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Diazepam Oral Solution BP 2mg/5ml

Last Updated on eMC 09-Feb-2015 View changes  | Actavis UK Ltd Contact details

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

Diazepam is contra-indicated for patients with:

• 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

• The concomitant use of diazepam with alcohol and/or CNS depressants should be avoided. Such concomitant use has the potential to increase the clinical effects of diazepam possibly including severe sedation, clinically relevant respiratory and/or cardio-vascular depression (see section 4.5).

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. The patient must be evaluated after a period of no more than 4 weeks and then regularly thereafter in order to assess the need for continued treatment, especially if the patient is free of symptoms. In general, treatment must not last any longer than 8-12 weeks, including the 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. 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. When benzodiazepines with a long duration of action are being used it is important to warn against changing to a benzodiazepine with a short duration of action, as withdrawal symptoms may develop.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 or drug dependants. Discontinuation should be gradual in order to minimise the risk of withdrawal symptoms.

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 or in patients with marked personality disorders. Regular monitoring in such patients is essential, routine repeat prescriptions should be avoided and treatment should be withdrawn gradually.

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

• Benzodiazepines are not indicated to treat patients with severe hepatic insufficiency as they may precipitate encephalopathy. In patients with chronic hepatic disease dosage may need to be reduced.

• The usual precautions in treating patients with impaired renal function should be observed. In renal failure, the half-life of diazepam is not clinically significantly changed, and dose adjustment is usually not necessary.

• 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. Amnestic effects may be associated with inappropriate behaviour.

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. Safety and effectiveness of diazepam in paediatric patients below the age of 6 months have not been established.

Elderly and debilitated patients should be given a reduced dose (see section 4.2). Due to the myorelaxant effect there is a risk of falls and consequently hip fractures in the elderly.

Psychiatric and 'paradoxical' reactions

Paradoxical reactions (such as restlessness, agitation, irritability, aggressiveness, delusion, rages, nightmares, hallucinations, psychoses, inappropriate behaviour and other adverse behavioural effects) have been reported from the use of benzodiazepines.

Such reactions are possibly seen more often in the treatment of children and elderly patients and should result in the discontinuation of treatment.

Potentially suicidal individuals should not have access to large amounts of diazepam due to the risk of overdosing.

4.5 Interaction with other medicinal products and other forms of interaction

Not recommended

Alcohol

Diazepam should not be used together with alcohol (CNS inhibition 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

Pharmacodynamic interactions

If diazepam is used with other centrally acting agents, careful consideration has to be given to the pharmacology of the agents employed, particularly with compounds that may potentiate or be potentiated by the action of diazepam, such as neuroleptics, anxiolytics/sedatives, hypnotics, antidepressants, anticonvulsants, sedating antihistamines, antipsychotics, anaesthetics for general anaesthesia and narcotic analgesics. Such concomitant use may increase sedative effects and cause depression of respiratory and cardiovascular functions. Concomitant use of narcotic analgesics may promote psychic dependency due to enhancement of euphorigenic effects.

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. Increased risk of sedation and respiratory depression. Phenobarbital is a known inducer of CYP3A4 and increases hepatic metabolism of diazepam. Reduced effect of diazepam.

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, tizanidine, suxethonium and tubocurarin.

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.

Rifamycins (rifampicin)

Rifampicin is a potent inducer of CYP3A4 and substantially increases the hepatic metabolism and clearance of diazepam. In a study with healthy subjects administered 600 mg or 1.2 g rifampicin daily for 7 days, the clearance of diazepam was increased by about fourfold. Co-administration with rifampicin gives rise to substantially decreased concentrations of diazepam. Reduced effect of diazepam. The concomitant use of rifampicin and diazepam should be avoided.

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.

Antiviral agents (atazanavir, ritonavir, delavirdine, efavirenz, indinavir, nelfinavir, saquinavir)

Antiviral agents may inhibit the CYP3A4 metabolic pathway for diazepam. Increased risk of sedation and respiratory depression. Therefore, concomitant use should be avoided.

Zidivudine

Increased zidovudine clearance by diazepam.

Oral contraceptives

Inhibition of oxidative metabolism of diazepam. Increased effects of diazepam.

Co-administration of diazepam and combined oral contraceptives has been known to cause breakthrough bleeding. The mechanism of this reaction is unknown. Breakthrough bleeding, but no contraceptive failures have been reported.Theophylline

A proposed mechanism is competitive binding of theophylline to adenosine receptors in the brain. Counteraction of the pharmacodynamic effects of diazepam, e.g. reduction of sedation and psychomotor effects.

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). Cmax is increased by 1.5 times and AUC by 3.2 times. Possible increased effect of diazepam.

This interaction may have 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.

Clozapine

Mechanism: Pharmacodynamic synergism.

Effect: Severe hypotension, respiratory depression, unconsciousness and potentially fatal respiratory and/or cardiac arrest. Therefore, concomitant use is not recommended and should be avoided.

Pharmacokinetic interactions

Diazepam is mainly metabolised to the pharmacologically active metabolites N-desmethyldiazepam, temazepam and oxazepam. The oxidative metabolism of diazepam is mediated by CYP3A4 and CYP2C19 isoenzymes. Oxazepam and temazepam are further conjugated to glucuronic acid. Inhibitors of CYP3A4 and/or CYP2C19 can give rise to increased concentrations of diazepam while enzyme inducing drugs such as rifampicin, hypericum perforatum and certain antiepileptics can result in substantially decreased plasma concentrations of diazepam.

Carbamazepine

Carbamazepine is a known inducer of CYP3A4 and increases hepatic metabolism of diazepam. This can result in up to three-fold greater plasma clearance and a shorter half-life of diazepam. Reduced effect of diazepam.

Phenytoin

Phenytoin is a known inducer of CYP3A4 and increases hepatic metabolism of diazepam. Reduced effect of diazepam.

The metabolism of phenytoin may be increased or decreased or remain unaltered by diazepam in an unpredictable way. Increased or decreased serum concentration of phenytoin. Phenytoin concentrations should be monitered more closely when diazepam is added or discontinued.

Azoles (fluconazole, itraconazole, ketoconazole, voriconazole)

Increased plasma concentration of benzodiazepines, due to inhibition of the CYP3A4 and/or CYP2C19 metabolic pathway.

Fluconazole: Co-administration with 400 mg fluconazole on the first day and 200 mg on the second day increased the AUC of a single 5 mg oral dose of diazepam 2.5-fold and prolonged the half-life from 31 hours to 73 hours.

Voriconazole: A study with healthy subjects found that 400 mg voriconazole twice daily on the first day and 200 mg twice daily on the second day increased the AUC of a single 5 mg oral dose of diazepam 2.2-fold and prolonged the half-life from 31 hours to 61 hours.

Increased risk of undesired effects and toxicity of benzodiazepine. Concomitant use should be avoided or the dose of diazepam reduced.

Fluvoxamine

Fluvoxamine inhibits both CYP3A4 and CYP2C19 which leads to inhibition of the oxidative metabolism of diazepam. Co-administration with fluvoxamine results in an increased half-life and an approximately 190% increased plasma concentrations (AUC) of diazepam. Drowsiness, reduced psychomotor performance and memory. Preferably, benzodiazepines that are metabolised via a non-oxidative pathway should be used instead.

Corticosteroids

Chronic use of corticosteroids may cause increased metabolism of diazepam due to induction of cytochrome P450 isoenzyme CYP3A4, or of enzymes responsible for glucuronidation. Reduced effects of diazepam.

Cimetidine

Cimetidine inhibits the hepatic metabolism of diazepam, reducing its clearance and prolonging its half-life. In one stude where 300 mg cimetidine was administered four times daily for 2 weeks, the combined plasma level of diazepam and its active metabolite, desmethyldiazepam,was found to be increased by 57%, but reaction times and other motor and intellectual tests remained unaffected. Increased action of diazepam and increased risk of drowsiness. Reduction of the diazepam dose may be necessary.

Omeprazole

Omeprazole inhibits the CYP2C19 metabolic pathway for diazepam. Omeprazole prolongs the elimination half-life of diazepam and increases the plasma concentrations (AUC) of diazepam approximately between 30% - 120%. The effect is seen in CYP2C19 extensive metabolisers but not in slow metabolisers, with a low clearance of diazepam. Increased action of diazepam. Reduction of the diazepam dose may be necessary.

Esomeprazole

Esomeprazole inhibits the CYP2C19 metabolic pathway for diazepam. Co-administration with ezomeprazole results in an extended half-life and an increase in plasma concentrations (AUC) of diazepam by approximately 80%. Increased effect of diazepam. Reduction of the diazepam dose may be necessary.

Isoniazid

Isoniazid inhibits the CYP2C19 and CYP3A4 metabolic pathway for diazepam. Co-administration with 90 mg isoniazid twice daily for 3 days resulted in a a prolonged elimination half-life of diazepam and in a 35% increased plasma concentration (AUC) of diazepam. Increased effect of diazepam.

Itraconazole

Increased plasma concentration of diazepam due to inhibition of the CYP3A4 metabolic pathway. In a study with healthy subject given 200 mg itraconazole daily for 4 days increased the AUC of a single 5 mg oral dose of diazepam by about 15%, but there was no clinically significant interaction as determined by psychomotor performance tests. Possible increased effect of diazepam.

Fluoxetine

Fluoxetine inhibits the metabolism of diazepam via CYP2C19 and other pathways, resulting in elevated plasma concentrations and decreased clearance of diazepam. Increased effect of diazepam. Concomitant use should be monitered closely.

Disulfiram

Reduced metabolism of diazepam leading to prolonged half-life and increased plasma concentration of diazepam. The elimination of the N-desmethyl metabolites of diazepam is slowed down which can give rise to marked sedative effects. Increased risk of CNS inhibition such as sedation.

Cisapride

Accelerated absorption of diazepam. Temporary increase of the sedative effects of orally administered diazepam.

Levodopa

Concomitant use with diazepam resulted in reduced effects of levodopa in a small number of case reports.

Ketamine

Due to similar oxidative processes, diazepam competitively inhibits ketamin metabolism. Pre-medication with diazepam leads to prolonged half-life of ketamine with enhanced effect as a result. Increased sedation.

4.6 Pregnancy and lactation

The safety of diazepam in human pregnancy has not been established. It should not be used in the first and third trimesters. There may be a small increase in the risk of congenital malformation, particularly oral cleft with the use of benzodiazepines in the first trimester but a causal relationship has not been established.

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.

Pregnancy

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 (“Floppy Infant Syndrome”), irregularities in the heart rate, poor suckling 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.

Studies in animals have shown reproductive toxicity (see section 5.3).

Lactation

Benzodiazepines are found in the breast milk -Reports have demonstrated milk: plasma concentration ratios to vary between 0.2 and 2.7. There is therefore a risk of accumulation in the breastfeeding child. Benzodiazepines should not be given to breast feeding mothers.

Fertility

Studies in animals have shown a decrease in pregnancy rate and reduced number of surviving offspring in rats at high doses. There are no human data.

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.

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

Drowsiness, numbed emotions, reduced alertness, confusion, fatigue, headache, dizziness, muscle weakness, ataxia or double vision predominantly occur at the start of therapy but usually disappear with repeated administration. Among elderly patients there may be confusion conditions at high dose levels. There is an increased risk of falls and associated fractures in elderly patients using benzodiazepines.

Increased salivary and bronchial secretion has been reported, in particular in children.

Amnesia

Anterograde amnesia may occur using therapeutic dosages, the risk increasing at higher dosages. Amnestic effects may be associated with inappropriate behaviour (see section 4.4).

Dependence

Chronic use (even at therapeutic doses) may lead to the development of physical and psychic dependence: discontinuation of the therapy may result in withdrawal or rebound phenomena (see section 4.4). Abuse of benzodiazepines has been reported.

The frequencies of adverse events are ranked according to the following:

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 (cannot be estimated from the available data).

System Organ Class

Frequency

Undesirable effects

Blood and lymphatic system disorders

Rare

Blood dyscrasias

Very rare

Leukopenia

Immune system disorders

Very rare

Anaphylaxis.

Psychiatric disorders

Common

Confusion.

Rare

Psychiatric and paradoxical reactions such as excitation, restlessness, agitation, irritability, aggressiveness, delusion, rages, hallucinations, psychoses, memory loss, nightmares, inappropriate behaviour and other adverse behavioural effects.a

Emotional poverty, decreased alertness and depression.b

Nervous system disorders

Very common

Drowsiness.

Common

Ataxia, impaired motor ability, tremor.

Uncommon

Anterograde amnesia.c

Concentration difficulties, balance disorders, dizziness, headache, slurred speech.

Rare

Unconsciousness, insomnia, dysarthria.

Eye disorders

Not known

Reversible disorders of vision: blurred vision, diplopia, nystagmus.

Cardiac disorders

Rare

Bradycardia, heart failure including cardiac arrest.

Vascular disorders

Rare

Hypotension, syncope.

Respiratory, thoracic and mediastinal disorders

Uncommon

Respiratory depression.

Rare

Respiratory arrest, increased bronchial secretion.

Not Known

Apnoea

Gastrointestinal disorders

Uncommon

Gastrointestinal disorders (nausea, vomiting, constipation, diarrhoea), increased salivary secretion.

 

Rare

Dry mouth, increased appetite.

Hepatobiliary disorders

Rare

Jaundice, changes of hepatic parameters (elevation of ALT, AST, alkaline phosphatase).

Skin and subcutaneous tissue disorders

Uncommon

Allergic skin reactions (itching, erythema, rash).

Musculoskeletal and connective tissue disorders

Uncommon

Myasthenia.

Renal and urinary disorders

Rare

Urinary retention, incontinence.

Reproductive system and breast disorders

Rare

Gynaecomastia, impotence, increased or reduced libido.

General disorders and administration site conditions

Common

Fatigue, withdrawal symptoms (anxiety, panic, palpitations, sweating, tremor, gastrointestinal disorders, irritability, aggression, disrupted sensory perception, muscle spasms, general malaise, loss of appetite, paranoid psychosis, delirium and epileptic attacks).d

Not known

Anaphylaxis

Investigations

Very rare

Elevation of transaminases.

a Known to occur when using benzodiazepines or benzodiazepine-like agents. These reactions may be quite severe. They are more likely to occur in children and the elderly. Diazepam should be discontinued if such symptoms occur (see section 4.4).

b Pre-existing depression may be unmasked during benzodiazepine use.

c May occur using therapeutic dosages, the risk increasing at higher dosages. Amnestic effects may be associated with inappropriate behaviour (see section 4.4).

d The likelihood and degree of severity of withdrawal symptoms is dependent on the duration of treatment, dose level and degree of dependency.

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; website: www.mhra.gov.uk/yellowcard

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

18 months from the date of manufacture.

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

14/01/2015

Company contact details

Actavis UK Ltd

Company image
Address

Whiddon Valley, Barnstaple, Devon, EX32 8NS, UK

Fax

+44 (0)1271 346 106

Medical Information e-mail
Telephone

+44 (0)1271 311 200

Medical Information Direct Line

+44 (0)1271 385 257

Before you contact this company: often several companies will market medicines with the same active ingredient. Please check that this is the correct company before contacting them. Why?

Active ingredients

diazepam

Legal categories

POM - Prescription Only Medicine

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