Diazepam Oral Solution BP 2mg / 5ml

1. Name Of The Medicinal Product

DIAZEPAM ORAL SOLUTION BP 2mg/5ml

2. Qualitative And Quantitative Composition

Each 5ml spoonful contains 2mg Diazepam BP.

3. Pharmaceutical Form

A pink syrup with an odour of raspberries.

4. Clinical Particulars

4.1 Therapeutic Indications

Diazepam has potent anxiolytic, anticonvulsant and central muscle-relaxing properties; these effects are probably mediated through special areas in the CNS. It also has uses in pre-operative medication and is used in the treatment of skeletal-muscle spasm, and the associated pain.

The main uses are:

Adults:

1) The short term relief (14 days) only of anxiety which 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 anxiety is considered to be inappropriate.

2) Cerebral palsy.

3) Muscle spasm; as an adjunct to the control of muscle spasm in tetanus.

4) As an adjunct to the management of certain types of epilepsy (eg myoclonus).

5) Symptomatic treatment of acute alcohol withdrawal.

6) As oral premedication for the nervous dental patient.

Children:

1) Control of tension and irritability in cerebral spasticity in selected cases.

2) Oral premedication.

4.2 Posology And Method Of Administration

Posology

As an anxiolytic, the lowest effective dose should be employed; dosage regimes should not exceed beyond 14 days. Patients who have received benzodiazepines for a long time may require an extended withdrawal period. Long-term chronic use is not recommended.

Adults:

Anxiety states, obsessive-compulsive neuroses, and other psychiatric disorders: 2-30mg daily in divided doses.

Insomnia associated with anxiety: 5-30mg before retiring.

Cerebral palsy: 2-60mg daily in divided doses.

Upper motor neuronic spasticity: 5-60mg daily in divided doses.

Muscle spasm of varied aetiology, fibrositis, cervical spondylosis: 2-15mg daily in divided doses.

Adjunct to the management of some types of epilepsy: Premedication: 2-60mg daily in divided doses. Adults: 5-20mg and children: 2-10mg.

Alcohol withdrawal: 5-20mg, repeated if necessary in 2 to 4 hours.

Oral premedication in dental patients: 5mg the night before, 5mg on waking and 5mg two hours before the appointment.

Children:

Conditions associated with muscle spasm: Control of tension and irritability in spasticity in selected cases; 2-40mg daily in divided doses. As an adjunct to the control of muscle spasm in tetanus; as for adults.

Spastic children with minimal brain damage: 2-40mg daily in divided doses.

Elderly and debilitated patients:

Doses should not exceed half the above recommended adult doses.

Method of Administration

For oral administration.

4.3 Contraindications

• Known hypersensitivity to diazepam, benzodiazepines or any of the excipients

• Phobic or obsessional states; chronic psychosis, hyperkinesis (paradoxical reactions may occur)

• Acute pulmonary insufficiency; respiratory depression, acute or chronic severe respiratory insufficiency (ventilatory failure may be exacerbated)

• Myasthenia gravis (condition may be exacerbated)

• Sleep apnoea (condition may be exacerbated)

• Severe hepatic insufficiency (elimination half-life of diazepam may be prolonged)

• Acute porphyria

• Diazepam should not be used as monotherapy in patients with depression or those with anxiety and depression as suicide may be precipitated in such patients.

• Planning a pregnancy (see section 4.6).

• Pregnancy (unless there are compelling reasons – see section 4.6).

4.4 Special Warnings And Precautions For Use

• Duration of Treatment - The duration of treatment should be as short as possible depending on the indication, but should not exceed 4 weeks including tapering off process. Treatment should not continue beyond 4 weeks without re-evaluation of the patient's condition. Where long-term therapy is essential, it is recommended that the patient's requirements be reviewed on a regular basis.

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. Moreover it is important that the patient should be aware of the possibility of rebound phenomena, thereby minimizing anxiety over such symptoms should they occur while diazepam is being discontinued.

There are indications that, in the case of benzodiazepines with a long duration of action such as diazepam, withdrawal phenomena can become manifest between doses, especially when the dosage is high. Care is needed when switching from long acting benzodiazepines, such as diazepam, to a benzodiazepine with a short duration of action due to the risk of withdrawal symptoms developing.

• Dependence and Withdrawal - Withdrawal symptoms occur with benzodiazepines following normal therapeutic doses given for short periods of time.

As sudden discontinuation of benzodiazepines may result in convulsions, particular care should be taken in patients with epilepsy, other patients who have had a history of seizures or in alcohol dependants.

Use of diazepam may lead to the development of physical and psychic dependence. The risk of dependence increases with the dose and duration of treatment, and in patients with a history of alcoholism and drug abuse.

Once physical dependence has developed, abrupt termination of treatment will be accompanied by withdrawal symptoms (see Section 4.8 Undesirable Effects).

Rebound insomnia and anxiety: a transient syndrome whereby the symptoms that led to treatment with diazepam may recur in an enhanced form 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.

• Tolerance - Limits of tolerance in patients with organic cerebral changes (particularly arteriosclerosis) or cardiorespiratory insufficiency may be very wide; care must be taken in adapting the dosage with such patients.

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

• Care should be taken in patients with chronic renal or hepatic disease (elimination half-life of diazepam may be prolonged).

• Alcohol should be avoided during treatment with diazepam (additive CNS depression).

• Amnesia: diazepam 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 uninterrupted sleep of 7-8 hours.

Anterograde amnesia may occur even if benzodiazepines are used within the normal dose range, though this is seen in particular at high dose levels.

• In cases of loss or bereavement, psychological adjustment may be inhibited by benzodiazepines.

• History of alcohol or drug abuse (as these are patients predisposed to habituation and dependence).

• Depression or anxiety associated with depression. Benzodiazepines should not be used alone in the treatment of depression or anxiety associated with depression as suicide may be precipitated in such patients.

• Hypoalbuminaemia (may predispose the patient to higher incidence of sedative side effects).

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

• Specific patient groups: benzodiazepines should not be given to children without careful assessment of the need to do so; the duration of treatment must be kept to a minimum. The elderly 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 not indicated to treat patients with severe hepatic insufficiency as they may precipitate encephalopathy. Benzodiazepines are not recommended for the primary treatment of psychotic illness.

Abnormal psychological reactions to benzodiazepines have been reported (see section 4.8). Such reactions are possibly seen more often in the treatment of children and elderly patients and should result in the discontinuation of treatment.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Not recommended

Alcohol

Diazepam should not be used together with alcohol (enhanced sedative effects: impaired ability to drive/ operate machinery).

Sodium oxybate

Avoid concomitant use (enhanced effects of sodium oxybate).

HIV-protease inhibitors

Avoid concomitant use (increased risk of prolonged sedation) – see below for zidovudine.

Take into account

Centrally acting drugs

Enhancement of the central depressive effect may occur if diazepam 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

Pharmacokinetic studies on potential interactions between diazepam and antiepileptic drugs have produced conflicting results. Both depression and elevation of drug levels, as well as no change, have been reported. Phenobarbital taken concomitantly may result in an additive CNS effect. Special care should be taken in adjusting the dose in the initial stages of treatment. Side effects may be more evident with hydantoins or barbiturates. Diazepam has been reported to be displaced from protein-binding sites by sodium valproate (increased serum levels: increased risk of drowsiness).

Narcotic analgesics

Enhancement of the euphoria may lead to increased psychological dependence.

Other drugs enhancing the sedative effect of diazepam

Cisapride, lofexidine, nabilone, disulfiram and the muscle-relaxants - baclofen and tizanidine.

Compounds that affect hepatic enzymes (particularly cytochrome P450):

• Inhibitors (eg cimetidine: isoniazid: erythromycin: omeprazole: esomeprazole) reduce clearance and may potentiate the action of benzodiazepines. Itraconazloe, ketoconazole, and to a lesser extent fluconazole and voriconazole are potent inhibitors of the cytochrome P450 isoenzyme CYP3A4 and may increase plasma levels of benzodiapines. The effects of benzodiapines may be

increased and prolonged by concomitant use. A dose reduction of the benzodiazepine may be required.

• Inducers (eg rifampicin) may increase clearance of benzodiazepines.

Antihypertensives, vasodilators& diuretics: Enhanced hypotensive effect with ACEinhibitors, alpha-blockers, angiotensin–II receptor antagonists, calcium channel blockers adrenergic neurone blockers, beta-blockers, moxonidine, nitrates, hydralazine, minoxidil, sodium nitroprusside and diuretics. Enhanced sedative effect with alpha-blockers or moxonidine.

Dopaminergics

Possible antagonism of the effect of levodopa.

Antacids

Concurrent use may delay absorption of diazepam.

Zidivudine

Increased zidovudine clearance by diazepam.

Oestrogen-containing contraceptives

Possible inhibition of hepatic metabolism of diazepam.

Theophylline

Increases metabolism of diazepam which possibly reduces the effect.

Caffeine

Concurrent use may result in reduced sedative and anxiolytic effects of diazepam.

Grapefruit juice

Inhibition of CYP3A4 may increase the plasma concentration of diazepam (possible increased sedation and amnesia). This interaction may of little significance in healthy individuals, but it is not clear is if other factors such as old age or liver cirrhosis increase the risk of adverse effects with concurrent use.

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 the 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 effect the ability to drive or to use machines. If insufficient sleep duration occurs, the likelihood of impaired alertness may be increased (see also Interactions). Patients should be warned that effects on the central nervous system may persist into the day after administration even after a single dose.

4.8 Undesirable Effects

During the first week of administration or when high doses are used they may have a sedative effect and cause some degree of drowsiness. In such cases there is an advantage in administering half the total daily intake at night, the remainder being given in divided doses during the day.

The elderly and debilitated are particularly sensitive to the effects of central depressant drugs and may experience confusion, especially if organic brain changes are present; the dosage of diazepam should not exceed one-half that recommended for other adults.

Skin and appendages disorders

Allergic reactions (skin rash or itching) occur rarely.

Central and peripheral nervous disorders

Drowsiness, sedation, unsteadiness, ataxia is common (these effects are dose-related and may persist into the following day even after a single dose), light-headedness, headache, vertigo, dystonic effects occur rarely. Impaired motor ability, dizziness, muscle weakness, tremor, slurred speech.

Vision disorders

Visual disturbances occur rarely.

Psychiatric disorders

Libido fluctuations occur rarely. Anterograde amnesia (amnesia may be associated with inappropriate behaviour), concentration difficulties, abnormal psychological reactions, behavioural adverse effects include paradoxical aggressive outbursts, excitement, confusion, restlessness, agitation, irritability, delusions, rages, nightmares, hallucinations, psychoses, inappropriate behaviour, numbed emotions, the uncovering of depression with suicidal tendencies and dependence (see section 4.4). Abuse of benzodiazepines has been reported.

Gastro-intestinal system disorders

Gastrointestinal upsets occur rarely. Increased salivary secretion.

Liver and billiary system disorders

Jaundice occurs rarely.

Endocrine disorders

Gynaecomastia.

Cardio disorders

Hypotension occurs rarely.

Respiratory system disorders

Respiratory depression, apnoea.

Blood disorders

Blood dyscrasias occur rarely.

Urinary system disorders

Urinary retention occurs rarely.

Body as a whole-general disorders

Fatigue, anaphylaxis.

Withdrawal effects

Withdrawal symptoms: Development of dependence is common after regular use, even in therapeutic doses for short periods, particularly in patients with a history of drug or alcohol abuse or marked personality disorders. Discontinuation of the therapy may result in withdrawal or rebound phenomena (see 4.4 Special Warnings and Special Precautions for Use). Symptoms of benzodiazepine withdrawal include anxiety, depression, impaired concentration, insomnia, headache, dizziness, tinnitus, loss of appetite, tremor, perspiration, irritability, perceptual disturbances such as hypersensitivity to physical, visual, and auditory stimuli and abnormal taste, nausea, vomiting, abdominal cramps, palpitations, mild systolic hypertension, tachycardia, and orthostatic hypotension.

Rare and more serious symptoms include muscle twitching, confusional or paranoid psychosis, convulsions, hallucinations, and a state resembling delirium tremens. Broken sleep with vivid dreams and increased REM sleep may persist for some weeks after withdrawal of benzodiazepines.

4.9 Overdose

Features

The symptoms of diazepam overdose are mainly an intensification of the therapeutic effects (ataxia, drowsiness, dysarthria, sedation, muscle weakness, profound sleep, hypotension, bradycardia, nystagmus) or paradoxical excitation. In most cases only observation of vital functions is required.

Extreme overdosage may lead to coma, areflexia, cardiorespiratory depression and apnoea, requiring appropriate countermeasures (ventilation, cardiovascular support). Benzodiazepine respiratory depressant effects are more serious in patients with severe chronic obstructive airways disease. Severe effects in overdose also include rhabdomyolysis and hypothermia.

Management

Maintain a clear airway and adequate ventilation.

Consider activated charcoal (50g for an adult, 1g/kg for a child) in adults who have taken more than 100mg or children who have taken more than 1mg/kg within one hour, provided they are not too drowsy.

Monitoring level of consciousness, respiratory rate, pulse oximetry and blood pressure in symptomatic patients.

Consider arterial blood gas analysis in patients who have a reduced level of consciousness (GCS < 8; AVPU scale P or U) or have reduced oxygen saturations on pulse oximetry.

Correct hypotension by raising the foot of the bed and by giving an appropriate fluid challenge. Where hypotension is thought mainly due to decreased systemic vascular resistance, drugs with alpha-adrenergic activity such as noradrenaline or high dose dopamine (10-30 micrograms/kg/min) may be beneficial. The dose of inotrope should be titrated against blood pressure.

If severe hypotension persists despite the above measures, then central venous pressure monitoring should be considered.

Supportive measures are indicated depending on the patient's clinical state.

Benzodiazepines are not significantly removed from the body by dialysis.

Flumazenil, a benzodiazepine antagonist, is not advised as a routine diagnostic test in patients with reduced conscious level. It may sometimes be used as an alternative to ventilation in children who are naive to benzodiazepines, or in patients with COPD to avoid the need for ventilation. It is not necessary or appropriate in cases of poisoning to fully reverse the benzodiazepine effect. Flumazenil has a short half-life (about an hour) and in this situation an infusion may therefore be required. Flumazenil is contraindicated when patients have ingested multiple medicines, especially after co-ingestion of a benzodiazepine and a tricyclic antidepressant or any other drug that causes seizures. This is because the benzodiazepine may be suppressing seizures induced by the second drug; its antagonism by flumazenil can reveal severe status epilepticus that is very difficult to control.

Contraindications to the use of flumazenil include features suggestive of a tricyclic antidepressant ingestion including a wide QRS, or large pupils. Use in patients postcardiac arrest is also contraindicated.

It should be used with caution in patients with a history of seizures, head injury, or chronic benzodiazepine use.

Occasionally a respirator may be required but generally few problems are encountered, although behavioral changes are likely in children.

If excitation occurs, barbiturates should not be used.

Effects of overdose are more severe when taken with centrally-acting drugs, especially alcohol, and in the absence of supportive measures, may prove fatal.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Diazepam is a benzodiazepine with anticonvulsant, anxiolytic, sedative, muscle relaxant and amnesic properties.

5.2 Pharmacokinetic Properties

Diazepam is readily and completely absorbed from the GI tract, peak plasma concentration occurring within 30-90 minutes of oral administration; the rate of absorption is age related and tends to be delayed in the elderly. Diazepam crosses the blood-brain barrier and is highly lipid soluble. It has a biphasic half-life with an initial rapid distribution phase followed by a prolonged terminal elimination phase of 1-2 days; its action is further prolonged by the even longer half-life of 2-5 days of its active principle metabolite, desmethyldiazepam, the relative proportion of which increases in the body on long-term administration.

Diazepam is extensively metabolised in the liver and, in addition to desmethyldiazepam, its active metabolites include oxazepam and temazepam. It is excreted in the urine, mainly in the form of its metabolites, either free or in conjugated forms. Diazepam is very extensively bound to plasma proteins.

The half-life of diazepam is prolonged in neonates, in the elderly and in patients with kidney or liver disease. Diazepam and its metabolites cross the placental barrier and are excreted in breast milk.

5.3 Preclinical Safety Data

Not applicable.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Also contains: docusate sodium, magnesium aluminium silicate, propylene glycol, raspberry flavour, saccharin sodium, percol erythrosine (E127), sorbic acid (E200), propyl hydroxybenzoate (E216), methyl hydroxybenzoate (E218), sorbital (E420), glycerol (E422).

6.2 Incompatibilities

None known.

6.3 Shelf Life

Shelf-life

Three years from the date of manufacture.

Shelf-life after dilution/reconstitution

Not applicable.

Shelf-life after first opening

Not applicable.

6.4 Special Precautions For Storage

Do not store above 25°C. Keep container in the outer carton and keep the container tightly closed.

6.5 Nature And Contents Of Container

The product containers are amber glass bottles with plastic screw caps contained in a carton.

Pack sizes: 50ml, 100ml, 150ml, 200ml, 300ml, 400ml, 500ml, 1000ml, 5000ml

6.6 Special Precautions For Disposal And Other Handling

Not applicable.

Administrative Data

7. Marketing Authorisation Holder

Name or style and permanent address of registered place of business of the holder of the Marketing Authorisation:

Actavis UK Limited

(Trading style: Actavis)

Whiddon Valley

BARNSTAPLE

N Devon EX32 8NS

8. Marketing Authorisation Number(S)

PL 0142/0103

9. Date Of First Authorisation/Renewal Of The Authorisation

15.5.78

Renewed: 15.5.83; 15.5.88; 23.6.93

10. Date Of Revision Of The Text

12/08/2011