, Brilliant Blue (E133) Indigo Carmine (E132)

6.2. Incompatibilities

Not applicable

6.3. Shelf life

36 months for cylindrical polypropylene containers 24 months for blister packs.

6.4. Special precautions for storage

Do not store above 25° C. Store in the original package. Keep in the outer container.

6.5. Nature and contents of container

Cylindrical, polypropylene container with polyethylene tamper-evident cap and polyethylene or polyurethane inserts or PVC/PVdC/Al blister packs Pack sizes: 28, 30, 50, 56, 60, 84, 100, 250, 500 & 1000 Not all packs may be marketed

6.6    Special precautions for disposal

No special requirements.

7.    MARKETING AUTHORISATION HOLDER

Dr. Reddy’s Laboratories (UK) Ltd

6 Riverview Road

Beverley

HU17 0LD

UK

8. MARKETING AUTHORISATION NUMBER

PL 08553/0070

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

10/12/2010

10    DATE OF REVISION OF THE TEXT

12/03/2016