Latest updates on the risk of lymphoma with topical calcineurin inhibitors (TCIs)

Summary of findings from the US Food and Drug Administration’s Paediatric Advisory Committee review

HSA has been monitoring the developments of the risk of lymphoma related to topical calcineurin inhibitors (TCIs) and would like to provide healthcare professionals with new safety updates on this topic.

Tacrolimus (Protopic® ointment, J&J) and pimecrolimus (Elidel® cream, Novartis), are the two TCIs licensed in Singapore since March 2004 and January 2003, respectively. Protopic® was approved as second-line therapy for the treatment of moderate to severe atopic dermatitis (AD) while Elidel® was approved as second-line therapy for the short-term and intermittent long-term treatment of mild to moderate AD in patients two years of age and older.

Summary of previous regulatory actions and clinical findings

This safety issue dates back to 2005 when the US Food and Drug Administration (FDA) issued a public health advisory and implemented a boxed warning for both tacrolimus and pimecrolimus on risk of malignancy. This arose due to increasing concern over the use of TCIs as first-line and off-label therapy, post-marketing reports of malignancy in children and adults, and carcinogenicity findings from animal studies1. In May 2011, the US FDA held a Paediatric Advisory Committee (PAC) meeting to discuss the findings from epidemiologic association studies2-4. The studies reviewed suggest that there is an increased risk of lymphoma, particularly T-cell lymphoma, in TCI-treated AD patients compared to untreated AD patients.

In one of the reviewed studies, Hui et al (n = 953,064) observed a significantly higher risk of cutaneous T-cell lymphoma, in topical tacrolimus-exposed AD patients (hazard ratio (HR) = 3.13, 95% CI 1.41 – 6.94); topical pimecrolimus-exposed AD patients were also at an increased risk (HR = 1.86, 95%CI 0.71 – 4.87) although not statistically significant.5 Likewise, a nested case-control study by Arana et al (n = 625,915) also reported an increased risk of T-cell lymphoma with the use of topical tacrolimus (adjusted odd ratio (OR) = 4.95, 95% CI 1.86 – 13.19), but not with topical pimecrolimus (adjusted OR = 0.85, 95% CI 0.25 – 2.90).6 Another study reviewed was by Schneeweiss et al who performed a nested case-control analysis, and observed a four- and three-fold increase in lymphoma risk in patients receiving high cumulative amount of topical pimecrolimus (>100 g) and corticosteroids (>100 g), respectively, compared with those receiving low cumulative amount of topical corticosteroids (≤60 g); tacrolimus analysis results were not interpretable due to small sample size.7

It is noteworthy that, although all of the studies included a proportion of paediatric patients, little information specific to this population was provided because the analyses were not stratified by age. The causal role of TCIs in lymphoma remains difficult to ascertain given the study limitations, such as misclassification of cases, relatively short duration of follow-up, and potential study biases. The PAC concurred that the applicability of the findings specifically to the paediatric population and to the long-term safety profile of TCIs remains questionable and agreed that the current US product labelling adequately represents the risks and benefits of Protopic® and Elidel® for their respective indicated use. US FDA was advised to continue monitoring occurrences of cancer cases with the use of these products and to update the PAC again with an updated literature review and an analysis from the registry on cancer cases at 5 years.

Similarly in May 2012, the UK Medicines and Healthcare products Regulatory Agency (MHRA) issued a Direct Healthcare Professional Communication to update healthcare professionals on the results of the above-mentioned epidemiological studies, and to remind them of risk minimisation measures for Protopic®. Further studies have also been planned, in agreement with the European Medicines Agency (EMA), to investigate the risk of cutaneous T-cell lymphoma following TCI therapy.

Local situation and HSA's advisory

In 2005, HSA and its Pharmacovigilance Advisory Committee (PVAC) had reviewed the available safety information and the recommendations for safe use of TCIs were published in the December 2005 issue of the Adverse Drug Reaction News bulletin.8 Since their initial approval, the local package insert (PI) for Protopic® and Elidel® have been updated several times to strengthen the safety labelling. To date, HSA has not received any local reports of lymphoma associated with the use of TCIs.

Healthcare professionals are reminded to adhere to the following precautions to minimise the risks of TCIs which are reflected in the local PI:

• Continuous long-term use of TCIs in any age group should be avoided, and application limited to areas of involvement with atopic dermatitis.

• TCIs are not indicated for use in children less than 2 years of age.

• Use of topical tacrolimus in children aged 2 to 16 years of age is restricted to the lower strength preparation (Protopic® 0.03% ointment).

• TCIs should not be applied to lesions that are considered to be potentially malignant or pre-malignant.

• Lymphadenopathy present at initiation of therapy should be investigated and kept under review. Patients who receive TCIs, and who develop lymphadenopathy should be monitored to ensure that the lymphadenopathy resolves. In case of persistent lymphadenopathy, the aetiology of the lymphadenopathy needs to be investigated. In the absence of a clear aetiology for the lymphadenopathy or in the presence of acute infectious mononucleosis, discontinuation of therapy should be considered.

• TCIs should not be used in patients with congenital or acquired immunodeficiencies or in patients on therapy that causes immunosuppression. Excessive exposure of the skin to ultraviolet light including light from a solarium, or therapy with PUVA (psoralen and ultraviolet A [UVA]), UVA or ultraviolet B (UVB) should be avoided during treatment with TCIs.

Healthcare professionals are encouraged to report any adverse reactions suspected to be related to the use of Protopic® or Elidel® to the Vigilance Branch of HSA.

References

1. http://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/PediatricAdvisoryCommittee/UCM208037.pdf

2. http://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/PediatricAdvisoryCommittee/ucm261385.pdf

3. http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/PediatricAdvisoryCommittee/UCM255139.pdf

4. http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/PediatricAdvisoryCommittee/UCM255140.pdf

5. Ann Pharmacother. 2009;43:1956-63.

6. Pharmacoepidemiol Drug Safety 2010;19:S12 (Abstract).

7. Dermatology 2009;219:7-21.

8. HSA ADR News bulletin December 2005; Vol. 7 No. 3.