Epistatus^® is for oromucosal (buccal) use only, and must only be administered into the mouth. It should be administered directly from the pre-filled buccal syringe into the patient’s buccal cavity (the space between the inner cheek and the gums) – half into one buccal cavity first, then the remainder into the other buccal cavity.^1-4

Posology and indication

The active ingredient in Epistatus^® is oromucosal midazolam (as maleate). Epistatus^® is indicated for the treatment of prolonged, acute, convulsive seizures in adults, infants, children and adolescents aged 3 months and above. Epistatus^® must only be used by parents / caregivers where the patient has been diagnosed to have epilepsy.^1-4

Epistatus^® is licensed in 4-age specific doses:

Epistatus^® 2.5 mg dose¹

• For children aged 3-6 months (in a hospital setting) and >6 months to <1 year the standard dose is 2.5 mg contained in a volume of 0.25 mL
  
  

Epistatus^® 5 mg dose²

• For children aged 1 year to less than 5 years of age the standard dose is 5 mg contained in a volume of 0.5 mL
  
  

Epistatus^® 7.5 mg dose³

• For children aged 5 years to less than 10 years of age the standard dose is 7.5 mg contained in a volume of 0.75 mL
  
  

Epistatus^® 10 mg dose⁴

• For children, adults, and adolescents aged 10 years and above, the standard dose is 10 mg contained in a volume of 1 mL
  
  

Mechanism of action

Midazolam is a rapid-acting member of the benzodiazepine class, which exerts its anti-convulsant effect via the potentiation of inhibitory GABA signalling.⁵

The GABA receptor is a ligand-gated chloride channel. In the presence of its natural ligand γ-Aminobutyric acid (GABA), the GABA receptor channel opens, allowing chloride ions to pass across the neural membrane into the cell.⁵ This causes hyperpolarisation of membrane potential, making the neurone less likely to form an action potential in response to excitatory stimuli.

Benzodiazepines bind via the α-subunit of the receptor (GABA-A), stabilising the open state of the chloride channel. ^5,6 GABA binding consequently results in a greater influx of chloride ions, which further stabilises the neurone against excitatory signals.^5,6 In addition to anti-convulsant activity, this hyperpolarisation can also result in a powerful hypnotic effect and anterograde amnesia.

Formulation and presentation

The formulation of Epistatus^® has been developed specifically for buccal administration. It is a sweetened, sugar-free, slightly viscous midazolam formulation, with the 2.5 mg, 5.0 mg, 7.5 mg or 10 mg dose contained in a volume of 0.25 mL, 0.5 mL, 0.75 mL or 1 mL, respectively. Epistatus^® is presented in a single-dose, pre-filled syringe that has been engineered specifically for buccal administration.^1-4

Epistatus^® is presented in a 0.25 mL, 0.5 mL, 0.75 mL, or 1 mL oral syringe with a Cyclic Olefin Polymer (COP) siliconised barrel and COP amber sheath cap. The product is supplied as a single dose pack, in a polypropylene container, each containing one syringe. The pre-filled oral syringe containing a nominal 0.25 mL, 0.5 mL, 0.75 mL, or 1 mL of product is capable of consistently delivering a 0.25 mL, 0.5 mL, 0.75 mL, or 1 mL dose respectively.^1-4

Oromucosal midazolam (as maleate) 2.5 mg in 0.25 mL.¹

Oromucosal midazolam (as maleate) 5 mg in 0.5 mL.²

Oromucosal midazolam (as maleate) 7.5 mg in 0.75 mL.³

Oromucosal midazolam (as maleate) 10 mg in 1 mL.⁴

There is 49 mg of alcohol (ethanol) in 0.25 mL (one syringe) of Epistatus^®.¹

There is 99 mg of alcohol (ethanol) in 0.5 mL (one syringe) of Epistatus^®.²

There is 148 mg of alcohol (ethanol) in 0.75 mL (one syringe) of Epistatus^®.³

There is 197 mg of alcohol (ethanol) in 1 mL (one syringe) of Epistatus^®.⁴

Assuming an average volume of distribution of 0.6 L/kg, a single dose of Epistatus^® will lead to blood ethanol concentrations of approximately 0.011% (11 mg/L) for a 10 year old.

This level is well below the maximum level of 0.125% recommended in the EMA Committee on Herbal Medicinal Products guideline (EMEA/HMPC/85114/2008). The maximum ethanol dose recommended in the herbal products guideline is also well in excess of that provided in the recommended posology for Epistatus^®, e.g. the maximum ethanol dose from a herbal product is stated as 2.2 g for a 10 year old, whereas the ethanol content of a single dose of Epistatus^® for this age is 0.2 g.^1-4,7

Epistatus^® does not contain flavouring agents.^1-4

Epistatus^® is indicated for the treatment of prolonged, acute, convulsive seizures in adults, infants, children and adolescents aged 3 months and above. Epistatus^® must only be used by parents / caregivers where the patient has been diagnosed to have epilepsy.^1-4

No.^1-4

Yes.^1-4

Epistatus^® is a sweetened, sugar-free, palatable, slightly viscous midazolam formulation.^1-4,8

Epistatus^® should always be administered as specified in the instructions in the patient’s care plan or as provided by the patient’s doctor or healthcare professional.^1-4

Epistatus^® is for oromucosal use. It is only to be used in the mouth.^1-4

Epistatus^® should always be administered as specified in the instructions in the patient’s care plan or as provided by the patient’s doctor or healthcare professional.^1-4

Epistatus^® is for oromucosal use. It is only to be used in the mouth.^1-4

Step 1^1-4

Check that the tamper-evident seal is not broken - if it is broken, do not use. Do not use if the syringe is damaged, the expiry date has passed, or the solution looks cloudy or has white particles in it.

Step 2^1-4

Pull the tamper evident tab on the side of the plastic outer case, open it and take the syringe out.

Step 3^1-4

Holding the clear finger grips, unscrew the amber sheath cap in an anti-clockwise direction.

Step 4^1-4

Remove the amber sheath cap and dispose of it responsibly.

Step 5^1-4

Ensure the patient’s head is supported, and locate the buccal cavity which is in the space between the inside of the patient’s cheek, and teeth and gums. By holding the cheek outwards and upwards, firmly, but gently, insert the syringe into the patient’s available buccal cavity. Do not put the syringe between the teeth.

Step 6^1-4

Push the plunger slowly. Approximately half the dose should be placed into each buccal cavity. But if the patient is lying down and access to the second buccal cavity is difficult, you can administer the whole dose over a duration of 4-5 seconds into the one buccal cavity.

A single-use oromucosal syringe containing 0.25 mL of solution. The 0.25 mL of solution contains 2.5 mg of midazolam (as maleate). ¹

A single-use oromucosal syringe containing 0.5 mL of solution. The 0.5 mL of solution contains 5 mg of midazolam (as maleate). ²

A single-use oromucosal syringe containing 0.75 mL of solution. The 0.75 mL of solution contains 7.5 mg of midazolam (as maleate). ³

A single-use oromucosal syringe containing 1 mL of solution. The 1 mL of solution contains 10 mg of midazolam (as maleate). ⁴

Each pack contains one single-use oromucosal syringe. ^1-4

The shelf-life is 18 months.^1-4

Keep this medicine out of the sight and reach of children. ^1-4

Do not store above 25°C. ^1-4

Do not put the product in the fridge or freezer. Store in the original package to protect from light.

Do not use this medicine after the expiry date which is stated on the syringe and container after EXP. The expiry date refers to the last day of that month. ^1-4

Do not give this medicine if you notice that the solution is not clear (e.g. cloudy or white particles are present). ^1-4

Disposal of oral syringes^1-4

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help to protect the environment.

The NHS cost per single-use oromucosal syringe 2.5 mg in 0.25 mL midazolam = £43.75 (ex. VAT).⁹

The NHS cost per single-use oromucosal syringe 5 mg in 0.5 mL midazolam = £43.75 (ex. VAT).⁹

The NHS cost per single-use oromucosal syringe 7.5 mg in 0.75 mL midazolam = £43.75 (ex. VAT).⁹

The NHS cost per single-use oromucosal syringe 10 mg in 1 mL midazolam = £45.76 (ex. VAT).⁹

Epistatus^® 2.5 mg Oromucosal Solution.¹

Each 0.25 mL of solution contains 2.5 mg of midazolam (as maleate).

Excipients with a known effect:

Ethanol 49 mg/dose

Liquid maltitol 169 mg/dose

Epistatus^® 5 mg Oromucosal Solution.²

Each 0.5 mL of solution contains 5 mg of midazolam (as maleate).

Excipients with a known effect:

Ethanol 99 mg/dose

Liquid maltitol 338 mg/dose

Epistatus^® 7.5mg Oromucosal Solution.³

Each 0.75 mL of solution contains 7.5 mg of midazolam (as maleate).

Excipients with a known effect:

Ethanol 148 mg/dose

Liquid maltitol 506 mg/dose

Epistatus^® 10 mg Oromucosal Solution.⁴

Each 1 mL of solution contains 10 mg of midazolam (as maleate).

Excipients with a known effect:

Ethanol 197 mg/mL.

Liquid maltitol 675 mg/dose

Other excipients include Glycerol, Purified water, Saccharin sodium and Sodium hydroxide (for pH adjustment).^1-4

For single-dose units, the equivalents per dose are:¹⁰

The pH of Epistatus^® 10mg oromucosal solution is between 4.6 - 5.6.¹

The pH of Epistatus^® 2.5 mg, 5.0 mg and 7.5 mg oromucosal solution is between 4.8 – 5.6.^2-4

Yes.¹¹