Midazolam

Registered South African indications:

• Short-term treatment of insomnia
  - When the disorder is severe, disabling, or subjecting the individual to extreme distress
• Anaesthetic premedication

Contraindications

South African recommendations

• Hypersensitivity to midazolam or any medicine from the benzodiazepines group or to any excipient within the medicine
• Myasthenia gravis
• Midazolam is not recommended for the primary treatment of psychotic illness
• Midazolam, as a single treatment regime, should not be used to treat depression or anxiety associated with depression (suicide may be precipitated in such patients)
• Severe hepatic impairment
• Children below 18 years
• Midazolam tablets should not be given to children 12 years or younger, because the available strengths do not allow for appropriate dosing in this patient population
• Respiratory insufficiency
• Sleep apnoea syndrome
• Concomitant therapy with ketoconazole, itraconazole, voriconazole, HIV protease inhibitors including ritonavir boosted protease inhibitors formulations and the HCV protease inhibitors boceprevir and telaprevir
• Galactose intolerance

Cautions

• Pregnancy
• Breastfeeding
• Renal impairment
• Mild to moderate hepatic impairment
• Elderly
• High dosages
• Long-term sedation
• Chronically ill or debilitated patients
• Chronic respiratory insufficiency
• Impaired cardiac function
• Low cardiac output
• Myasthenia gravis
• History of alcohol or drug abuse
• Abrupt withdrawal
• May impair ability to drive and operate machinery

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

Dosages below include:

• South African registered indications and dosages

South African registered indications and dosages

Short-term treatment of insomnia
- When the disorder is severe, disabling, or subjecting the individual to extreme distress

• Oral (tab): Initial: 7.5mg, just before bedtime; Dose range: 7.5-15mg, just before bedtime; Treatment duration: Few days to a max. of 2 weeks

Patients should be advised to take midazolam for short-term treatment only. Treatment should be started with the lowest recommended dose

The maximum dose should not be exceeded because of the increased risk of unacceptable CNS adverse effects, possibly including clinically relevant respiratory and cardiovascular depression

The tapering off process should be tailored to the individual. Treatment with midazolam should not be terminated abruptly. In certain cases, extension beyond the maximum treatment period may be necessary; if so, it should not take place without re-evaluation of the patient's status

Anaesthetic premedication

• Oral (tab): 15mg, 30-60min before the operation (unless the parenteral route is preferred)

Contraindicated

Pregnancy

• Caution; not recommended
• Insufficient data is available on midazolam to assess its safety during pregnancy. Benzodiazepines, including midazolam, should be avoided in pregnancy unless there is no safer alternative
• An increased risk of congenital malformation associated with the use of midazolam during the first trimester of pregnancy may occur
• If midazolam is prescribed to a woman of childbearing potential, she should contact her medical practitioner regarding discontinuation of midazolam, if she intends to become or suspects that she may be pregnant
• If, exceptionally, it is considered by a medical practitioner that administration of midazolam during the last three months of pregnancy, or during labour, is essential, effects on the neonate such as irregularities in the foetal heart rate, hypothermia, hypotonia, poor sucking and moderate respiratory depression can be expected, due to the pharmacological action of the product
• 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 of developing withdrawal symptoms in the postnatal period

Breastfeeding

• Caution; not recommended
• Midazolam is excreted in breast milk. Do not use during lactation

Fertility

• Animal studies did not show an impairment of fertility

Renal Impairment

• Caution; dose adjustment recommended
  In patients with severe renal impairment, accumulation of the major midazolam metabolite, 1’- hydroxymidazolam glucuronide, may occur resulting in more apparent and prolonged sedation, possibly including clinically relevant respiratory and/or cardiovascular depression
• Midazolam should therefore be dosed carefully in this patient population. The recommended dose is 7.5mg and when needed a lower dose should be considered

Hepatic Impairment

• Mild to moderate: Caution; dose adjustment recommended
  In patients with impaired liver function the recommended dose is 7.5mg
  In patients with mild to moderate hepatic impairment, the lowest dose possible should be considered, not exceeding 7.5mg
  Midazolam should be used very carefully in patients with hepatic impairment with the dosage reduced by as much as 50% as deemed necessary
• Severe: Contraindicated

Elderly

• Caution; dose adjustment recommended
  Recommended dose is 7.5mg
  Elderly patients showed a larger sedative effect, therefore they may be at increased risk of cardio-respiratory depression as well
  Thus, midazolam should be used very carefully in elderly patients, and if needed, a lower dose should be considered

Porphyria Information

• Probably not porphyrinogenic (PNP)

Drugs in Sport

• Permitted - No warnings

Central Nervous System Disorders

• Confusion
• Disorientation
• Emotional
• Libido disorder
• Mood disturbances
• Physical drug dependence and withdrawal syndrome
• Abuse
• Involuntary movements (including tonic/clonic movements and muscle tremor)
• Hyperactivity
• Sedation (prolonged and postoperative)
• Decreased alertness
• Headache
• Somnolence
• Dizziness
• Ataxia
• Anterograde amnesia
• Seizures (premature infants and neonates)
• Drug withdrawal seizures
• Depression
• Fatigue
• Paradoxical reactions
  - Restlessness
  - Agitation
  - Irritability
  - Nervousness
  - Hostility
  - Anger
  - Aggressiveness
  - Anxiety
  - Nightmares
  - Abnormal dreams
  - Hallucinations
  - Psychoses
  - Inappropriate behaviour
  - Paroxysmal excitement

Cardiovascular Disorders

• Cardiac arrest
• Bradycardia
• Hypotension
• Vasodilation
• Thrombophlebitis
• Thrombosis

Respiratory Disorders

• Respiratory depression
• Respiratory arrest
• Apnoea
• Dyspnoea
• Laryngospasm
• Hiccups

Gastrointestinal Disorders

• Nausea and vomiting
• Constipation
• Dry mouth

Musculoskeletal Disorders

• Falls
• Fractures

Skin and Subcutaneous Tissue Disorders

• Rash
• Urticaria
• Pruritis
• Injection site erythema
• Injection site pain

Immune, Blood and Lymphatic System Disorders

• Hypersensitivity
• Angioedema
• Anaphylactic shock

• CYP3A4 inhibitors
• CYP3A4 inducers
• Central nervous system depressants
• Centrally acting antihypertensives
• Inhalational anaesthetics
• Azole antifungals
• Ketoconazole
• Voriconazole
• Fluconazole
• Itraconazole
• Posaconazole
• Macrolide antibiotics
• Erythromycin
• Clarithromycin
• Telithromycin
• Roxithromycin
• Propofol
• HIV protease inhibitors
• Saquinavir 
• Ritonavir boosted protease inhibitors formulations
• Ritonavir-boosted lopinavir
• HCV protease inhibitors
• Boceprevir
• Telaprevir
• Calcium-channel blockers
• Diltiazem
• Verapamil
• Atorvastatin
• Fentanyl
• Nefazodone
• Aprepitant
• Ticagrelor
• Valproic acid
• Analgesics
• Antitussives
• Antipsychotics
• Other benzodiazepines
• Anxiolytics
• Hypnotics
• Barbiturates
• Ketamine
• Etomidate
• Sedative antidepressants
• Non-recent H1-antihistamines
• Carbamazepine
• Rifampicin
• Phenytoin
• Enzalutamide
• Clobazam
• Efavirenz
• Vemurafenib
• St John's wort
• Quercetin
• Ginkgo biloba
• Panax ginseng
• Alcohol

• Respiratory function
• Pulse oximetry
• Vital signs
• Heart rate
• Blood pressure

The central actions of benzodiazepines are mediated through an enhancement of the GABAergic neurotransmission at inhibitory synapses. In the presence of benzodiazepines the affinity of the GABA receptor for the neurotransmitter is enhanced through positive allosteric modulation resulting in an increased action of released GABA on the postsynaptic transmembrane chloride ion flux. Chemically midazolam is a derivative of the imidazobenzodiazepine group. Although the free base is a lipophilic substance with low solubility in water, the basic nitrogen in position 2 of the imidazobenzodiazepine ring system enables the active ingredient of midazolam to form water-soluble salts with acids, producing a stable and well tolerated injection solution. This together with rapid metabolic transformation is the reason for rapid onset and short duration of effects. Due to its low toxicity, midazolam has a wide therapeutic range. 

Tablet 7.5mg 

• Dormicum (Roche) originator

Tablet 15mg

• Dormicum (Roche) originator