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Actavis UK Ltd

Whiddon Valley, Barnstaple, Devon, EX32 8NS, UK
Telephone: +44 (0)1271 311 200
Fax: +44 (0)1271 346 106
WWW: http://www.actavis.co.uk
Medical Information Direct Line: +44 (0)1271 311 257
Medical Information e-mail: medinfo@actavis.co.uk

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Summary of Product Characteristics last updated on the eMC: 10/06/2011
SPC Diazemuls


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1. Name of the medicinal product

Diazemuls


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2. Qualitative and quantitative composition

Each emulsion contains Diazepam 0.5% w/v


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3. Pharmaceutical form

Sterile, milky white emulsion


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4. Clinical particulars

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4.1 Therapeutic indications

1. Sedation prior to procedures such as endoscopy, dentistry, cardiac catheterisation and cardioversion.

2. Premedication prior to general anaesthesia.

3. Control of acute muscle spasm due to tetanus or poisoning.

4. Control of convulsions; status epilepticus.

5. Management of severe acute anxiety or agitation including delirium tremens.


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4.2 Posology and method of administration

Diazemuls may be administered by slow intravenous injection (1ml per min), or by continuous infusion. Diazemuls should be drawn into the syringe immediately prior to administration.

Sedation: 0.1-0.2mg diazepam/kg body weight by iv injection. The normal adult dose is 10-20 mg, but dosage should be titrated to the patient's response.

Premedication: 0.1-0.2mg diazepam/kg body weight by iv injection. Dosage should be titrated to the patient's response. In this indication, prior treatment with diazepam leads to a reduction in fasciculations and postoperative myalgia associated with the use of suxamethonium.

Tetanus: 0.1-0.3mg diazepam/kg body weight by iv injection repeated every 1-4 hours as required. Alternatively, continuous infusion of 3-10mg/kg body weight over 24 hours may be infused.

Status epilepticus: An initial dose 0.15-0.25mg/kg body weight by iv injection repeated in 30 to 60 minutes if required, and followed if necessary by infusion (see below) of up to 3mg/kg body weight over 24 hours.

Anxiety and tension, acute muscle spasm, acute states of excitation, delirium tremens: The usual dose is 10mg repeated at intervals of 4 hours, or as required.

Elderly or debilitated patients: Elderly and debilitated patients are particularly sensitive to benzodiazepines. Dosage should initially be reduced to one half of the normal recommendations.

If a continuous infusion is required, Diazemuls can be added to dextrose solution 5% or 10% to achieve a final diazepam concentration within the range 0.1-0.4mg/ml (i.e. 2-8ml Diazemuls per 100ml dextrose solution). A dextrose solution containing Diazemuls should be used within 6 hours of the admixture. Diazemuls can be mixed in all proportions with intralipid 10% or 20% but not with saline solutions. It can be injected into the infusion tube during an ongoing infusion of isotonic saline or dextrose solution 5% or 10%. As with other diazepam injections, adsorption may occur to plastic infusion equipment. This adsorption may occur to a lesser degree with Diazemuls than with aqueous diazepam injection preparations when mixed with dextrose solutions.


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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.

• Hypersensitivity to egg or soyabean as egg phospholipid and soyabean oil are included in the preparation.

• Planning a pregnancy (see section 4.6).

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


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4.4 Special warnings and precautions for use

Tolerance

Loss of efficacy effects may develop after repeated use for a few weeks. Limits of tolerance in patients with organic cerebral changes (particularly arteriosclerosis) or cardiorespiratory insufficiency may be very wide (see also section 4.3); care must be taken in adapting the dosage with such patients.

Dependence

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 use 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 and irritability, sleep disturbance, diarrhoea and mood changes. In severe cases the following may occur: a feeling of unreality or of being separated from the body, depersonalisation, confusional states, numbness and tingling of the extremities, hypersensitivity to light, noise and physical contact, psychotic manifestations including hallucinations or epileptic seizures. Withdrawal symptoms will be worse in patients who have been dependent on alcohol or other narcotic drugs in the past, but can occur following abrupt cessation of treatment in patients receiving normal therapeutic doses for a short period of time.

Rebound symptoms

Symptoms including insomnia and anxiety may occur on withdrawal of treatment. As this is greater after abrupt discontinuation, the dose should be 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 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

Patients with depression

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

Patients with a history of alcohol & drug abuse, and patients on disulfiram

Diazepam should be used with extreme caution in patients with a history of alcohol or drug abuse (risk of abuse/dependence). Diazemuls should not be used concomitantly with disulfiram due to its ethanol content. A reaction may occur as long as two weeks after cessation of disulifram (see section 4.5).

Patients with phobias and/or chronic psychoses

Diazepam is not recommended (inadequate evidence of efficacy and safety)


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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

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.


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4.6. Pregnancy and lactation

If Diazemuls is prescribed to a woman of childbearing potential, she should be warned to contact her physician regarding discontinuance of Diazemuls if she intends to become, or suspects that she is pregnant.

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

Moreover, infants borne 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.


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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 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.


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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.

General disorders and administration site conditions

This formulation may rarely cause local pain of thrombophlebitis in the vein used for administration.

Rare instances have been reported of a local painless erythematous rash round the site of injection, which has resolved in 1-2 days. Urticaria and, rarely anaphylaxis have been reported following the injection of Diazemuls.

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.


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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.

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.


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5. Pharmacological properties

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5.1 Pharmacodynamic properties

Diazepam is a potent anxiolytic, anticonvulsant and central muscle relaxant mediating its effects mainly via the limbic system as well as the postsynaptic spinal reflexes. Diazemuls contains diazepam dissolved in the oil phase of an oil-in-water emulsion. Release of the diazepam from the lipid particles of the emulsion has been demonstrated by clinical studies showing comparable efficacy with injectable diazepam preparations.


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5.2 Pharmacokinetic properties

Diazepam is metabolised to two active metabolites, one of which, desmethyldiazepam, has an extended half-life. Diazepam is therefore a long acting benzodiazepine and repeated doses may lead to accumulation.

Diazepam is metabolised in the liver and excreted via the kidney. Impaired hepatic or renal function may prolong the duration of action of diazepam. It is recommended that elderly and debilitated patients receive initially one half the normal recommended dose.

During prolonged administration, for example in the treatment of tetanus, the dosage should generally be reduced after 6-7 days, to reduce the likelihood of accumulation and prolonged CNS depression.


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5.3 Preclinical safety data

Not applicable.


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6. Pharmaceutical particulars

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6.1 List of excipients

Fractionated soy bean oil, diacetylated monoglycerides, fractionated egg phospholipids, glycerol (anhydrous), sodium hydroxide (to pH8), water for injections (to 2ml).


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6.2 Incompatibilities

Diazemuls should only be mixed in the same container or syringe with dextrose solution 5% or 10% or intralipid 10% or 20%. The contents of the ampoule should not be mixed with any drugs other than the infusion solutions mentioned above. Store at room temperature. Do not freeze.


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6.3 Shelf life

24 months.


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6.4 Special precautions for storage

Store below 25°C. Do not freeze.


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6.5 Nature and contents of container

2ml glass type 1 ampoules in cartons of 10.


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6.6 Special precautions for disposal and other handling

Not applicable.


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Administrative data

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7. Marketing authorisation holder

Actavis Group PTC ehf.

Reykjavikurvegi 76-78

220 Hafnarfjordur

Iceland


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8. Marketing authorisation number(s)

PL 30306/0038


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9. Date of first authorisation/renewal of the authorisation

15.3.89

Renewed: 10.2.97; 10.2.02


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10. Date of revision of the text

25.03.2011



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