Choosing An Injectable Medicine For Intrathecal Administration – SPS

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.

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Use a licensed medicine

Medicinal products that are licensed for intrathecal use are preferred

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Licensed for intrathecal use

A medicine licensed for intrathecal use should be used where available, with administration being undertaken following the SmPC.

Not licensed for intrathecal use

Where a drug is not licensed for intrathecal use, careful consideration by the clinical team is required.

The dose required for intrathecal administration must be carefully determined.

Cytotoxic medicines

Only a small number of cytotoxic medicines are suitable for intrathecal administration. Wrong route administration of cytotoxic medicines can be fatal.

Intrathecal chemotherapy must be given in line with national guidance and your local intrathecal policy.

2

Assess the risk of an unlicensed product

Unlicensed products may be considered if there are no licensed alternatives

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Off-label use and unlicensed products

There may be circumstances where a prescriber considers intrathecal treatment essential and there is no licensed product. In this situation, it may be necessary to assess the relative risks and benefits of using the following alternatives:

• off-label use of a product licensed for other parenteral routes
• an unlicensed medicine manufactured under Manufacturing Specials (MS) licence, also known as a ‘Specials’ license.

The prescriber should carry out a risk assessment to establish the risk/benefit balance in compliance with their organisation’s unlicensed medicines policies.

3

Obtain information on neurotoxins

Establish relevant excipients, endotoxin level and pH

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Licensed for intrathecal use

It should not be assumed that because a particular preservative is present in a specific product licensed for intrathecal use, that the same preservative is acceptable in another product that is to be administered intrathecally.

4

Calculate the endotoxin level

Calculate the potential endotoxin load for your patient

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Worked example 1 – bolus intrathecal administration

We have a 35kg patient who is to have a bolus dose of 10 micrograms/kg of clonidine hydrochloride.

Clonidine hydrochloride 1mg/mL injection is to be used and the manufacturer’s stated maximum allowed endotoxin content for this product is 17 IU/mL.

If K = IU/kg, then rearranging IU = K x W where W is the bodyweight in kg.

Decision to proceed is based on the premise that the value for IU (K x W) is less than IU/mL x dose volume

Threshold pyrogenic dose calculation

K x W is: 0.2 x 35 = 7 IU

So, the maximum endotoxin load this patient can tolerate is 7 IU.

Dose volume calculation

10 micrograms/kg x 35kg = 350 micrograms total daily dose

350 micrograms of a 1mg/mL solution = 0.35mL

Endotoxin load calculation

Clonidine hydrochloride injection endotoxin limit is 17 IU/mL. The intended dose volume of 0.35mL would contain a maximum of:

17 IU/mL x 0.35mL = 5.95 IU

5.95 IU is less than 7 IU, therefore this dose is below the endotoxin limit and may be suitable for intrathecal administration.

Worked example 2 – continuous infusion by intrathecal administration

We have a patient on a hydromorphone 50mg/mL continuous infusion via an implanted reservoir.

To prepare a refill for an implanted intrathecal pump, the Pharmacy has obtained a hypothetical hydromorphone 50mg/mL injection from overseas.

The patient weighs 70kg and is on the highest dose, prescribed 900mg in 40mL over 10 weeks. The product meets the USP monograph standard which states the endotoxin limit for hydromorphone injection is 88 IU per mg*

*Note – for this product the endotoxin limit is quoted in the USP in IU per mg – therefore we will be calculating the infusion rate in mg/hour.

Endotoxin Limit (EL) = K / M

where:

• K is 0.2 IU/kg of body weight for intrathecally administered products
• M is the maximum dose in mg administered per hour

If K = IU/kg, then rearranging IU = K x W where W is the bodyweight in kg.

Threshold pyrogenic dose calculation

K x W is 0.2 IU/kg x 70kg = 14 IU/hr

So, the maximum endotoxin load this patient can tolerate is 14 IU per hour.

Infusion rate calculation (in mg/hr)

Total dose to be given = 900 mg over 10 weeks (= 1680 hours)

Dose per hour = 900 mg / 1680 hours = 0.54 mg/hr

Endotoxin load calculation

88 IU/mg x 0.54mg/hr = 47.5 IU/hr

i.e. the endotoxin load for this product could be up to 47.5 IU/hr, which exceeds the acceptable endotoxin limit for the patient (14 IU/hr).

The decision would therefore be that this product is unsuitable for administration via the intrathecal route.

5

Perform clinical risk assessment

Provide the prescriber with all the relevant information to help inform a treatment decision

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Assessing risk

The risk/benefit analysis establishes the product is within the safe limits for intrathecal use and there are:

• no excipients of risk
• endotoxin limits are within range for intrathecal use
• non-extreme pH and osmolarity

The prescriber can then make an informed decision on whether to proceed with using a medicinal product that is not licensed for intrathecal administration.

6

Seek further advice

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If you cannot find any information, or your clinical scenario is complex, refer to your clinical specialist for further advice and support.

Information to support the risk assessment process

The intrathecal administration SPS page (SPS page) collates information on available products to help inform your local risk assessment on the safety and suitability of a medicine for intrathecal administration.

Update history

13 June 2025

1. Link to the intrathecal administration page added for collated product information to support risk assessment

12 July 2024

1. Additional information added regarding epidural conformity

12 September 2022

1. Wording in calculations further clarified

6 September 2022

1. Implication of answer in worked example 1 clarified. Worked example 2 added.

17 August 2022

1. Corrected typo in dose volume calculation example 1. Removed worked example 2.

11 August 2022

1. Republished

6 July 2022

1. Published

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