Midazolam in palliative care

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• Note: There are a number of different strengths of midazolam injection available (1mg/ml, 2mg/ml, 5mg/ml). In palliative care the most concentrated form of the injection is prescribed to maximise dosing options for single site subcutaneous injection where the volume limit is approximately 2ml i.e. 10mg in 2ml.
• Buccolam and Epistatus are not licensed for use in adults. Please check your local formulary for preferred product.
• Buccolam is half the strength of Epistatus – be aware of difference in strength when prescribing.

Clinical indications and †off label use

• Status epilepticus, as an alternative to rectal diazepam
• Prolonged (longer than 5 or 10mins) convulsive epileptic seizures
• Sedation prior to procedures
• Confusion and restlessness
• †Sedative/anxiolytic in terminal haemorrhage or agitation at the end of life
• †Spasticity or skeletal muscle spasm
• †Persistent hiccups
• †Anxiety/panic e.g. in severe breathlessness at end of life – seek specialist advice
• †Alcohol withdrawal at end of life

Use with caution in:

• Elderly patients
• Chronic renal failure
• Impaired hepatic function
• Impaired cardiac function
• In obese patients, the half life can be increased due to increased volume of distribution

Contraindications:

• Known hypersensitivity
• Marked neuromuscular respiratory weakness including unstable myasthenia gravis
• Severe respiratory depression
• Acute pulmonary insufficiency
• These are not absolute contraindications if the patient is in the last days of life. Careful titration is however necessary

Important drug interactions

• Midazolam is a major substrate of CYP3A4.
• Please refer to current edition of BNF for significant drug interactions.
• Fatalities have occurred after concurrent administration with higher than approved doses of olanzapine.

Midazolam pharmacokinetic data

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Switching between benzodiazepines

Changing benzodiazepines - seek specialist advice if uncertain

• These doses/ratios are approximate (≈) and not exact equivalent doses and should be used as a guide.
• Dose conversions should be conservative and doses are usually rounded down (Note – check available strengths).
• Adjust doses in accordance with patient’s condition; reduce less if severe pain.
• Monitor closely; extra care if frail, elderly patient; renal or hepatic impairment.

Approximate equivalent anxiolytic-sedative doses (PCF6)

• As an antiepileptic agent - in single doses midazolam is considered to be twice as potent as diazepam.
• As a sedative, in single doses, midazolam is considered to be three times more potent than diazepam.
• With multiple doses midazolam gains in potency because of a prolonged plasma half-life.

Side effects

• As for other benzodiazepines
• Drowsiness and sedation (may persist for several hours after administration)
• Respiratory depression occurs in about 5% patients.

Seizures (refer to seizures guideline)

• Generally administered sublingually or bucally: 10mg initially; repeated after 10 minutes if no effect and the patient is breathing normally. If no effect apparent 5 minutes after the second dose, seek medical help.

Note: Consider a reduced dose (5mg) in elderly patients and patients under 50kg.

• Using the oral syringe provided administer over a period of 2 to 3 seconds, about half of the prescribed dose to each buccal cavity (between the gums of the lower jaw and the cheek). If administration to the patient is very difficult to control, then administer the whole dose, over a period of 4 to 5 seconds, to one buccal cavity.
• As a last resort, can be administered intra-nasally if the patient foams at the mouth.

Dying patients unable to take oral medication

• Anti-epileptic drugs have a long half-life, however ongoing management should be considered:
  • †Midazolam 5mg subcutaneously (SC). Buccal midazolam is another option and can be acceptable for patients.
  • †Midazolam 20mg to 30mg via continuous subcutaneous infusion (CSCI) over 24 hours can be used as maintenance therapy.

Sedative/anxiolytic in terminal haemorrhage (refer to bleeding guideline)

Midazolam 5mg to 10mg buccal/SC/IM/IV

†Spasticity or skeletal muscle spasm (seek specialist advice)

If muscle spasms fail to respond to oral muscle relaxants such as baclofen, tizanadine, dantrolene or diazepam: Midazolam: 2mg to 5mg SC or 10mg in 24 hours by CSCI.

†Persistent hiccups (refer to hiccups guideline)

Where hiccups fail to respond to other measures such as prokinetics seek specialist advice.

†Anxiety/panic, for example, in severe breathlessness at end of life

2mg to 5mg SC/SL/buccal. CSCI 5 to 10mg over 24 hours. Seek specialist advice

Agitation or delirium

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†Alcohol withdrawal at end of life

Seek specialist advice

• Midazolam is a Schedule 3 CD (Controlled Drug), therefore all prescriptions must satisfy CD prescription requirements to be valid and include details of the dose, form, strength, directions for use and total quantity (in both words and figures. Please refer to sample prescription.
• The injection preparation prescribed for adults and held by the palliative care community networks is 10mg in 2ml.
• Patients on regular benzodiazepines who have developed a tolerance to their effects may require a higher dose.
• An overdose can be treated with Flumazenil (short-acting benzodiazepine antagonist). Flumazenil should be available in in-patient settings where midazolam is used (NPSA alert).
• Epistatus is an unlicensed medication and as such has no marketing authorisation in the UK.
• Epistatus can be prescribed by the patient’s GP for the indications listed in liaison with local palliative care specialists.
• Patients should receive an initial supply on discharge to allow adequate time for the community pharmacist to order. The lead time for Epistatus is approximately 4 working days although may be longer in remote and rural areas.
• Midazolam injection can be administered via the buccal route. The volume, however, is often impractical.

Patient and carer advice points

• Buccolam ­– remove oral syringe cap before use to avoid risk of choking.
• Epistatus (5ml bottle) – the bottle cap must be replaced immediately to prevent evaporation. If the liquid is allowed to evaporate some of the midazolam will precipitate, exhibited as cloudiness or as white particles in the liquid. The pack must be discarded if the solution is not clear.
• Do not store in a fridge.
• Epistatus (5ml bottle) – the dose markings are on the syringe plunger not the syringe barrel.
• Do not place the syringe between the patient’s teeth as they might bite the syringe
• If using the injectable solution sublingually or buccally, ensure needle is removed from syringe tip prior to administration.