Medicines Q&As
Q&A 314.2
Is there a topical preparation of chlormethine available for the
treatment of mycosis fungoides?
Prepared by UK Medicines Information (UKMi) pharmacists for NHS healthcare professionals
Before using this Q&A, read the disclaimer at www.ukmi.nhs.uk/activities/medicinesQAs/default.asp
Date prepared: 11th May 2012
Background
Mycosis fungoides is the most common form of cutaneous T-cell lymphoma. For early stage mycosis
fungoides (stages IA, 1B and IIA), skin-directed therapy (e.g. topical therapy, superficial radiotherapy
or phototherapy) is recommended as first-line treatment (1,2).
Topical chlormethine (also known as mechlorethamine, mustine or nitrogen mustard) (3) is a
suggested treatment option for early stage mycosis fungoides (1,2,3). However, as there is currently
no licensed formulation of topical chlormethine available in the UK, this Medicines Q&A discusses the
various options for obtaining an appropriate preparation.
Answer
Two formulations of topical chlormethine are described in the literature and in current guidelines,
namely an aqueous solution or an ointment-based preparation.
Aqueous chlormethine
Limited published information is available on the formulation of aqueous chlormethine. Older studies
describe the use of 10-40mg chlormethine dissolved in 40ml water (4) or 10mg chlormethine in 60ml
water (5) for the treatment of mycosis fungoides. However, in a more recent report a 10 to
20mg/100ml solution was prepared (6) and current guidelines also suggest the use of a 0.01% or
0.02% aqueous solution (1,2).
Contact hypersensitivity reactions to topical chlormethine have been reported. However, one study
suggests that in most cases this can be managed by reducing the concentration of chlormethine or
the frequency of application, with a subsequent increase over a period of months (6).
A patient information leaflet containing information on the use of topical chlormethine (nitrogen
mustard) has been produced by the British Association of Dermatologists (7) and is available here.
Chlormethine ointment
It has been suggested that hypersensitivity to topical chlormethine is less likely with an ointment
formulation (2,6), which can be applied at a concentration of 0.01% or 0.02% (1,2). Lower
concentrations may be used in patients with a history of hypersensitivity to chlormethine. Patients
may also find an ointment preparation more convenient to use (8).
There is limited published information available on the preparation of chlormethine ointment. Various
examples of ointment formulations of chlormethine are described in the literature (6,8), but some of
these include ingredients e.g. Aquaphor (an ointment base)(8), which are currently not available in the
UK (3). The preparations were prepared by a pharmacy department (6,8).
One study has determined the stability of an ointment formulation of chlormethine. The ointment was
freshly prepared as follows and stored in clear glass jars: 10mg chlormethine powder (Mustine
Hydrochloride for Injection BP) was dissolved in 1ml acetone which was then worked into 50g white
soft paraffin to produce an even consistency. The ointment was shown to be stable for 84 days when
stored at 4oC and for 40 days when stored at 37oC (9).
From the NHS Evidence website www.evidence.nhs.uk
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Medicines Q&As
A stability study, published as a conference report, has calculated the shelf life of a 0.01%w/w
chlormethine in 50/50 liquid paraffin/white soft paraffin ointment. On the basis of the findings of this
study, shelf lives of 217 days when stored at 25oC/60% relative humidity or 218 days when stored at
7oC were allocated. The only physical change noted was an oily layer that dispersed with mixing,
which appeared at 25oC/60% relative humidity (10).
Availability of topical chlormethine
There is no licensed formulation of topical chlormethine available in the UK.
A solution for dermal application of chlormethine (Caryolysine®) which was licensed in France has
recently been discontinued (11,12).
A chlormethine (mechlorethamine) gel formulation has been granted Orphan Drug Status in the US
and a New Drug Application was submitted to the US Food and Drug Administration (FDA) for the
treatment of early stage (stages I-IIA) mycosis fungoides in July 2011 (13). However, a US product
has not yet been marketed (11).
The European Medicines Agency (EMA) Committee for Orphan Medicinal Products (COMP) is
currently reviewing chlormethine for the treatment of cutaneous T-cell lymphoma. A positive opinion
was adopted by the COMP recommending orphan designation to the European Commission in
January 2012 (14). However, orphan designation has not yet been granted (14).
At the time of writing, no topical or any other formulations of chlormethine could be sourced
(11,12,15,16). There is currently a global supply problem with mechlorethamine (chlormethine)
hydrochloride for injection (Mustargen®) (17), which has been used to prepare chlormethine ointment
(8). The product is not expected to be available again until late 2012. As Mustargen ® is not licensed in
the UK it would be available on a named-patient basis via a pharmaceutical importer (17).
Summary

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Topical chlormethine (also known as mechlorethamine, mustine or nitrogen mustard) (3) is a
suggested first-line treatment option for early stage mycosis fungoides (1,2,3).
There is currently no licensed formulation of topical chlormethine available in the UK.
Two formulations of topical chlormethine are described in the literature and in current guidelines,
namely an aqueous solution or an ointment-based preparation. However, details on the
preparation of these products are limited.
Guidelines suggest that a 0.01% or 0.02% aqueous solution may be used to treat mycosis
fungoides (1,2).
It has been suggested that hypersensitivity to topical chlormethine is less likely with an ointment
formulation (2,6), which can be applied at a concentration of 0.01% or 0.02% (1,2). Ointment
preparations would need to be prepared by a pharmacy department.
At the time of writing, no topical or any other formulations of chlormethine could be sourced
(11,12,15,16). There is currently a global supply problem with mechlorethamine (chlormethine)
hydrochloride for injection (Mustargen®) (17), which has been used to prepare chlormethine
ointment (8).
Licence applications for topical chlormethine preparations have been submitted to the US Food
and Drug Administration (FDA) and the European Medicines Agency (EMA) (13,14).
Limitations
 Only the use of topical chlormethine for the treatment of mycosis fungoides has been considered
in this Medicines Q&A. Its use for other conditions has not been addressed.
 Data on the clinical efficacy and safety of topical chlormethine for mycosis fungoides has not been
evaluated.
 Details about the optimum method, timing and duration of administration have not been included.
From the NHS Evidence website www.evidence.nhs.uk
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Medicines Q&As


The information on the availability of chlormethine was correct at the time of writing. However, this
situation may be subject to change and alternative supply routes may be investigated to source
the product, if required.
The clinical staging system for cutaneous T-cell lymphoma has not been discussed. See
Appendix B in reference 1 for more details.
References
1. Whittaker SJ, Marsden JR, Spittle M et al. Joint British Association of Dermatologists and UK
Cutaneous Lymphoma Group guidelines for the management of primary cutaneous T-cell
lymphomas. Br J Dermatol 2003;149: 1095-1107. Available via
http://www.bad.org.uk/site/622/default.aspx (update in progress).
2. Trautinger F, Knobler R, Willemze R et al. EORTC consensus recommendations for the
treatment of mycosis fungoides/Sézary syndrome. Eur J Cancer 2006; 42:1014-1030.
3. Chlormethine hydrochloride monograph. Sweetman SC, editor. Martindale: The Complete
Drug Reference. Electronic edition. London: Pharmaceutical Press. Accessed via
http://www.medicinescomplete.com/ on 11th May 2012.
4. Zachariae H, Thestrup-Pedersen K, Søgaard H. Topical nitrogen mustard in early mycosis
fungoides. A 12-year experience. Acta Derm Venereol 1985;65: 53-58.
5. Ramsay DL, Halperin PS, Zeleniuch-Jacquotte A. Topical mechlorethamine therapy for early
stage mycosis fungoides. J Am Acad Dermatol 1988;19:684-91.
6. Kim YH, Martinez G, Varghese A et al. Topical nitrogen mustard in the management of
mycosis fungoides. Update of the Stanford experience. Arch Dermatol 2003;139:165-173.
7. Patient Information Leaflet. Nitrogen mustard:a preparation to be applied to the skin. British
Association of Dermatologists.Updated May 2010. Accessed via
http://www.bad.org.uk/Portals/_Bad/Patient%20Information%20Leaflets%20(PILs)/Nitrogen%
20Mustard%20Update%20May%202011%20-%20lay%20reviewed%20Feb%202011.pdf on
14th May 2012.
8. Price NM, Hoppe RT, Deneau DG. Ointment-based mechlorethamine treatment for mycosis
fungoides. Cancer 1983;52:2214-2219.
9. Cummings J, Maclellan A, Langdon SJ et al. The long term stability of mechlorethamine
hydrochloride (nitrogen mustard) ointment measured by HPLC. J Pharm Pharmacol 1993;45:
6-9.
10. Holmes A, Jones MF, Stapleton M. A stability study of mechlorethamine hydrochloride
ointment using direct HPLC measurement of mechlorethamine (abstract). J Pharm Pharmacol
2002;54;S3-S4.
11. Personal communication. Durbin PLC 28th May 2012.
12. Personal communication. Mawdsleys Unlicensed Medicines 18th May 2012.
13. Ceptaris Therapeutics Website. Accessed via http://www.ceptaris.com on 16th May 2012.
14. Personal communication. Medical Information. European Medicines Agency (EMA) 23 rd May
2012.
15. Personal communication. UL Medicines 16th May 2012.
16. Personal communication. IdisPharma 14th May 2012.
17. Personal communication. Medical Information. Lundbeck Ltd UK 29th May 2012
From the NHS Evidence website www.evidence.nhs.uk
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Medicines Q&As
Quality Assurance
Prepared by
Kate Pickett, Medicines Q&A Pharmacist, Wessex Drug and Medicines Information Centre, University
Hospital Southampton NHS Foundation Trust.
Date Prepared
11th May 2012
Checked by
Sue Gough (based on the Q&A originally checked by Sandra Hicks),Critical Evaluation Pharmacist,
Wessex Drug and Medicines Information Centre, University Hospital Southampton NHS Foundation
Trust.
Date of check
20th September 2012
Search strategy
DRUGDEX System. Electronic version. Greenwood Village, Colorado: Thomson Micromedex.
Accessed via http://www.thomsonhc.com/
Martindale: The Complete Drug Reference. Accessed via http://www.medicinescomplete.com/
AHFS. Accessed via http://www.medicinescomplete.com/
Electronic Medicines Compendium. Accessed via http://www.medicines.org.uk
British Association of Dermatologists Website. Accessed via http://www.bad.org.uk/
BNF No 63 March 2012. Accessed via www.bnf.org
EMA Website. Accessed via http://www.ema.europa.eu/ema/
MHRA Website. Accessed via http://www.mhra.gov.uk/index.htm
NHS Evidence. Accessed via https://www.evidence.nhs.uk
New Drugs Online. Accessed via http://www.ukmi.nhs.uk/applications/NDO/dbSearch.asp
European Organisation for Research and Treatment of Cancer (EORTC) website. Accessed via
http://www.eortc.org/
International Society for Cutaneous Lymphomas. Accessed via http://www.cutaneouslymphoma.org/
NICE Website. Accessed via http://www.nice.org.uk/
FDA Website. Accessed via http://www.fda.gov/default.htm
Personal communication with IdisPharma via email 14th May 2012.
Personal communication with Durbin PLC via email 28th May 2012.
Personal communication with Pharamarama via email 15th May 2012.
Personal communication with UL Medicines via email 16th May 2012.
Personal communication with Mawdsleys Unlicensed Medicines via email 18th May 2012.
Personal communication with the European Medicines Agency (EMA) via email 23 rd May 2012.
Personal communication with Lundbeck Ltd UK via email 29th May 2012.
Ceptaris Therapeutics Website. Accessed via http://www.ceptaris.com
From the NHS Evidence website www.evidence.nhs.uk
4