- 1. Name of the medicinal product
- 2. Qualitative and quantitative composition
- 3. Pharmaceutical form
- 4. Clinical particulars
- 4.1 Therapeutic indications
- 4.2 Posology and method of administration
- 4.3 Contraindications
- 4.4 Special warnings and precautions for use
- 4.5 Interaction with other medicinal products and other forms of interaction
- 4.6 Pregnancy and lactation
- 4.7 Effects on ability to drive and use machines
- 4.8 Undesirable effects
- 4.9 Overdose
- 5. Pharmacological properties
- 5.1 Pharmacodynamic properties
- 5.2 Pharmacokinetic properties
- 5.3 Preclinical safety data
- 6. Pharmaceutical particulars
- 6.1 List of excipients
- 6.2 Incompatibilities
- 6.3 Shelf life
- 6.4 Special precautions for storage
- 6.5 Nature and contents of container
- 6.6 Special precautions for disposal and other handling
- Administrative data
- 7. Marketing authorisation holder
- 8. Marketing authorisation number(s)
- 9. Date of first authorisation/renewal of the authorisation
- 10. Date of revision of the text
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.
PosologyAs 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 AdministrationFor oral administration.
AlcoholDiazepam should not be used together with alcohol (enhanced sedative effects: impaired ability to drive/ operate machinery).
Sodium oxybateAvoid concomitant use (enhanced effects of sodium oxybate).
HIV-protease inhibitorsAvoid concomitant use (increased risk of prolonged sedation) see below for zidovudine.
Take into account
Centrally acting drugsEnhancement 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 drugsPharmacokinetic 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 analgesicsEnhancement of the euphoria may lead to increased psychological dependence.
Other drugs enhancing the sedative effect of diazepamCisapride, 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 beincreased 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, angiotensinII 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.
DopaminergicsPossible antagonism of the effect of levodopa.
AntacidsConcurrent use may delay absorption of diazepam.
ZidivudineIncreased zidovudine clearance by diazepam.
Oestrogen-containing contraceptivesPossible inhibition of hepatic metabolism of diazepam.
TheophyllineIncreases metabolism of diazepam which possibly reduces the effect.
CaffeineConcurrent use may result in reduced sedative and anxiolytic effects of diazepam.
Grapefruit juiceInhibition 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.
Skin and appendages disordersAllergic reactions (skin rash or itching) occur rarely.
Central and peripheral nervous disordersDrowsiness, 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 disordersVisual disturbances occur rarely.
Psychiatric disordersLibido 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 disordersGastrointestinal upsets occur rarely. Increased salivary secretion.
Liver and billiary system disordersJaundice occurs rarely.
Cardio disordersHypotension occurs rarely.
Respiratory system disordersRespiratory depression, apnoea.
Blood disordersBlood dyscrasias occur rarely.
Urinary system disordersUrinary retention occurs rarely.
Body as a whole-general disordersFatigue, anaphylaxis.
Withdrawal effectsWithdrawal 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.
FeaturesThe 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.
ManagementMaintain 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.
Shelf-lifeThree years from the date of manufacture.
Shelf-life after dilution/reconstitutionNot applicable.
Shelf-life after first openingNot applicable.
Actavis UK Ltd
Whiddon Valley, Barnstaple, Devon, EX32 8NS, UK
+44 (0)1271 346 106
+44 (0)1271 311 200
+44 (0)1271 311 257