Symptoms
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 behavioural 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.
24 months.
-
- 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.
- Pregnancy (unless there are compelling reasons - see section 4.6).
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.
Fractionated soy bean oil, diacetylated monoglycerides, fractionated egg phospholipids, glycerol (anhydrous), sodium hydroxide (to pH8), water for injections (to 2ml).
Sterile, milky white emulsion
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.
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. 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 |
|
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.
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.
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
Not applicable.
- Sedation prior to procedures such as endoscopy, dentistry, cardiac catheterisation and cardioversion.
- Premedication prior to general anaesthesia.
- Control of acute muscle spasm due to tetanus or poisoning.
- Control of convulsions; status epilepticus.
- Management of severe acute anxiety or agitation including delirium tremens.
Mechanism of action
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.
Biotransformation
Diazepam is metabolised in the liver. 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. Impaired hepatic function may prolong the duration of action of diazepam.
Elimination
Diazepam is excreted via the kidney. Impaired renal function may prolong the duration of action of diazepam.
Special populations
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.
07/02/2018
Accord Healthcare Limited
Sage House
319 Pinner Road
North Harrow
Middlesex
HA1 4HF
United Kingdom
Store below 25°C. Do not freeze.
2ml glass type 1 ampoules in cartons of 10.
PL 20075/0679
Pregnancy
There are limited amount of data from the use of diazepam in pregnant women.
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 (“Floppy Infant Syndromeâ€), irregularities in the heart rate, poor suckling and moderate respiratory depression; can be expected, due to the pharmacological action of Diazemuls.
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.
Diazepam should only be used in pregnant women on compelling indication.
Breast-feeding
Since benzodiazepines are found in the breast milk, 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.
Each emulsion contains Diazepam 0.5% w/v
Also contains fractionated soy bean oil. One 1ml of emulsion contains 150mg soya bean oil.
Concomitant use of alcohol/CNS depressants
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.
Tolerance
Loss of efficacy effects may develop after repeated use for a few weeks.); 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.
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, derealisation, 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 insomnia and anxiety
A transient syndrome whereby the symptoms that led to treatment with a benzodiazepine recur in an enhanced form, may occur on withdrawal of treatment. It may be accompanied by other reactions including mood changes, anxiety or sleep disturbances and restlessness. Since the risk of withdrawal phenomena/rebound phenomena is greater after abrupt discontinuation of treatment, it is recommended that the dosage is decreased gradually.
Sudden discontinuation of treatment with diazepam in patients with epilepsy or other patients who have had a history of seizures can result in convulsions or epileptic status. Convulsions can also be seen following sudden discontinuation in individuals with alcohol or drug abuse.
Discontinuation should be gradual in order to minimise the risk of withdrawal symptoms.
Duration of treatment
The duration of treatment should be as short as possible depending on the indication. 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 minimising anxiety over such symptoms should they occur while the medicinal product is being discontinued. There are indications that, in the case of benzodiazepines with a short duration of action, withdrawal phenomena can become manifest within the dosage interval, 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.
Amnesia
Anterograde amnesia may occur even if benzodiazepines are used within the normal dose range, though this is seen in particular at high dose levels.). Amnestic effects may be associated with inappropriate behaviour.
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.
Paediatric population
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
Patients should be given a reduced dose. Due to the myorelaxant effect there is a risk of falls and consequently hip fractures in the elderly.
Chronic respiratory insufficiency
A lower dose is also recommended for patients with chronic respiratory insufficiency due to the risk of respiratory depression.
Hepatic insufficiency
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.
Impaired renal function
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.
Psychotic illness
Benzodiazepines are not recommended for the primary treatment of psychotic illness.
Potentially suicidal individuals should not have access to large amounts of diazepam due to the risk of overdosing.
Sedation, amnesia, impaired concentration, and impaired muscular function may adversely affect the ability to drive or use machines. If insufficient sleep duration occurs, the likelihood of impaired alertness may be increased. 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
Posology
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.
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.
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.
Not applicable.
Date of first authorisation: 15th March 1989
Date of latest renewal: 10th February 2002
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, suxamethonium 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
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.
