Advisory Committee on Safety of Medicinal Products (ACSoMP): Measures to minimize the risk of ocular adverse events with miltefosine

The WHO Advisory Committee on Safety of Medicinal Products (ACSoMP), supports the recommendations of the WHO ad-hoc Multidisciplinary Technical Group (MTG) which was set up to investigate a signal of ocular adverse events following the use of miltefosine, and provides the following advice to minimize the risks of ocular adverse events in patients exposed to miltefosine:

Information for patients

• Before starting the treatment containing miltefosine, tell your healthcare professional if you currently have any eye problem or history of eye problem as an ocular examination should be done first in these situations
• If you experience any eye discomfort during the treatment, discontinue miltefosine immediately and contact your nearest healthcare centre or a healthcare professional as soon as possible
• Please contact your nearest healthcare professional if you have any question or concern.

Information for healthcare professionals

• Before starting the miltefosine treatment the history of eye disorders should be collected and an eye examination should be done as appropriate.
• In case of current or past history of ocular disorder, the benefits and the risks of treating a patient with miltefosine should be carefully considered, and advice from an ophthalmologist should be sought where feasible.
• All patients should be informed before starting the treatment that in case of eye problems during the treatment (e.g. red eyes, increased watering, eye pain, blurred vision) they should discontinue miltefosine and contact their healthcare professional immediately.
• If ocular complications occur and a connection with miltefosine cannot be excluded, miltefosine should be discontinued immediately and an alternative treatment for leishmaniasis should be initiated if necessary. Since miltefosine has a very long half-life (>6 days), it is possible that ocular changes will not be reversible without treatment even after discontinuation of miltefosine. Therefore, an eye specialist should be consulted in such cases to avoid the possibility of permanent damage.
  • Please refer to the Guiding principles, provided below, for prevention, early detection and management of eye complications in patients treated with miltefosine, for further information.
• Suspected adverse events should be reported to local health authorities and the national pharmacovigilance programme without delay.

Background information

Miltefosine is an oral anti-infective and one of the medicines with established efficacy in the treatment of some forms of leishmaniasis, a parasitic infection spread by the bite of infected female phlebotomine sandflies. Leishmaniasis can take different clinical forms, including cutaneous leishmaniasis, mucocutaneous leishmaniasis, and visceral leishmaniasis (VL).

Post-Kala-Azar Dermal Leishmaniasis (PKDL) is a sequela which can generally occur 6 months to several years after apparent cure of VL. Although uncommon, leishmanial ocular manifestations have been reported, and keratitis and uveitis can also occur with the disease. A 12-week treatment course of Miltefosine is used to treat PKDL specific to VL endemic countries in South-East Asia. 

Following reports of ocular disorders following miltefosine use originating mostly from South-Asia, ACSoMP had recommended WHO to further investigate this issue[1]. The proposed method was discussed with ACSoMP in June 2022 and WHO established an ad-hoc Multidisciplinary Technical Group (MTG) to advise on the causality, the risk characteristics and frequency, risk minimization measures, risk communication, remaining uncertainties and the need for further studies.

To facilitate the work from the MTG, the WHO, supported by the German National Regulatory Authority (BfArM) and the Uppsala Monitoring Centre (UMC), collected and compiled all available evidence and information on the causal relationship between reports of serious ocular events and exposure to miltefosine.

Based on the available data, the MTG considered that a causal relationship between ocular adverse events and the exposure to miltefosine is at least a reasonable possibility. The risk of ocular adverse events, such as redness of the eye, inflammation of different eye structures (keratitis, scleritis, uveitis) and visual impairment up to blindness has been observed mostly during the treatment of patients with PKDL in South Asia in both men and women, including in children under 18-year-old, and mostly beyond 28 days of treatment. No further risk factor could be identified. When the information was available, most of the cases resolved after miltefosine was withdrawn, sometimes after a symptomatic treatment was started. However, in some cases, the adverse ocular event led to permanent loss of sight. The frequency of adverse ocular events during treatment with miltefosine could not be estimated based on the available data, and the mechanism of action remains unclear.

The ACSoMP discussed during its meeting on 14 December 2022 the issue of ocular adverse events with miltefosine and advised the following (https://covid.comesa.int/publications/m/item/2022-december-acsomp-recommendations):

• the inclusion of the proposed warning and list of ocular adverse events in the summary of product characteristics and the patient information leaflet for miltefosine. All stakeholders should ensure that product information is provided in a language that is understood by local healthcare professionals and patients to enable effective risk communication;
• the additional guiding principles for the prevention, early detection and management of eye complications in patients treated with miltefosine;
• the development of a patient information brochure by WHO based on the MTG recommendations to facilitate risk communication;
• communication via a statement on WHO’s website, the publication of the public assessment report and publications in peer-reviewed journals
• communication of conclusions through disease programmes and to investigators of identified ongoing clinical trials;
• in countries where it is feasible, a Direct Healthcare Professional Communication by national regulatory authorities;
• the use of active surveillance (such as a cohort event monitoring (CEM) study), supported by a follow-up questionnaire, to characterize the risk and its frequency and to assess the effectiveness of the risk minimization measure;
• Collaboration of PV programme with disease progamme, to ensure efficient real time data sharing, rapid analysis and interpretation;
• implement a study analysing miltefosine pharmacokinetics, the presence of parasites and immune reactions in patients with PKDL to assess the specificity and causality of this adverse event in these patients.

As a precautionary measure, and although the risk appears to be mostly reported in patients with PKDL in South-Asia, the above recommendations and advisories should also be considered in other patients exposed to miltefosine.

Further details are provided in annex attached, including:

• Wording recommendations for product information
• Guiding principles for prevention, early detection and management of eye complications in patients treated with miltefosine
• A follow-up questionnaire for incorporation into active surveillance projects
  

Contact: pvsupport@who.int