Diazepam

Registered South African indications:

• Conscious sedation
• Premedication of anaesthesia
• Seizures
  - Second line treatment for seizures in eclampsia
• Excitation states associated with psychiatric disorders
  - Acute anxiety and panic
  - Motor unrest
  - Delirium tremens
• Status epilepticus
• Other convulsive states (including tetanus)

Registered South African contraindications

• Hypersensitivity to the active ingredient or any of its excipients
• Known history of hypersensitivity to benzodiazepines
• Severe respiratory insufficiency
• Severe hepatic insufficiency
• Sleep apnoea syndrome
• Myasthenia gravis
• Diazepam is not recommended for the primary treatment of psychotic illness
• Diazepam should not be used alone to treat depression or anxiety associated with depression as suicide may occur in such patients
• Dependence on other CNS depressants including alcohol, except in the acute withdrawal reactions

Contraindications registered in other jurisdictions

• Hypersensitivity to the active ingredient or any of its excipients
• Known hypersensitivity to other benzodiazepines or propylene glycol
• Phobic or obsessional states; chronic psychosis, hyperkinesis
• Acute pulmonary insufficiency, respiratory depression, acute or chronic severe respiratory insufficiency
• Sleep apnoea syndrome
• Marked neuromuscular respiratory weakness including unstable myasthenia gravis
• Severe hepatic impairment
• Acute porphyria
• Planning a pregnancy
• Pregnancy (unless there are compelling reasons)
• Diazepam injection should not be used alone in the treatment of depression or anxiety associated with depression due to the risk of precipitation of suicide in this patient group

• Pregnancy (South African recommendations)
• Breastfeeding
• Renal impairment
• Mild to moderate hepatic impairment
• Elderly
• Marked personality disorder 
• Abrupt withdrawal
• Epilepsy or history of seizures 
• Prolonged duration of treatment
• Bereavement
• Monotherapy in psychotic illness
• Coma
• Organic brain changes, particularly arteriosclerosis
• Tolerance
• Children
• Debilitated patients  
• History of alcohol or drug abuse
• Personality disorders
• May impair ability to drive and operate machinery

Forms avail. in SA and covered in this monograph: inj

South African registered indications and dosages

General dose range

• IV/IM: 2-20mg, depending on bodyweight, indication, and symptom severity; Higher doses may be required in some cases

---

For optimal effect, the dosage should be carefully individualised. The usual daily doses given above will meet the needs of most patients, though there will be cases requiring higher doses

---

Premedication of anaesthesia
- Allaying anxiety and tension prior to surgical procedures

• IM: 10mg, 1hr before anaesthesia

Conscious sedation
- Before stressful therapeutic interventions such as cardioversion, cardiac catheterisation, endoscopy, radiological procedures, minor surgical interventions, reduction of dislocations and fractures, biopsies and dressing of burns, etc. in order to relieve apprehension, anxiety, acute stress and to diminish recollections of such procedures

• IM: 10mg, adapting to patients individual needs by initiating at 5mg; Followed every 30 seconds by increments of 50% of the initial dose

Eclampsia - actual or threatened convulsions
- Where magnesium sulphate cannot be used

• IV: 10-20mg; Repeat as needed either IV bolus or continuous infusion; Max: 100mg/24hrs

- If seizures continue despite the administration of magnesium sulphate

• IV: 5-10mg

Tetanus

• IV: 0.1-0.3mg/kg bodyweight, 1-4hrly

OR

• IV (continuous infusion or by gastric tube): 3-4mg/kg bodyweight in 24hrs

Status epilepticus

• IV: 0.15-0.25mg/kg bodyweight; Repeated as necessary after 10-15min OR by continuous infusion; Max: 3mg/kg bodyweight in 24hrs

Excitation states associated with psychiatric disorders
- Acute anxiety and panic
- Motor unrest
- Delirium tremens

• IV: Initial: 0.1-0.2mg/kg bodyweight, repeated 8hrly until acute symptoms subside; Thereafter, switch to oral treatment

---

Diazepam is only indicated when the disorder is severe, disabling or when the individual is subject to extreme stress

---

IV injection should always be slow (0.5-1.0ml/min) to prevent apnoea; ensure resuscitation apparatus is ready

---

Diazepam injection can be diluted with Sodium chloride 0.9%, Glucose 5%, or Glucose 10%. Chemically and physically stable for 24 hours at room temperature (25°C). If not used immediately, storage times and conditions before use are the user's responsibility

---

The duration of treatment should be short, not exceeding 2-3 months, including the tapering-off period. Extension beyond this requires re-evaluation

---

Patients should be informed about the limited duration of treatment and explain the tapering process to minimize anxiety during withdrawal

---

There's a risk of withdrawal symptoms when transitioning from long-acting benzodiazepines like diazepam to short-acting ones

Paed. forms avail. in SA and covered in this monograph: inj

South African registered indications and dosages

General dose range

• IV/IM: 2-20mg, depending on bodyweight, indication, and symptom severity; Higher doses may be required in some cases

---

For optimal effect, the dosage should be carefully individualised. The usual daily doses given above will meet the needs of most patients, though there will be cases requiring higher doses

---

Premedication of anaesthesia
- Allaying anxiety and tension prior to surgical procedures

• IM: 0.1-0.2mg/kg bodyweight, 1hr before anaesthesia

Conscious sedation
- Before stressful therapeutic interventions such as cardioversion, cardiac catheterisation, endoscopy, radiological procedures, minor surgical interventions, reduction of dislocations and fractures, biopsies and dressing of burns, etc. in order to relieve apprehension, anxiety, acute stress and to diminish recollections of such procedures

• IM: 0.1-0.2mg/kg bodyweight, adapting to patients individual needs by initiating at 0.1mg/kg bodyweight; Followed every 30 seconds by increments of 50% of the initial dose

---

Diazepam is only indicated when the disorder is severe, disabling or when the individual is subject to extreme stress

---

IV injection should always be slow (0.5-1.0ml/min) to prevent apnoea; ensure resuscitation apparatus is ready

---

Diazepam injection can be diluted with Sodium chloride 0.9%, Glucose 5%, or Glucose 10%. Chemically and physically stable for 24 hours at room temperature (25°C). If not used immediately, storage times and conditions before use are the user's responsibility

---

The duration of treatment should be short, not exceeding 2-3 months, including the tapering-off period. Extension beyond this requires re-evaluation

---

Patients should be informed about the limited duration of treatment and explain the tapering process to minimize anxiety during withdrawal

---

There's a risk of withdrawal symptoms when transitioning from long-acting benzodiazepines like diazepam to short-acting ones

---

Since the safety and effectiveness in paediatric patients below the age of 6 months have not been established, diazepam should be used in this age group with extreme caution and only when other therapeutic alternatives are not available

Pregnancy 

South African recommendations

• Caution; positive evidence of risk
• The safety of diazepam during pregnancy has not been established
• An increased risk of congenital malformation has been suggested when benzodiazepines are used during the first trimester of pregnancy
• Continuous administration of benzodiazepines during pregnancy might lead to the floppy-infant syndrome, characterized by hypotension, reduced respiratory function, and hypothermia in the newborn
• Withdrawal symptoms in newborn infants have been associated with diazepam
• Special care is required when diazepam is used during labour and delivery. High single doses can cause irregularities in the fetal heart rate and lead to symptoms such as hypotonia, poor sucking, hypothermia, and moderate respiratory depression in the neonate
• It's important to note that the enzyme system responsible for breaking down the medication is not fully developed in newborns, especially in premature infants

Recommendations in other jurisdictions

• Contraindicated (unless there are compelling reasons)
• There is no evidence regarding the safety of diazepam in human pregnancy, and animal studies do not confirm it to be free from hazard
• Diazepam injection contains propylene glycol, which, though not shown to cause reproductive or developmental toxicity, may reach the foetus
• Diazepam should not be used during pregnancy, especially in the first and last trimesters, unless there are compelling reasons
• Women of childbearing potential should be informed to contact their physician about discontinuing diazepam if they intend to become pregnant or believe they are pregnant
• Retrospective studies suggest an increased risk of congenital malformation in infants whose mothers took diazepam during the first trimester
• Chronic use of benzodiazepines during the later stages of pregnancy may result in the newborn developing physical dependence and potential withdrawal symptoms postnatally
• An increase in foetal heart rate has been observed with diazepam use during labour
• In neonates whose mothers received large doses of diazepam (typically more than 30mg) shortly before delivery, hypoactivity, hypotonia, hypothermia, apnoea, feeding problems, hyperbilirubinemia, and kernicterus have been reported

Breastfeeding

South African recommendations

• Caution; not recommended
• Diazepam is excreted into breast milk and should not be administered to breastfeeding mothers

Recommendations in other jurisdictions

• Caution
• Diazepam has been detected in breast milk
• Diazepam injection contains propylene glycol, which has also been found in breast milk
• Administration of diazepam injection to lactating patients should be considered on a case-by-case basis

Fertility

South African recommendations

• No information available

Recommendations in other jurisdictions

• 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

South African recommendations

• Caution; no dose adjustment recommended
  The usual precautions in treating patients with impaired renal function should be observed

Recommendations in other jurisdictions

• Caution; no dose adjustment recommended
  In renal failure there is no clinically significant change to the half-life of diazepam and a dose adjustment is usually not necessary. Medical monitoring is required in patients with impaired renal function when diazepam injection is administered at doses of 0.45mg/kg/day (equivalent to 50mg/kg/day of propylene glycol) and above

South African recommendations

• Mild to moderate: Caution; dose adjustment recommended
  Patients with impaired hepatic function should be given a reduced dose
• Severe: Contraindicated

Recommendations in other jurisdictions

• Mild to moderate: Caution; dose adjustment recommended
  In patients with chronic hepatic disease dosage may need to be reduced. Medical monitoring in patients with impaired hepatic function may be required
  Medical monitoring is required in patients with impaired hepatic function when diazepam injection is administered at doses of 0.45mg/kg/day (equivalent to 50mg/kg/day of propylene glycol) and above
• Severe: Contraindicated
  Benzodiazepines are not indicated to treat patients with severe hepatic insufficiency as they may precipitate encephalopathy

South African recommendations

• Caution; dose adjustment recommended
  Elderly and debilitated patients who are at particular risk of over sedation, respiratory depression and ataxia should be given half of the usual adult dose
  These patients should be checked regularly at the start of treatment in order to minimise the dosage and/or frequency of administration to prevent overdose due to accumulation

Recommendations in other jurisdictions

• Caution; dose adjustment recommended
  Elderly and debilitated 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

Central Nervous System Disorders

• Confusion
• Paradoxical reactions 
• Emotional poverty
• Depression
• Drowsiness
• Ataxia
• Impaired motor ability
• Tremor
• Anterograde amnesia
• Concentration difficulties
• Balance disorders
• Dizziness
• Headache
• Slurred speech
• Unconsciousness
• Insomnia
• Dysarthria
• Fatigue

Cardiovascular Disorders

• Bradycardia
• Cardiac failure 
• Cardiac arrest
• Hypotension
• Syncope

Respiratory Disorders

• Respiratory depression
• Respiratory arrest
• Increased bronchial secretions
• Apnoea

Gastrointestinal Disorders

• Nausea and vomiting
• Constipation
• Diarrhoea
• Increased salivary secretion
• Dry mouth 
• Increased appetite

Hepatobiliary Disorders

• Jaundice
• Changes of hepatic parameters

Genitourinary Disorders

• Urinary retention
• Incontinence
• Gynaecomastia
• Impotence
• Increased or reduced libido

Musculoskeletal Disorders

• Myasthenia 

Skin and Subcutaneous Tissue Disorders

• Allergic skin reactions 

Immune, Blood and Lymphatic System Disorders

• Blood dyscrasias
• Leukopenia
• Anaphylaxis

Sensory Disorders

• Blurred vision
• Diplopia
• Nystagmus

Others

• Withdrawal 

• Central nervous system depressants
• Narcotic analgesics
• CYP450 inhibitors
• CYP450 inducers
• Sodium oxybate
• HIV protease inhibitors
• Cisapride
• Zidovudine
• Antibacterials
• Antihypertensives
• Lofexidine
• Digoxin
• Disulfiram
• Levodopa
• Muscle-relaxants 
• Nabilone
• Nicotine
• Oral contraceptives
• Theophylline
• Ketamine
• Caffeine
• Omeprazole

Other interactions

• Alcohol

None routine. Specific cases may require

• Mental status
• Hepatic function
• Vital signs
• Respiratory function

Diazepam binds nonspecifically to benzodiazepine receptors and facilitates the action of gamma aminobutyric acid, an inhibitory neurotransmitter in the central nervous system. It is found in high concentrations in the cortex and limbic system.

Injection (per 2ml) 10mg

• A-Lennon diazepam (Pharmacare)
• Diazepam PharmC (Pharmacorp)
• Pax (Pharmacare)
• Pharma-Q diazepam (Pharma-Q)
• Valium (Roche) originator