Suitability for intrathecal use
This guidance brings together all the available technical information from manufacturers on excipients, pH and endotoxin content of a range of injectable medicines.
This information will assist healthcare professionals in making a risk assessment and subsequent robust prescribing decisions about selection of injectable medicines currently available in the UK, which may be appropriate for intrathecal administration.
Intrathecal vs. epidural
Intrathecal administration is a route of administration for medicines via an injection into the spinal canal, or into the subarachnoid space so that it reaches the cerebrospinal fluid (CSF) and is useful in spinal anaesthesia, chemotherapy, or pain management.
Epidural administration is a route of administration where the medicine is placed into the space around the spinal cord, also known as the epidural space, usually to provide temporary or prolonged relief from pain or inflammation.
The BP does not specify a maximum endotoxin dose per hour for epidural solutions. Due to diffusion of epidural injections across the dura and the risks of dural puncture there is a strong rationale to apply the specified maximum endotoxin dose for intrathecal injections. USP Chapter <727> states that “Compounded Sterile Preparations (CSPs) administered epidurally should have the same endotoxin limit as that of intrathecally administered CSPs”. As this aligns with the (unwritten) MHRA expectation that “if tested, epidural solutions would conform to the standards for intrathecals” it would be prudent to adhere to this position.
Meeting the BP standards
All injectable medicines must meet the specification in the British Pharmacopoeia (BP) monograph for parenteral preparations.
The limits in the specification are the same for intrathecal medicines as for other parenteral products in most respects, but there is a lower limit for the presence of bacterial endotoxins.
Endotoxins
The BP monograph for intrathecal injections has a significantly lower endotoxin limit than the intravenous injections.
Threshold Pyrogenic Dose
The body generally has endotoxin tolerance levels, defined as the maximum acceptable endotoxin levels at which no associated adverse events occur. This limit is the “Threshold Pyrogenic Dose”.
Endotoxin levels
Endotoxin levels are measured in Endotoxin Units (EU) or International Units (IU), which are considered interchangeable, and the acceptable endotoxin limit for intrathecal use is 0.2 IU per kg of bodyweight (maximum 14 IU per person).
The endotoxin limit is dependent on product and dose. It is expressed as follows:
Endotoxin Limit (EL) = K / M
Where K is:
- 5 IU/kg of body weight for any parenteral route of administration other than intrathecal, which is the threshold pyrogenic dose of endotoxin per kg of body weight.
- 0.2 IU/kg of body weight for intrathecally administered products.
Where M is:
- the maximum recommended bolus dose of drug per kg of body weight, or
- the maximum total dose administered per hour, for injections to be administered at frequent intervals or by continuous infusions
For intrathecal administration, the maximum permissible endotoxin dose is 25 x less than for the same product administered via the IV route. This estimate can be used as part of an initial assessment to determine whether an injectable medicine licensed for parenteral use is likely to be suitable for administration by the intrathecal route.
Worked examples of endotoxin calculations can be found in step 4 below.
Preservatives
Injections for intrathecal administration are usually preservative-free.
Preservatives, e.g. parabens and benzyl alcohol, cause inflammation of the arachnoid membrane and are neurotoxic. Other excipients can also be neurotoxic.
pH and osmolarity
It is recommended that the pH and osmolarity of the injection solution are as close as possible to the normal physiological ranges for cerebrospinal fluid (CSF).
The physicochemical properties of CSF are usually:
- Osmolarity 292-297mOsmol/L
- pH 7.31
Please refer to the normal ranges quoted by your Trust’s laboratory.
Risk assessment process overview
The following process highlights the points to consider for medicines that are to be administered via the intrathecal route.
Update history
- Additional information added regarding epidural conformity
- Wording in calculations further clarified
- Implication of answer in worked example 1 clarified. Worked example 2 added.
- Corrected typo in dose volume calculation example 1. Removed worked example 2.
- Published