e a-t 6/2015a

ADVERSE DRUG REACTIONS MISSING FROM PRODUCT INFORMATION

Gliptins and bullous pemphigoid: A French regional pharmacovigilance centre evaluated 41 reports of cases of bullous pemphigoid that are attributed to the class of antidiabetic agents known as gliptins (DDP-4 inhibitors) (1). Vildagliptin (GALVUS, JALRA; no longer sold in Germany) was involved in 28 cases, sitagliptin (JANUVIA, XELEVIA) in 12 cases and saxagliptin (ONGLYZA) in 1 case. As is typical with bullous pemphigoid, primarily older patients were affected: the mean age was 72 years. The period of treatment after which the adverse reaction occurred varied greatly: after 10 days to 24 months, on average after 9 months. According to the evaluation of data from the French pharmacovigilance database, gliptins are involved in 20% of the reports on this autoimmune disorder causing blistering of the skin. According to a case-control study, there is a 200-fold greater probability that patients with bullous pemphigoid will have taken vildagliptin than patients without pemphigoid (95% confidence interval 125-323). The other two gliptins also showed a significant association with the skin disease (1). In the database (2) of the Federal Institute for Drugs and Medical Devices (BfArM), we found eight reports of pemphigoid associated with treatment with vildagliptin and four with sitagliptin. The mechanism by which the damage occurs is unclear. The German Summaries of Product Characteristics (SPCs) only mentions bullous skin lesions in connection with vildagliptin (3), which is no longer on offer. Due to the suspicion of severe adverse effects such as pancreatitis and the lack of proof of benefit from studies with clinical end points, we have repeatedly advised against the use of DPP-4 inhibitors (e.g. a-t 2013; 44: 73-5).

Anal fissure with the anti-acne retinoid isotretinoin (ISOGALEN, generics): The Dutch pharmacovigilance centre Lareb reports the cases of two young women who developed an anal fissure four days and two weeks, respectively, after starting treatment with the oral retinoid isotretinoin (ISOGALEN, generics), approved exclusively for use in severe acne (4). The BfArM has received one such report (2), and the WHO 310 (4). In the literature there are reports of four patients with acne who developed anal fissures under treatment with isotretinoin after a latency period of a few days to up to two months. Following discontinuation of the retinoid, the symptoms resolved within two to four weeks, while with an unchanged or reduced dose of the drug and symptomatic treatment of the fissures, for example with nitrate cream, symptoms took up to four to eight months to resolve (4). A possible mechanism of damage could be that the skin dryness that is typical with retinoids also affects the anoderm and promotes mechanical trauma, for example due to hard stools. However, there is no evidence to support this. In light of the unambiguous individual reports and the large number of reports received by the WHO, this adverse effect should be included in the Summaries of Product Characteristics (SPCs) for isotretinoin compounds (4).

The antifungal terbinafine (LAMISIL, generics) and erectile dysfunction: The allylamine derivative terbinafine (LAMISIL, generics) is an oral antifungal used as a reserve agent, amongst other reasons due to frequent adverse effects such as impairment of taste and even total loss of taste lasting for months and even years (a-t 2010; 41: 98), as well as hearing impairment and even deafness (a-t 2011; 42: 56). Over a period of two decades, the Dutch pharmacovigilance centre Lareb has received seven reports of erectile dysfunction in association with terbinafine, occurring a few hours to four months after the start of treatment. In four of five men, the potency problems resolved after discontinuation of the antifungal, in one with positive re-exposure. Two men did not discontinue terbinafine and the impotence persisted (5). In the literature there is one report of erectile dysfunction (6), and in the adverse drug reaction database of the BfArM (2) there are four. The WHO overviews 57 reports up to summer 2014 (4). There is no relevant advice in the prescribing information.