Adult: 5-15 mg at bedtime. Elderly: Reduce to half of the dose.
Oral Adjunct in seizures
Adult: 2-60 mg daily in divided doses. Elderly: Reduce to half of the dose.
Oral Premedication before anaesthesia, Sedation in minor surgical and medical procedures
Adult: 5-20 mg. Elderly: Reduce to half of the dose. Child: 2-10 mg.
Oral Muscle spasms
Adult: 2-15 mg daily in divided doses, may increase up to 60 mg/day in severe spastic disorders (e.g. cerebral palsy). Elderly: Reduce to half of the dose. Child: 2-40 mg daily in divided doses.
Oral Severe anxiety
Adult: 2-10 mg 2-4 times daily depending on the severity of symptoms. Elderly: Reduce to half of the dose. Child: 1-2.5 mg 3-4 times daily, increase gradually as needed and tolerated.
Oral Alcohol withdrawal syndrome
Adult: 5-20 mg, may be repeated in 2-4 hours, as necessary. Alternatively, 10 mg 3-4 times during the first 24 hours, reducing to 5 mg 3-4 times daily as needed. Elderly: Reduce to half of the dose.
Parenteral Severe anxiety
Adult: 2-10 mg via IM or slow IV inj, may be repeated after 4 hours. Elderly: Reduce to half of the dose.
Parenteral Muscle spasms
Adult: 5-10 mg via IM or slow IV inj, may be repeated after 4 hours. Muscle spasm due to tetanus: Initially, 0.1-0.3 mg/kg via slow IV inj (1 mL/min), may be repeated at intervals of 1-4 hours. Alternatively, 3-10 mg/kg continuous IV infusion over 24 hours. May increase dose based on severity of case. Elderly: Reduce to half of the dose. Child: Same as adult dose.
Parenteral Premedication before anaesthesia
Adult: 10-20 mg, may increase dose based on clinical response or as necessary. Elderly: Reduce to half of the dose. Child: 0.2 mg/kg slow injection over 0.5 mL/min.
Parenteral Alcohol withdrawal syndrome
Adult: Severe and with delirium tremens: 10-20 mg via IM or IV inj, may increase dose depending on severity of symptoms. Elderly: Reduce to half of the dose.
Parenteral Seizures
Adult: 10-20 mg via IM or slow IV inj (1 mL/min), may be repeated after 30-60 minutes, as necessary. May be followed by slow IV infusion if indicated. Max: 3 mg/kg over 24 hours. Child: 1 month to <5 years 0.2-0.5 mg via IM or slow IV inj every 2-5 minutes up to Max of 5 mg; ≥5 years 1 mg every 2-5 minutes up to Max of 10 mg. May be repeated in 2-4 hours if necessary.
Rectal Adjunct in seizures
Adult: 0.5 mg/kg, may be repeated every 12 hours. Max: 30 mg. Elderly: Reduce to half of the dose. Child: 2-5 years 0.5 mg/kg. 6-11 years 0.3 mg/kg. ≥12 years 0.2 mg/kg. All doses may be repeated once after 4-12 hours, as necessary.
Rectal Muscle spasms, Premedication before anaesthesia, Sedation in minor surgical and medical procedures, Severe anxiety
Adult: 0.5 mg/kg, may be repeated every 12 hours. Max: 30 mg. Elderly: 0.25 mg/kg, may be repeated every 12 hours. Max: 30 mg. Child: >1 year: Same as adult dose.
Special Patient Group
Debilitated patients: Initially, 2-2.5 mg 1-2 times daily, increase gradually as needed and tolerated.
Pharmacogenomics:
Diazepam is mainly metabolised in the liver by CYP2C19 and CYP3A4 to its major active metabolite, desmethyldiazepam, and two minor active metabolites, temazepam and oxazepam. According to a study, approx 3% of Caucasians and 15-20% of Asians are poor metabolisers of CYP2C19 or have decreased or absent CYP2C19 enzyme activity. Available references suggest that genetic polymorphism of CYP2C19 gene may affect the pharmacokinetics of diazepam and emergence from general anaesthesia of the patient.
For patients receiving diazepam to relieve preoperative anxiety:
CYP2C19 extensive metabolisers (e.g. *1/*1)
Increased metabolism of diazepam and more rapid emergence from anaesthesia than intermediate or poor metabolisers have been reported.
CYP2C19 intermediate metabolisers (e.g. *1/*2 or *1/*3)
Increased metabolism of diazepam has been reported and recovery from anaesthesia may be prolonged.
CYP2C19 poor metabolisers (e.g. *2/*2, *3/*3 or *2/*3)
Decreased metabolism and reduced plasma clearance of diazepam have been reported. Studies suggest that patient may emerge from anaesthesia less rapidly than extensive metabolisers. No dosage adjustment needed.
Renal Impairment
Oral:
Severe anxiety; Insomnia associated with anxiety; Muscle spasms; Adjunct in seizures; Alcohol withdrawal syndrome; Premedication before anaesthesia; Sedation in minor surgical and medical procedures:
Severe: Reduce dose.
Hepatic Impairment
Reduce dose. Severe: Contraindicated.
Administration
May be taken with or without food.
Reconstitution
Do not mix IV product with other medications in the same infusion solution or syringe.
Contraindications
Acute or chronic severe respiratory insufficiency, respiratory depression, myasthenia gravis, sleep apnoea, severe hepatic insufficiency, acute narrow-angle glaucoma, phobic or obsessional states, chronic psychosis, hyperkinesis, acute porphyria. Avoid alcohol. Infants <6 months.
Special Precautions
Patient with convulsive disorder, history of alcoholism and/or drug abuse open-angle glaucoma, cardiorespiratory insufficiency, chronic respiratory insufficiency, ataxic, obese, and debilitated patient; neurologic damage (rectal). Avoid abrupt withdrawal. CYP2C19 extensive, intermediate and poor metabolisers. Renal and mild to moderate hepatic impairment. Children and elderly. Pregnancy and lactation. Not intended as monotherapy in patients with depression, anxiety as suicide may be precipitated in such patients.
Adverse Reactions
Significant: Withdrawal symptoms (e.g. rebound insomnia and anxiety, panic, palpitations, sweating, paranoid psychosis, epileptic attacks, delirium), anterograde amnesia, paradoxical reactions (e.g. restlessness, agitation, irritability, aggressiveness, delusion, rages, nightmares, psychoses), habituation, drug dependence. Eye disorders: Blurred vision, diplopia. Gastrointestinal disorders: Constipation, nausea, gastrointestinal disturbances, altered salivation. General disorders and admin site conditions: Fatigue, ataxia, local reactions at the injection site e.g. thrombophlebitis and venous thrombosis. Investigations: Elevated transaminases and alkaline phospahatase. Nervous system disorders: Impaired motor ability, tremor, headache, vertigo. Psychiatric disorders: Confusion, depression, slurred speech. Renal and urinary disorders: Urinary incontinence, urinary retention. Reproductive system and breast disorders: Change in libido. Vascular disorders: Hypotension.
This drug may cause CNS depression (e.g. sedation, amnesia, impaired concentration, dizziness, drowsiness), blurred vision and impaired muscular function, if affected, do not drive or operate machinery.
Monitoring Parameters
Monitor heart rate, respiratory rate, blood pressure, mental state, liver enzymes and CBC. Assess for history of addiction; signs and symptoms of dependence, abuse, or tolerance for long-term use.
Overdosage
Symptoms: Ataxia, drowsiness, dysarthria, sedation, muscle weakness, profound sleep, hypotension, restlessness, nystagmus, confusion. Severe cases may lead to ataxia, cardiorespiratory depression, coma, and very rarely, death. Management: Supportive and symptomatic treatment. Initiate IV fluids administration, adequate ventilation and clear airway. Administration of activated charcoal may be given within 1 hour of ingestion. If hypotension occurs, raise foot of the bed and give appropriate fluid; administer α-adrenergic agents such as norepinephrine to decrease systemic vascular resistance. Flumazenil may be used for the complete or partial reversal of the sedative effects provided that necessary measures in initial supportive treatment is established.
Drug Interactions
Potentiated effects with other centrally acting agents (e.g. antipsychotics, anxiolytics, anticonvulsants, antihistamines, MAO inhibitors, anaesthetics, barbiturates). Enhanced sedative effect with other drugs such as lofexidine, nabilone, and disulfiram. Reduce clearance and potentiate action with CYP3A4 inhibitors (e.g. cimetidine, isoniazid, erythromycin, omeprazole, ketoconazole). Increased metabolism and clearance with CYP3A4 inducers (e.g. rifampicin, carbamazepine, phenytoin). Antagonised effect with theophylline. Delayed absorption with antacids. Potentially Fatal: Concomitant use with opioids may result in sedation, respiratory depression, coma and death. Increased risk of prolonged sedation with zidovudine. May enhance CNS depressant effect of sodium oxybate.
Food Interaction
Reduced sedative and anxiolytic effects with caffeine. Increased plasma concentration with grapefruit or grapefruit juice. Decreased serum concentration with St John’s wort. Enhanced CNS depressant effect with alcohol.
Lab Interference
May result to false-negative urinary glucose determination when using Clinistix® or Diastix®.
Action
Description: Mechanism of Action: Diazepam is a long-acting benzodiazepine that exerts anxiolytic, sedative, anticonvulsant, muscle relaxant and amnestic effect. It binds to stereospecific benzodiazepine receptors on the postsynaptic gamma-aminobutyric acid (GABA) neuron in different regions of the central nervous system, e.g. brain and spinal cord thereby, increasing the inhibitory effects of GABA which is involved in sleep induction, control of hypnosis, memory, anxiety, epilepsy and neuronal excitability. Onset: Status epilepticus: 1-3 mins (IV); 2-10 mins (rectal). Duration: Status epilepticus: 15-30 mins. Pharmacokinetics: Absorption: Readily and completely absorbed from the gastrointestinal tract or after rectal administration. Delayed and decreased absorption with a moderate fat meal. Bioavailability: >90%. Time to peak plasma concentrations: Approx 30-90 minutes (oral); approx 10-30 minutes (rectal). approx 1 min (IV); 0.25-2 hours (IM). Distribution: Crosses the blood-brain barrier and placental barrier; redistributed into fat depots and tissues. Enters breast milk. Volume of distribution: 1.1 L/kg (oral); 1.2 L/kg (IV); 1 L/kg (rectal). Plasma protein binding: 98% (oral); 95-98% (rectal). Metabolism: Metabolised in the liver via N-demethylation by CYP3A4 and CYP2C19 to N¬-desmethyldiazepam, hydroxylation by CYP3A4 to temazepam and further metabolised to oxazepam. Excretion: Via urine (mainly as glucuronide conjugates). Elimination half-life: 44-48 hours (oral); 33-45 hours (IV); approx 60-72 hours (IM); 45-46 hours (rectal).
Chemical Structure
Source: National Center for Biotechnology Information. PubChem Database. Diazepam, CID=3016, https://pubchem.ncbi.nlm.nih.gov/compound/Diazepam (accessed on Jan. 21, 2020)
N05BA01 - diazepam ; Belongs to the class of benzodiazepine derivatives anxiolytics. Used in the management of anxiety, agitation or tension.
References
Dean, L. Diazepam Therapy and CYP2C19 Genotype. Medical Genetics Summaries [Internet]. Bethesda (MD):National Center for Biotechnology Information (US). 2012. Accessed 02/07/2019. PMID: 28520370Inomata S, Nagashima A, Itagaki F et al. CYP2C19 Genotype Affects Diazepam Pharmacokinetics and Emergence from General Anesthesia. Clinical Pharmacology and Therapeutics. 78(6):647-655. doi: 10.1016/j.clpt.2005.08.020. Accessed 02/07/2019. PMID: 16338280Anon. Diazepam. Lexicomp Online. Hudson, Ohio. Wolters Kluwer Clinical Drug Information, Inc. https://online.lexi.com. Accessed 21/03/2019.Buckingham R (ed). Diazepam. Martindale: The Complete Drug Reference [online]. London. Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 21/03/2019.Clinical Annotation for CYP2C19; Diazepam. Pharmacogenomics Knowledgebase (PharmGKB). https://www.pharmgkb.org/. Accessed 02/07/2019.Diastat Gel (Valeant Pharmaceuticals North America LLC). DailyMed. Source: U.S. National Library of Medicine. https://dailymed.nlm.nih.gov/dailymed/. Accessed 22/04/2014.Diazepam Gel (Oceanside Pharmaceuticals). DailyMed. Source: U.S. National Library of Medicine. https://dailymed.nlm.nih.gov/dailymed/. Accessed 21/03/2019.Diazepam Injection (Hospira, Inc.). DailyMed. Source: U.S. National Library of Medicine. https://dailymed.nlm.nih.gov/dailymed/. Accessed 21/03/2019.Diazepam Solution (Precision Dose Inc). DailyMed. Source: U.S. National Library of Medicine. https://dailymed.nlm.nih.gov/dailymed/. Accessed 22/04/2014.Diazepam Tablet (Bryant Ranch Prepack). DailyMed. Source: U.S. National Library of Medicine. https://dailymed.nlm.nih.gov/dailymed/. Accessed 21/03/2019.Joint Formulary Committee. Diazepam. British National Formulary [online]. London. BMJ Group and Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 22/04/2014.McEvoy GK, Snow EK, Miller J et al (eds). Diazepam. AHFS Drug Information (AHFS DI) [online]. American Society of Health-System Pharmacists (ASHP). https://www.medicinescomplete.com. Accessed 22/04/2014.Valium (Diazepam) Tablets. U.S. FDA. https://www.fda.gov/. Accessed 22/04/2014.
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