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Administration of PC medications |
The route for administration of medications in a terminally ill patient is a vitally important topic. Questions are often asked about what medications can be given rectally, or subcutaneously. If given subcutaneously, what can be mixed with what for administering through a subcutaneous needle or syringe driver? This excellent article by Judy Winning, pharmacist in charge, Neringah Hospital, will provide the answers. ~ Andrew Binns
Medications that have been given by non-traditional ways in palliative care
Striving for excellence in symptom control in patients unable to take oral medication has led to the administration of medications by routes such as subcutaneous (SC), sublingual (SL) and rectal: the reason for this is that these are usually the kindest and most practical options. Although pharmaceutical manufacturers may be aware of the use of medications by these non-traditional routes, there is usually in sufficient data or controlled studies for the inclusion of this sort of information into the product literature.
The success and technological refinement of infusion pumps for administering SC morphine for pain control has led to the addition of other medications such as midazolam (Hypnovel) for terminal restlessness and haloperidol (Serenace) for nausea. Combinations of medications have been administered together in the same syringe with good clinical results. The compatibility and stability of the individual agents when combined with other medications has not been determined for the vast majority of these combinations: the clinical response usually serves as an indicator of activity.
Before the use of SC midazolam and SC or SL clonazepam to control terminal restlessness, the rectal route was more commonly used for the administration of diazepam. Rectal administration of liquid dosage forms in palliative care is usually achieved by using a syringe attached to an infant feeding tube. The rectal route is often unreliable because of bowel problems or the lack of a suitable dosage form. In order for a drug to be absorbed by any route it must be solubilised. Therefore, if there is no suppository form, liquid preparations are preferable for rectal administration. Syrup formulations have been used rectally: these may have to be diluted with water if their hypertonicity or high sorbitol concentration causes bowel evacuation. Of the anticonvulsant oral liquids that have been used recently, sodium valproate (Epilim) and caramazepine (Tegretol) are suitable, whereas phenytoin (Dilantin) is not suitable: the manufacturers claim that absorption from the syrup is too unreliable, whereas the ampoules have a pH of 12 and are far too irritant.
Larger palliative care units are likely to be familiar with these non-traditional routes, but many smaller centres may not have access to this sort of information. It is hoped that this article will be helpful by documenting published and anecdotal reports of the use of medications by routes not included in the product literature. The author does not take responsibility for any medico-legal issues arising as a result of the administration of medications in non-traditional ways. Contributions for future updates would be gratefully received.
Information on injectable solutions commonly given by subcutaneous infusion in palliative care.
The convenience and success of administering medications by continuous SC infusion has led to an increase in this mode of administration, particularly in the community.
In palliative care various medications are routinely given by the SC route although this mode of administration is not documented in the product literature. Midazolam (Hypnovel), clonazepam (Rivotril), dexamethasone (Decadron), hyoscine-N-butylbromide (Buscopan), metoclopramide (Maxolon) and haloperidol (Serenace) have all been successfully given by the SC route. Some drugs such as prochloperazine (Stemetil), chlorpromazine (Largactil) and promethazine (Phenergan) are not suited to continuous SC administration because they are too irritant. Dexamethasone is more commonly given by intermittent SC injection: it does tend to be irritant, and having a high pH, precipitation occurs when mixed with certain medications (see section on incompatibilities).
The preferred dilutent for these small volume infusion solutions is water 1 rather than saline. Addition of an extra salt adds a further complexity to the solution and may even prolong absorption from SC tissues.
Many combinations of two and three drugs have been used together in palliative care without knowing if the drugs are microscopically compatible or remain active for the duration of the infusion: their immediate visual compatibility and clinical response have prompted their use.
Compatibility and stability information
Standard texts on injectable drugs are not particularly helpful when it comes to mixing solutions for SC infusion. This is because usually very short term compatibility only is documented and, at best, combinations of two drugs only have been studied.
Most combinations of injectable solutions used in palliative care do appear quite clear on immediate mixing. There may, however, be microscopic incompatibilities or drug inactivations that occur when these solutions are mixed or subjected to pH changes, as well as changes which may occur on storage.
Further studies are planned to establish the compatibility and stability of the numerous combinations of injectable solutions useful in palliative care. Limited studies2 on combinations of morphine with other medications have been conducted: the results are reported in the following section.
Chemical compatibility of morphine injections when mixed with various other injections 2
In the TGA Laboratory study five solutions for injection were studied as follows:
| Morphine tartrate 120mg/1.5mL |
MT |
| Morphine sulphate 30mg/1mL |
MS |
| Hyoscine-N-butylbromide 20mg/1mL |
HB |
| Metoclopramide hydrochloride 10mg/2mL |
M |
| Haloperidol 5mg/1mL |
H
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The following combinations of solutions for injection were found to be stable for one week when mixed in a ratio of one volume to one volume and stored at room temperature away from light.
| Combinations of 2 drugs |
Combinations of 3 drugs |
| MT + MS |
MT + MS + HB |
| MT + HB |
MT + MS + M |
| MT + M |
MT + MS + H |
| MS + HB |
MS + M
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Incompatibilities
Listed below are physical incompatibilities known to the author that are of importance to the practice of palliative medicine. The manufacturers' codes are the same as those used in the Schedule of Pharmaceutical Benefits.
| Drug |
Incompatible with |
Comments |
| Morphine tartrate (BL) |
Midazolam HCI (RO) |
Crystallisation has been reported on several occasions when these two drugs were mixed. The combination is therefore not recommended. Clonazepam SL or SC is the usual alternative to midazolam. |
| Dexamethasone sodium phosphate (BL) |
Cyclizine lactate (BW), Haloperidol (SR), Midazolam HCI (RO) |
Immediate precipitation occurs when dexamethasone sodium phosphate is mixed with any of the drugs listed. Dexamethasone sodium phosphate has a high pH and may be irritant to SC tissues.
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Information on medications that have been given by non-traditional ways (other than subcutaneously)
| Route of formulation not in product literature |
Administration |
Comments |
| |
| CARBAMAZEPINE Oral liquid 20mg/mL (Tegretol) |
Rectal |
Rectal absorption is comparable to that following oral administration provided that the liquid is retained in the rectum for a two hour period.(3) |
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| CLONAZEPAM ampoules 1mg/mL (Rivotril) |
Rectal |
Clonazepam is well absorbed after rectal administration with peak blood levels occurring in 10 to 30 minutes.(4) |
|
| CLONAZEPAM drops 2.5mg/mL (Rivotril) |
Sublingual |
The oral drops are a concentrated liquid solution and therefore sublingual administration should be facilitated. There are no known published studies, but anecdotal clinical reports support its use in the management of fitting and terminal restlessness. |
|
| DEXTROMORAMIDE tablets 5 mg (Palfium) |
Sublingual |
Useful when a fast onset of action is required for a short boost of analgesia prior to a painful procedure. Therapeutic plasma levels are obtained in about 12 minutes.(5) |
|
| DIAZEPAM ampoules 10mg/2mL (Valium) |
Rectal |
Rectal route provides faster, more reliable absorption. Absorption via IM route from oil-based preparation is slow and variable.(6) Diazepam injection is oil-based and immiscible with water-soluble drugs.(6) |
|
| DIAZEPAM tablets (Valium) |
Sublingual |
Tablets readily disperse in a tiny volume of water. Anecdotal clinical reports support the efficacy of sublingual diazepam. |
|
| HYOSCINE HYDROBROMIDE tablets 0.3mg (Kwells) |
Sublingual |
Useful option for a fast onset of action, particularly if the oral route is not possible. Alternative to transdermal hyoscine (Scop). |
|
| LORAZEPAM tablets (Ativan) |
Sublingual |
Bioavailability of lorazepam following oral and sublingual administration is not significantly different.(7) |
| MIDAZOLAM ampoules 5mg/mL (Hypnovel) |
Rectal, Sublingual |
Pharmacokinetic studies of midazolam following rectal administration is not significantly different.(7) |
| MIDAZOLAM ampoules 5mg/mL (Hypnovel) |
Rectal, Sublingual |
Pharmacokinetic studies of midazolam following administration in children8 support its efficacy. The use of sublingual midazolam is anecdotal. |
|
| MORPHINE HYDROCHLORIDE mixture |
Rectal, Sublingual |
A small volume of mixture is usually more practical. Rectal dose is comparable to oral.9 Sublingual bioavailability of morphine is less than oral.(10) |
|
| MORPHINE SULPHATE ampoules 10mg/mL |
Nebulised |
Useful in selected patients to control early stage dyspnoea.(11) Recommended starting concentration is 1mg/mL, diluted with saline to 4mL. |
|
| MORPHINE SULPHATE tablets controlled release (MS Contin) |
Rectal |
MS Contin tablets have been used rectally with effective maintenance of pain control.(12) |
|
| TEMAZEPAM capsules (Normison) |
Rectal |
The fact that temazepam capsules are liquid filled should facilitate rectal absorption. Anecdotal clinical reports support the efficacy of rectal temazepam using intact capsules. |
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| VALPROATE SODIUM syrup 40mg/mL (Epilim) |
Rectal |
The bioavailability of rectally administered valproate sodium syrup is comparable to that following oral administration.13 Dilute with at least an equal volume of water to prevent bowel evacuation.(14)
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Judy Winning, BPharmHons MPS, is the pharmacist-in-charge at Neringah Hospital.
References
1. Johnson, I. Drugs used in combination in the syringe driver - a survey of hospice practice. Palliative Medicine 1992; 6:125-130.
2. Bradshaw, K. Chemical compatibility and stability of morphine when mixed with various other injections. TGA Laboratory Information Bulletin. July 1992 Vol. 4 No. 1.
3. Neuvonen, P.J. & Tokola, O. Bioavailability of rectally administered carbamazepine mixture. Br. J. Clin. Pharmac. (1987), 24, 839-841.
4. Jensen, P.K., Abild, K et al. Serum concentrations of clonazepam after rectal administration. Acta Neurologica Scardinavica 1983; 68, 417-20.
5. Doyle, D. Lecture notes, May 1986.
6. Twycross, R.G. & Lack, S.A. Therapeutics in Terminal Cancer. Churchill Livingstone 2nd Edition 1990.
7. Current Drug Information. Vol. 3 August 1989, 119.
8. Tolia, V., Brennan, S. et al. Pharmacokinetic and pharmacodynamic study of midazolam in children during esophagogastroduodenoscopy. Journal of Pediatrics 1991; 119, No. 3 467-71.
9. Breda, M., Bianchi, M. Et al. Plasma morphine and morphine-6-glucuronide patterns in cancer patients after oral, subcuaneous, sublabial and rectal short-term administration Int. J. Clin.Pharmacol. Res.(Switzerland) 1991, 11 (2), 93-97.
10. Weinber, D.S., Inturrisi, C.E. et al. Sublingual absorption of selected opioid analgesics. Clin. Pharmacol. Ther. Sep. 1988 44(3), 335-42.
11. Yound, I. Unpublished information R.P.A.H. 1992.
12. Maloney C.M., Kesner R.K. et al. The rectal administration of MS Contin: clinical implications of use in end stage cancer. Am J. Hosp. Care Jul-Aug. 1989 6 (4), 34-35.
13. Scanabissi, E., Dal Pozzo, D. Et al. Rectal administration of sodium valproate in children. Hal. J. Neurol. Sci: 1984 189-193.
14. Cloyd, J.C. & Kriel, R.L. Bioavailability of rectally administered valproic acid syrup. Neurology (Ny) 1981; 31: 1384-1352.
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