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E-IJD® - CORRESPONDENCE
Year : 2022  |  Volume : 67  |  Issue : 5  |  Page : 627
Nicorandil-induced bullous fixed drug Eruption on the glans penis


1 Department of Dermatology, Venereology and Leprosy, R.G. Kar Medical College, Kolkata, West Bengal, India
2 Department of Cardiology, R.G. Kar Medical College, Kolkata, West Bengal, India

Date of Web Publication29-Dec-2022

Correspondence Address:
Sudip Kumar Ghosh
Department of Dermatology, Venereology and Leprosy, R.G. Kar Medical College, Kolkata, West Bengal
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijd.ijd_18_22

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How to cite this article:
Ghosh SK, Majumder B, Mondal S. Nicorandil-induced bullous fixed drug Eruption on the glans penis. Indian J Dermatol 2022;67:627

How to cite this URL:
Ghosh SK, Majumder B, Mondal S. Nicorandil-induced bullous fixed drug Eruption on the glans penis. Indian J Dermatol [serial online] 2022 [cited 2023 Feb 8];67:627. Available from: https://www.e-ijd.org/text.asp?2022/67/5/627/366106




Nicorandil, an oral vasodilator drug is commonly being used to treat angina.[1] The drug acts by stimulating guanylyl cyclase and increasing cyclic GMP (cGMP) level as well as by a second mechanism resulting in activation of the K+ channel and hyperpolarization.[2]

Although nicorandil is well tolerated by most patients, the use of this drug may be associated with an increased risk for oral and cutaneous skin ulceration, especially in the first year after incident exposure.[1] However, the precise mechanism of skin ulceration remains elusive. We report here a case of bullous fixed drug eruption (FDE) on the glans penis of a young man after nicorandil therapy, a hitherto unreported occurrence.

A 49-year-old man presented to our facility with a complaint of gradually progressive blistering over the glans penis for the preceding 2 days. It was associated with a sensation of pruritus and burning. There was no history of any topical application. He had no other constitutional symptom. He had no previous history of adverse effects from any drug. The patient was on isosorbide mononitrate (20 mg orally twice daily) and aspirin (75 mg orally once daily) for the last 3 years for ischemic heart disease. Three days before the appearance of the genital lesion, he consulted a cardiologist outside for his ailment. The cardiologist added a nicorandil tablet (5 mg) orally twice daily to the previous drugs to improve his chest pain. He had no history of high-risk sexual behavior.

An examination showed a bullous lesion containing sero-sanguineous fluid on the glans penis. There was no other muco-cutaneous lesion elsewhere in the body. The results of the biochemical panel, complete hemogram, and human immunodeficiency virus (HIV) serology revealed no abnormality.

With the presumption of nicorandil-induced drug eruption, the drug was stopped. Autoimmune bullous disorder and irritant or allergic contact dermatitis were also considered in the differential diagnosis.

The patient was advised to apply mometasone furoate cream twice daily for 3 weeks. The genital lesion gradually subsided leaving no sequel. We planned a drug challenge test 1 month after the episode. However, the patient was lost to follow-up. Six months after the initial episode, the patient returned back to the dermatology outpatient department with a complaint of a similar bullous lesion on the glans penis [Figure 1]. An examination revealed a bullous lesion containing hemorrhagic fluid. In the vicinity of the bulla, there was a settling bulla, the margins of which were clearly visible. In addition, there were multiple areas of hypo/depigmentation visible on the glans penis. From the previous prescriptions of the patient, we came to know that he had again taken nicorandil (5 mg orally twice daily) on the day before the presentation from outside although in a different trade name.
Figure 1: A bullous lesion on the glans penis containing hemorrhagic fluid. In the vicinity of the bulla, there was a settling bulla, and there were multiple areas of hypo/depigmentation visible on the glans penis

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This lesion appeared with an associated burning sensation within a few hours of taking nicorandil and was precisely located over the site of the previous lesion. A histopathological examination could not be performed, as the patient did not give consent for a skin biopsy. Based on the clinical history, morphology of the lesions, and history of recurrence at the identical site on inadvertent drug challenge, a diagnosis of fixed drug eruption (FDE) from nicorandil therapy was made. According to the objective causality assessment by the Adverse Drug Reaction Probability Scale (Naranjo),[2] this diagnosis was definite (score: 9). According to the World Health Organization-Uppsala Monitoring Centre (WHO-UMC) system for standardized case causality assessment,[3] the causal role of nicorandil, in this case, was certain.

The genital lesions subsided within a couple of weeks after the application of fluticasone propionate (0.05%) cream. This time also we strongly advised the patient not to take nicorandil in the future, and a drug card was provided to avoid serious consequences. The genital lesions did not recur within the next 1 year of follow-up. According to Hartwig's Severity Assessment Scale, the patient had a level 3 severities. This ADR was “definitely preventable” according to the modified Schumock and Thornton scale.

Fixed drug eruptions (FDE), first described by Brocq in 1894, are common, immune-mediated, recurrent muco-cutaneous eruptions that are characteristical of acute onset and appear as annular, edematous, sometimes blistering, reddish-brown to violaceous macules or plaques.[4],[5] Intra epidermal CD8þ T-cells resident in the FDE lesions clearly have a major causal role in the development of localized tissue damage.[6] Rechallenge with the suspected drug remains the most reliable method to diagnose FDE.[4] However, topical provocation on the sites of previous lesions has increasingly been adopted, as it may provide a simple and safer option for oral challenge. But the patch tests are not universally positive in cases of FDE.[7] When patch tests are negative or uncertain, an oral challenge may be carried out to confirm the association. However, a lesional patch test could not be done in the present patient due to operational difficulty to perform a patch test on the glans penis. Genital fixed drug eruptions, in particular, cause panic in the sufferer and confusion in the treating physician about the possible origin of the lesion. Sexually transmitted infections can be excluded by a negative temporal association between sexual exposure and the manifestation of the lesion (s) and by undertaking the appropriate laboratory investigations.[8] Several drugs are known to induce genital FDE [Table 1].[8],[9],[10],[11],[12]
Table 1: Drugs causing genital fixed drug eruptions[8],[9],[10],[11],[12]

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Nicorandil-related penile ulcers have also been sporadically reported; either as a solitary lesion or in combination with ulcers located somewhere else.[13] The pathogenesis of nicorandil-induced penile ulcers remains elusive. The “vascular steal” effect has been implicated, based on the fact of redistribution of arterial and venous flow caused by nicorandil and the fact that the penis is supplied by end arteries.[13] The first episode of penile FDE due to nicorandil may be clinically indistinguishable from penile skin ulceration due to it. However, an oral provocation test may prove the diagnosis of FDE.

In cases of genital FDE, the glans penis is the most common site of involvement, followed by the prepuce, vagina, and vulva.[8] Bullous pemphigoid may also rarely be present with bullous eruption over the glans penis.[14]

With the regular introduction of a large number of new drugs, the list of the offending drugs is ever-growing. However, even after an extensive search of the literature, we could not find any report of FDE owing to nicorandil therapy. In this report, we would also like to emphasize that the clinicians should keep FDE in the differential diagnosis of any patients presenting with recurrent bullous or ulcerative lesions on the genitalia.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
   References Top

1.
Lee M-TG, Lin H-Y, Lee S-H, Lee S-H, Chang S-S, Chen S-C, et al. Risk of skin ulcerations associated with oral nicorandil therapy: A population-based study. Br J Dermatol 2015;173:498-509.  Back to cited text no. 1
    
2.
Kukovetz WR, Holzmann S, Pöch G. Molecular mechanism of action of nicorandil. J Cardiovasc Pharmacol 1992;20:S1-7.  Back to cited text no. 2
    
3.
Naranjo CA, Busto U, Sellers EM, Sandor P, Ruiz I, Roberts EA, et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther 1981;30:239-45.  Back to cited text no. 3
    
4.
The use of the WHO-UMC system for standardized case causality assessment. Available from: http://safety_efficacy/WHOcausality_assehttps://www.who.int/medicines/areas/quality_safetyssment.pdf. [Last accessed on: 2020 May 17].  Back to cited text no. 4
    
5.
Gupta R. Drugs causing fixed drug eruptions: Confirmed by provocation tests. Indian J Dermatol Venereol Leprol 2003;69:120-1.  Back to cited text no. 5
[PUBMED]  [Full text]  
6.
Shiohara T. Fixed drug eruption: Pathogenesis and diagnostic tests. Curr Opin Allergy Clin Immunol 2009;9:316-21.  Back to cited text no. 6
    
7.
Duarte de Sousa IC. Fixed drug eruption. N Engl J Med 2011;365:e12.  Back to cited text no. 7
    
8.
Andrade P, Brinca A, Gonçalo M. Patch testing in fixed drug eruptions--A 20-year review. Contact Dermatitis 2011;65:195-201.  Back to cited text no. 8
    
9.
Sehgal VH, Gangwani OP. Genital fixed drug eruptions. Genitourin Med 1986;62:56-8.  Back to cited text no. 9
    
10.
Kanodia SK, Seth AK, Shukla SR. A study on genital fixed drug eruption in a tertiary care hospital. Journal of Clinical and Diagnostic Research 2011;5:700-2.  Back to cited text no. 10
    
11.
Nussinovitch M, Prais D, Ben-Amitai D, Amir J, Volovitz B. Fixed drug eruption in the genital area in 15 boys. Pediatr Dermatol 2002;19:216-9.  Back to cited text no. 11
    
12.
Fischer G. Vulvar fixed drug eruption. A report of 13 cases. J Reprod Med 2007;52:81-6.  Back to cited text no. 12
    
13.
Yap T, Philippou P, Perry M, Lam W, Corbishley C, Watkin N. Nicorandil-induced penile ulcerations: A case series. BJU Int 2011;107:268-71.  Back to cited text no. 13
    
14.
Mirza M, Zamilpa I, Wilson JM. Localized penile bullous pemphigoid of childhood. J Pediatr Urol 2008;4:395-7.  Back to cited text no. 14
    


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