Chemical Compatibility of Drugs for Continuous Subcutaneous Infusions

Project Team:

Andrew Dickman, MCPCIL
Diane Rigge, Quality Control North West
Phil Weir, Quality Control North West

Project Start: Autumn 2009
  

Background: A continuous subcutaneous infusion (CSCI) is an effective method of drug administration that is commonly encountered in palliative medicine.  When the oral route is no longer available, the use of a CSCI is the preferred method of drug administration to maintain symptom control.  A syringe driver, or pump, is used to deliver a CSCI.

In March 2007, the National Patient Safety Agency (NPSA) issued a patient safety alert promoting the safer use of injectable medicines.  The NPSA had received around 800 reports a month relating to errors with injectable medicines.  While the majority were minor, several caused serious harm and even death. In order to reduce future risks, the NPSA has produced guidance which includes the statement that healthcare staff need to have full technical information about the stability in solution and compatibility of commonly used mixtures used in specialist areas only.

Presently there is only one major source of such information relating to CSCIs in palliative care.  This reference source provides useful information mainly about the physical compatibility of drug combinations.  Chemical incompatibilities cannot be discounted.  Indeed, it is known that mixtures containing dexamethasone/glycopyrronnium and dexamethasone/midazolam are physically compatible, but chemically incompatible.  It is unknown whether symptom deterioration that may occur in some patients using a CSCI is due to disease progression, or chemical incompatibilities within the syringe reducing the concentrations of active drugs.

There is a definite need for chemical compatibility studies of commonly used drug mixtures to be performed.  There has been extensive chemical compatibility work performed on tramadol mixtures, but this drug is rarely administered via CSCI in the UK.  Ideally, combinations of the commonly used parenteral opioids, together with two or three supportive drugs encountered on the Liverpool Care Pathway for the Dying Patient (LCP), should be examined for chemical compatibility.  The information gained by undertaking this work would have both national and international appeal and has the potential to be of great importance for palliative medicine.

Aims:  To determine the chemical compatibility/stability of a selection of drug combinations commonly encountered in end-of-life care.  A database search of over 1,000 entries identified 10 frequently used combinations of supportive (i.e. non-opioid) drugs.  The chemical compatibility and stability of these mixtures with 5 different opioids will be tested.   The doses have been selected to represent clinical practice.

 Initial 10 combinations to be tested:

1. Cyclizine 150mg and Haloperidol 5mg
2. Cyclizine 150mg and Midazolam 30mg
3.  Glycopyrronium 1.2mg and Midazolam 30mg
4.  Haloperidol 5mg and Midazolam 30mg
5.  Hyoscine butylbromide 120mg and Levomepromazine 12.5mg
6.  Levomepromazine 50mg and Midazolam 30mg
7.  Metoclopramide 30mg and Midazolam 30mg
8.  Cyclizine 150mg, Glycopyrronium 1.2mg and Haloperidol 5mg   
9.  Cyclizine 150mg, Haloperidol 5mg and Midazolam 30mg
10. Glycopyrronium 2.4mg, Levomepromazine 50mg and Midazolam 30mg                           

These combinations will be tested for chemical compatibility in the presence of:

• Alfentanil 10mg

• Morphine 120mg

• Diamorphine 100mg

• Hydromorphone 50mg

• Oxycodone 100mg

Dexamethasone (1mg) is occasionally mixed with other drugs in CSCI in an attempt to improve site tolerability.  Such practice frequently results in precipitation, but the chemical stability of apparently stable combinations has never been studied.  In addition to the combinations described above, the following is hoped to be examined with dexamethasone 1mg:

1.       Cyclizine 150mg
2.       Ketamine 300mg
3.       Levomepromazine 6.25mg
4.       Levomepromazine 100mg
5.       Methadone 30mg
6.       Metoclopramide 30mg
7.       Promethazine 50mg
8.       Morphine 120mg,  Haloperidol 5mg and  Ketamine 300mg

Methods: Chemical stability of the selected mixtures will be determined by HPLC.  Each study will examine the stability of the solution under normal use conditions, i.e. a syringe driver will be set to run over 24 hours at room temperature/light and samples will be taken from the administration line at several time intervals over the study period. 

Finish Date: Autumn 2010

Outputs: Poster presentation at the 6th Research Forum of the European Association for Palliative Care (EAPC) in June 2010.  It is proposed that at least two papers will be generated by this project; one will appear in a palliative care journal, another in a pharmacy/pharmaceutical journal.