General

Combinations of drugs mixed in Subcutaneous Infusions (CSCI)

The mixing of drugs prior to administration, unless specifically mentioned in the product licence, constitutes 'off-label' prescribing. Many patients receiving palliative care will need an analgesic, one or more antiemetic, an anxiolytic / sedative, and possibly an antimuscarinic drug. Profound weakness or vomiting often necessitates a non-oral route; the concurrent use of up to 5 syringe drivers is impractical. Therefore drugs are commonly used in combination as subcutaneous infusions via a syringe driver.

Potential problems include degradation of the drug(s) and therefore reduced efficacy, and precipitation/crystallisation. Degradation rate may be increased by other drugs which alter the pH of the mixture. Crystallisation can occur either through formation of an insoluble product of drug interaction, or because a drug alters the pH of the solution rendering a second drug insoluble.

The more drugs mixed, the greater is the potential for interaction. Drugs which have a high or low pH in solution are more likely to interact with others.

Data from compatibility studies are only available for a few combinations. Turbidometers (or similar) detect crystallisation or precipitation by optical means. HPLC methods determine drug stability as e.g. the percentage of original drug present after 24h.

The possibility exists of two drugs chemically interacting to form a new - potentially toxic - compound. Neither turbidometry nor HPLC will detect this. Therefore, even 'gold-standard' studies using HPLC will not prove that a combination is 'safe'. Simple visual inspection of a mixture before and during administration will detect most problems of crystallisation/precipitation, although fine particles may not be visible to the naked eye. However, some combinations have been shown to interact without any visible change, e.g. dexamethasone, which inactivates glycopyrronium without causing precipitation.

Doctors wishing to prescribe a combination of drugs they have not previously used, should:

• Be aware of the risks (see above).
• Refer to appropriate sources of evidence:
  • local Palliative Care Centres
  • Palliative Care Formulary[1]
  • www.pallcare.info (database of drug mixtures for syringe drivers)
  • SIGN cancer pain guidelines[2]
  • 'The syringe driver in palliative care' (Dickman, 1998)[3]
  • Drug Information Centres & hospital pharmacists
• Have considered the use of more than one syringe driver.
• Use as few drugs in combination as possible.
• Carefully inspect the mixture before use for any signs of crystallisation/precipitation.
• Continue to inspect regularly during its use - preferably 4-hourly for the first 24h.
• Monitor the patient carefully, especially for evidence of reduced efficacy of any of the drugs.

Diluent

Water for injection should be considered the standard diluent for drug mixtures for use in a syringe driver.

Saline is recommended as the diluent for levomepromazine used alone, to make the solution isotonic and reduce site inflammation.[4] Many centres use saline for all drug combinations containing levomepromazine, but there is no evidence to support this.

Saline has also been recommended for granisetron, ketamine, ketorolac, octreotide and ondansetron,[1] but water may be better when these drugs are used in combination with others.

Cyclizine tends to precipitate if saline is used as diluent,[3] so water is recommended for any mixture containing cyclizine.

Commonly used drugs

• diamorphine
• haloperidol
• metoclopramide
• cyclizine
• levomepromazine
• hyoscine hydrobromide (HBr)
• midazolam

Chemically stable and compatible

The following drug mixes have been shown to be physically compatible and chemically stable, although there are limits on the maximum concentrations of each drug, especially diamorphine and cyclizine.[1]

• Cyclizine, Diamorphine[5-8]
• Diamorphine, Haloperidol[5-8]
• Diamorphine, Hyoscine HBr[5,6]
• Diamorphine, Levomepromazine[6]
• Diamorphine, Metoclopramide[5,6]
• Diamorphine, Midazolam[9]
• Cyclizine, Diamorphine, Haloperidol[8]

Incompatibility

There are no consistent incompatibilities between any of these 7 drugs, even in combinations of up to five drugs; however cyclizine and metoclopramide have occasionally caused precipitation (this is not a combination of antiemetics usually recommended).

Compatible (visually) - common drugs

The following drug mixes have been used successfully in palliative care units, and are visually compatible.

• Cyclizine, Diamorphine, Haloperidol, Hyoscine HBr (water)[10]
• Cyclizine, Diamorphine, Haloperidol, Midazolam (water)[10]
• Cyclizine, Diamorphine, Hyoscine HBr (water)[10]
• Cyclizine, Diamorphine, Hyoscine HBr, Midazolam (diluent not stated)[11]
• Cyclizine, Diamorphine, Midazolam (water)[10,11]
• Diamorphine, Haloperidol, Hyoscine HBr (water)[10]
• Diamorphine, Haloperidol, Hyoscine HBr, Levomepromazine (saline)[10]
• Diamorphine, Haloperidol, Hyoscine HBr, Midazolam (water)[10,11]
• Diamorphine, Haloperidol, Levomepromazine (saline)[10]
• Diamorphine, Haloperidol, Levomepromazine, Midazolam (water)[10]
• Diamorphine, Haloperidol, Midazolam (water)[10-12]
• Diamorphine, Hyoscine HBr, Levomepromazine (saline or water)[10,13]
• Diamorphine, Hyoscine HBr, Levomepromazine, Midazolam (saline)[10]
• Diamorphine, Hyoscine HBr, Metoclopramide, Midazolam (water)[10]
• Diamorphine, Hyoscine HBr, Midazolam (water)[10,11]
• Diamorphine, Levomepromazine, Metoclopramide (saline)[10]
• Diamorphine, Levomepromazine, Metoclopramide, Midazolam (saline or water)[10]
• Diamorphine, Levomepromazine, Midazolam (saline or water)[10]
• Diamorphine, Metoclopramide, Midazolam (water)[10,11]

Less commonly used drugs

The following drugs, amongst others, have also been used in palliative care units by CSCI. Refer to the Palliative care formulary,[1] 'The syringe driver in palliative care' (Dickman, 1998),[3] or on-line database[10] for further details.

Drug	Notes
Alfentanil	Compatible with commonly used drugs (except cyclizine in certain mixes)
Clonazepam	Compatible with commonly used drugs and glycopyrronium
Dexamethasone	Inactivates glycopyrronium although no precipitation seen. Precipitation seen quite commonly, but unpredictably. If used, dilute dexamethasone before adding other drugs
Fentanyl	Compatible with commonly used drugs (except cyclizine in certain mixes), and also: ketamine, ketorolac, octreotide, ondansetron and glycopyrronium.
Glycopyrronium	Compatible with commonly used drugs, ketamine and octreotide. Inactivated by dexamethasone although no precipitation seen
Hyoscine butylbromide	Compatible with commonly used drugs (except cyclizine in certain mixes); also compatible with octreotide and fentanyl
Ketorolac	Compatible with diamorphine and fentanyl; incompatible with cyclizine, haloperidol, and levomepromazine; mixed reports with midazolam.
Ketamine	Compatible with commonly used drugs; also compatible with fentanyl, lidocaine, glycopyrronium, ondansetron, hyoscine butylbromide and ketorolac
Octreotide	Incompatible with cyclizine or dexamethasone. Compatible with commonly used drugs except cyclizine; also compatible with hyoscine butylbromide, fentanyl, glycopyrronium and ondansetron
Ondansetron	Compatible with diamorphine, hyoscine hydrobromide, metoclopramide, midazolam; also compatible with fentanyl, alfentanil, glycopyrronium, octreotide, and dexamethasone
Phenobarbital	Compatible with diamorphine and fentanyl otherwise incompatible.

Chemically stable and compatible - less common drugs

The following drug mixes have been shown to be physically compatible and chemically stable.

• Diamorphine, Hyoscine butylbromide[5]
• Diamorphine, Ketorolac[14]
• Diamorphine, Octreotide[15]

Incompatible mixes

• Cyclizine, Hyoscine butylbromide[10]
• Cyclizine, Ketorolac[1]
• Cyclizine, Octreotide[16]
• Dexamethasone, Octreotide[16]
• Dexamethasone, Glycopyrronium[3]
• Haloperidol, Ketorolac[17]

Compatible (visually) - less common drugs

The following drug mixes have been used successfully in palliative care units, and are visually compatible.

• Cyclizine, Diamorphine, Glycopyrronium, Haloperidol, Midazolam (water)[10]
• Cyclizine, Diamorphine, Glycopyrronium, Midazolam (water)[10]
• Cyclizine, Diamorphine, Haloperidol, Octreotide (water)[10]
• Dexamethasone, Diamorphine (diluent not stated)[18]
• Dexamethasone, Diamorphine, Ketamine, Metoclopramide (water)[10]
• Diamorphine, Fentanyl, Levomepromazine, Metoclopramide (saline)[10]
• Diamorphine, Glycopyrronium (water)[10]
• Diamorphine, Glycopyrronium, Haloperidol (water)[10]
• Diamorphine, Glycopyrronium, Haloperidol, Ketamine, Midazolam (water)[10]
• Diamorphine, Glycopyrronium, Haloperidol, Levomepromazine, Midazolam (saline)[10]
• Diamorphine, Glycopyrronium, Haloperidol, Midazolam (water)[10]
• Diamorphine, Glycopyrronium, Ketamine, Midazolam (water)[10]
• Diamorphine, Glycopyrronium, Levomepromazine (saline)[10]
• Diamorphine, Glycopyrronium, Levomepromazine, Metoclopramide (saline)[10]
• Diamorphine, Glycopyrronium, Levomepromazine, Metoclopramide, Midazolam (saline)[10]
• Diamorphine, Glycopyrronium, Levomepromazine, Midazolam (saline or water)[10]
• Diamorphine, Glycopyrronium, Metoclopramide, Midazolam (water)[10]
• Diamorphine, Glycopyrronium, Midazolam (water)[10]
• Diamorphine, Haloperidol, Hyoscine butylbromide, Midazolam (water)[10]
• Diamorphine, Haloperidol, Hyoscine butylbromide, Octreotide (water)[10]
• Diamorphine, Haloperidol, Ketamine, Midazolam (water)[10]
• Diamorphine, Haloperidol, Octreotide (diluent not stated)[19]
• Diamorphine, Hyoscine butylbromide, Levomepromazine (water)[10]
• Diamorphine, Hyoscine butylbromide, Levomepromazine, Midazolam (water)[10]
• Diamorphine, Hyoscine butylbromide, Levomepromazine, Octreotide (saline)[10]
• Diamorphine, Hyoscine butylbromide, Midazolam (water)[10]
• Diamorphine, Hyoscine butylbromide, Octreotide (water)[10]
• Diamorphine, Hyoscine HBr, Levomepromazine, Octreotide (saline)[10]
• Diamorphine, Hyoscine HBr, Midazolam, Octreotide (water)[10]
• Diamorphine, Hyoscine HBr, Midazolam, Ondansetron (water)[10]
• Diamorphine, Ketamine, Levomepromazine (saline)[10]
• Diamorphine, Ketamine, Levomepromazine, Midazolam (water)[10]
• Diamorphine, Ketamine, Metoclopramide, Midazolam (water)[10]
• Diamorphine, Ketamine, Midazolam (water)[10]
• Diamorphine, Ketorolac, Midazolam (water)[10]
• Diamorphine, Levomepromazine, Midazolam, Octreotide (saline or water)[10]
• Diamorphine, Levomepromazine, Octreotide (saline or water)[10]
• Diamorphine, Metoclopramide, Midazolam, Octreotide (water)[10]
• Diamorphine, Metoclopramide, Octreotide (water)[10]
• Diamorphine, Midazolam, Octreotide (water)[10,19]
• Diamorphine, Ondansetron (water)[10]
• Diamorphine, Phenobarbital (water)[10]