| · Adverse reactions
· Drug interactions (2)
· Packaging
· GHP (2)
· Pricing
· Clinical governance
· The profession
· Pharmacy workforce
· Communication
· Registration
Letters to the Editor
|
Drug interactions
Compatibility of itraconazole and ciclosporin injections
From Mrs C. L. Mathieson, MRPharmS, and Dr C. G. Cable, MRPharmS
Multiple myeloma, a malignant neoplasm involving the proliferation of
abnormal plasma cell precursors in the bone marrow, leads to suppression
of normal haematopoiesis and skeletal destruction. Conventional drug
therapy cannot cure the condition, but can prolong survival and alleviate
symptoms; allogenic peripheral blood stem cell (PBSC) or bone marrow
transplants (BM) are potentially curable options in younger, fitter patients.
At the Western General Hospital (WGH) in Edinburgh, patients undergoing
allogenic PBSC or BM transplant receive chemotherapy, anti-infective
agents, ciclosporin, analgesics and anti-emetics during their admission.
Such patients invariably develop severe mucositis, with eventual loss
of the oral route, requiring intravenous administration of medicines
and total parenteral nutrition, usually via a previously inserted multiple
lumen central line.
In one patient receiving several IV injections (meropenem, vancomycin,
itraconazole, aciclovir, ciclosporin, granisetron), nurses reported that
two lumen of the central line had become blocked with crystals which
could not be cleared using normal methods (subsequently it transpired
that crystallisation had already been observed in another patient). Ciclosporin
and/or itraconazole were thought to be implicated, since crystallisation
had never been observed in patients receiving autologous transplants
with a similar drug regimen but with fluconazole replacing itraconazole,
and no ciclosporin.
Nothing in the literature indicated that the compatibility of itraconazole
or ciclosporin injections had been investigated.
Both ciclosporin and itraconazole are practically insoluble in water
(less than 0.1 mg/ml). In Sandimmun concentrate for injection, ciclosporin
solubility is increased through the inclusion of a non-ionic surfactant
(Cremophor EL) and a solvent (ethanol); sorption of ciclosporin to administration
sets and leaching of plasticisers from polyvinyl chloride containers
by Cremophor EL has been reported.1
Itraconazole is highly lipophilic, and injection formulations include
cyclodextrins, which increase drug solubility through the formation of
inclusion complexes. These inclusion complexes are dynamic systems and
changes to the local environment (eg, concentration, temperature or pH
changes, other drugs, salts or additives) can result in dissociation
of the drug from the complex. To avoid the risk of drug precipitation,
itraconazole injection must be prepared exactly as described by the manufacturer.2
Although a chemical interaction between ciclosporin and itraconazole
cannot be dismissed, the observed crystallisation was probably due to
drug precipitation. Itraconazole injection is a relatively unstable product
that is prone to gross precipitation if not prepared and handled as directed;
it is probable that the crystals formed were itraconazole. Although the
administration of itraconazole through a dedicated line would minimise
the risk of precipitation, this was considered impractical for these
patients. The decision was to use fluconazole rather than itraconazole,
since the altered antifungal spectrum was less of a concern than the
risks associated with replacing a central line. Since fluconazole was
introduced, there have been no further reports of crystallisation or
lumen blockage.
References
1. Trissel LA. Handbook on injectable drugs. 13th ed. Bethesda: American
Society of Health-System Pharmacists, 2005:418–20.
2. Association of the British Pharmaceutical Industry. Medicines Compendium
2005. Surrey: Datapharm Communications Ltd, 2005: 2234–6.
Claire Mathieson
Senior Haematology Pharmacist
Colin Cable
Royal Pharmaceutical Society Fellow in Pharmaceutics
Western General Hospital, Edinburgh
Levonelle 1500 and liver-enzyme inducing drugs
From Mr P. Williams, MRPharmS
I refer to the discontinuation of Levonelle-2 and its replacement: Levonelle
1500 (PJ, 15 October, p477). Could Schering Health Care outline guidance for
the treatment of patients on enzyme-inducing medication? Currently, under
Cheshire patient group direction guidance, patients taking enzyme-inducing
medicines are advised to take 1500µg stat (two tablets) with a further
750µg (one tablet) 12 hours later.
Paul Williams
Chester
| |
LINDA KEEBLE, senior information scientist at Schering Health Care,
responds:
Currently with Levonelle-2, the two tablets are taken together.
Taking liver enzyme-inducing drugs may reduce the efficacy of Levonelle-2.
An intra-uterine device is an alternative option for women taking
these medicines. Any increase in the dose of Levonelle-2 would be off-licence,
therefore, we could not recommend any increase in the number of tablets
taken.
In Guillebaud’s book, ‘Contraception: your questions answered’1 he writes that the Faculty of Family Planning guidelines (2003) state that
the dose can be increased by 50 per cent: two tablets of Levonelle-2 stat followed
by one 12 hours later or three tablets at once. The Faculty of Family Planning
and Reproductive Health Care guidance on drug interactions with hormonal contraception
(April 2005) says that “women using liver enzyme-inducing drugs should
be advised to take a total of 2.25mg levonorgestrel (three Levonelle-2 tablets)
as soon as possible. They should be told that this use is outside the product
licence and be informed about the alternative use of an IUD.”2
For Levonelle One Step, which is available as a P medicine, our advice is
that the pharmacist should not sell it to a customer taking a liver enzyme-inducing
drug. Women taking these medicines should be referred to a prescriber of
emergency
contraception.
Regarding Levonelle 1500 which will be available in November 2005, the FFPRHC
guidance on the use of contraception outside the terms of the product licence
(July 2005)3 includes this topic. It discusses the possibility of taking
the single tablet (1.5mg) as soon as possible and within 72 hours of unprotected
sex or potential contraceptive failure, and then repeating the same dose
12
hours later (100 per cent increase in dose).
We have to point out that increasing the dose of Levonelle 1500 is outside
the product licence so we could not recommend any increase in the number
of tablets taken. The FFPRHC continuing education unit advises that women
should
be informed about the lack of data on efficacy of Levonelle when using liver
enzyme-inducers and be offered an IUD as an alternative. Clinicians may consider
using the regimen that is most acceptable to an individual woman.
References
1. Guillebaud J. Contraception: your questions answered. 4th ed. London:
Churchill Livingstone; 2004:472.
2. The Faculty of Family Planning and Reproductive Health Care. Drug interactions
with hormonal contraception. Available at: www.ffprhc.org.uk. Accessed 7 November
2005.
3. The Faculty of Family Planning and Reproductive Health Care. The use of
contraception outside the terms of the product licence. Available at: www.ffprhc.org.uk.
Accessed 7 November 2005. |
|
The
Pharmaceutical Journal