Acenocoumarol is the most widely prescribed vitamin K antagonist (VKA) to prevent and treat thromboembolic disorders. It keeps a major place in many indications despite the introduction of new direct oral anticoagulants (DOACs). However, a narrow therapeutic range, an intra-individual variability and drug interactions may lead to serious adverse drug reactions.  Sometimes, a genetic or acquired resistance to this drug may lead to a risky situation. Hopefully, resistance to acenocoumarol is a very rare phenomen.Here in we present an unsusual case of a suspected resistance to acenocoumarol. This case was notified to the Tunisian National Center of Pharmacovigilance on October 2017 and registered under the number 2449/2017. A 67-year-old patient with hypertension, diabetes, and coronary disease was treated with captopril, atenolol, atorvastatin, and salicylic acid. In 2017, acenocoumarol treatment was introduced. At biological control, the prothrombin time (PT) was 100%. The doses of acenocoumarol were raised progressively with iterative controls of PT. PT was always 100% even when acenocoumarol reached the dose of 2 g/day. A resistance to acenocoumarol was suspected. The patient was referred to pharmacovigilance department for case analysis. During the patient interview, we discover that the patient was confusing acenocoumarol with atenolol. In fact, when his doctor was increasing the doses of acenocoumarol, the patient increased her intake of atenolol believing that it was acenocoumarol. A resistance to acenocoumarol was eliminated in this patient since she had never taken the drug. We highlight through this case the importance of patient’s interview. Explaining the indications and the potential adverse events of the drug to patients taking VKA is crucial to ensure a better efficiency of treatment without increasing the risk of bleeding complication.

Iopromide is one of the latest generations of non-ionic monomers (NIM) iodinated contrast media (CM). Its use is generally considered to be safe but can occasionally results in adverse events. The frequency of late adverse reactions to non-ionic monomers is between 0.52 and 23%. Delayed adverse reactions mainly manifest as skin reactions such as erythema, maculopapular exanthema and exceptionally as fixed drug eruption (FDE). To the best of our knowledge this is an exceptional case of bullous FDE diagnosed after administration of iopromide. This case was notified to the Tunisian Center of Pharmacovigilance on December 2020 and registered under the number 1925/2020. A 75-year-old woman, with a history of breast carcinoma underwent a chest CT scan with injection of contrast product (ultravist® iopromide) in November 2020. The same day, she developed four, 2 cm in diameter, well limited and oval shaped slightly erythematous itchy plaques on the trunk and right lower limb with a burning sensation. The next day, some of these lesions developed to bullae and erosions. There was not any pathological finding in the physical examination. Biopsy findings were in line with the clinical diagnosis of FDE. The skin lesions were treated with topical corticoids and showed complete resolution one month later with residual hyperpigmentation. Although very uncommon, bullous FDE induced by CM does exist and should be known by radiologists. In this case, we emphasize the importance of a thorough pharmacovigilance investigation with a detailed history and a careful examination of physical and histopathological findings, since patch tests expose the patient to the risk of reactivation and more severe reactions.

Fatma Zgolli 1 2, Imen Aouinti 1 2, Ons  Charfi1 2, Sarrah Kastalli1 2, Daghfous Riadh1 2, Sihem EL Aidli 1 2, Ghozlane Lakhoua 1 21National Center Chalbi Belkahia of Pharmacovigilance, 9 Avenue du Dr Zouhaier Essafi 1006, Tunis, Tunisia.2University of Tunis El Manar, Faculty of Medicine, Research unit: UR17ES12, 15 Rue Djebel Lakhdhar, La Rabta, 1007, Tunis, Tunisia.Leukocytoclasticvasculitis (LCV) is a hypersensitivity vasculitis. It may be secondary to infections, drugs, collagen tissue disorders, and malignities(1). Drug-induced LCV represents approximately 10-15% of LCV cases (2). Calcium channel blockers are little involved in this skin impairment. In fact, only few cases of LCV induced by amlodipine and diltiazem LCV were reported (3-5).We report herein an exceptional case of LCV induced by lercanidipine (LER). It was notified in the Tunisian National Centre of Pharmacovigilance.An 87-year-old woman was treated with flecainide and bisoprolol during ten years for cardiac disease. In 2016, she started LER (10 milligram per day). Seven months later, in January 2017, she developed a polymorphic and pruritic cutaneous eruption limited to forearms and legs. A symptomatic treatment (dermocoticoids and antihistamincs) was initiated without improvement of the eruption. Skin examination showed an erythematous maculopapular eruption, necrotic and purpuric lesions and ulcerations. The rest of the physical examination was normal. Laboratory findings showed an accelerated erythrocyte sedimentation rate and a high level of C-Reactive Protein (82mg/l), the serum protein electrophoresis was normal. The diagnosis of vasculitis was suspected by dermatologists. A skin biopsy was performed and revealed characteristic perivascular neutrophilic infiltrates, a leukocytoclasis and extravasated erythrocytes in favour of LCV. The responsibility of LER was suspected and this medication was stopped. The other drugs were continued. The pruritus and cutaneous lesions started to subside few days later after the drug cessation. Symptoms had completely resolved in two weeks.LCV is the inflammation of small blood vessels.Its clinical features are generally a palpable purpura on gravity-dependent body parts. Also it can occur as urticaria, ulcers, nodules or haemorrhagic bullae (6). It is diagnosed by histopathological evaluation of the biopsy from the lesion.LCV is idiopathic up to 50% of the cases.  Infections and drugs are the most common triggers for secondary LCV. Drug-induced LCV is approximately 10-15% of cases (2). Merkel PA had defined drug-induced LCV as “any case of inflammatory vasculitis in which a specific drug is established as a causal agent of disease when other forms of vasculitis are excluded” (7). The onset is typically 1 to 3 weeks after drug initiation (2).The exact pathogenesis of drug-induced LCV remains unclear, but studies suggest that the offending drug may act as a hapten, which stimulates antibody production and immune complex formation. These immune complexes are subsequently deposited in postcapillaryvenules leading to complement activation and vascular damage (8).More than 100 drugs are implicated as causes of drug-induced LCV. Commonly, offending drugs include antibiotics such as beta-lactams, erythromycin, clindamycin, vancomycin, sulfonamides, and other molecules such as furosemide, allopurinol, NSAIDs, amiodarone, gold, thiazides, phenytoin, beta-blockers, TNF-alpha inhibitors, selective serotonin reuptake inhibitors, metformin, warfarin, valproic acid, among many others (2).In our case, the responsibility of LER was retained in front of the onset of the reaction after a compatible delay (seven months after beginning the treatment), and mainly the improvement of the condition after drug withdrawal. According to Naranjo probability scale, the score was 4 (9).In literature, calcium channel blockers are little involved in this skin impairment. After a MEDLINE search (vasculitis, drug-induced vasculitis, leucocytoklasis, calcium channel blockers, lercanidipine, amlodipine, nifedipine, diltiazem), we have only found few cases of LCV induced by amlodipine and diltiazem(3–5). Concerning LER, only one previous case of an enalapril-LER combination induced LCV was reported (10). But, no cases are available on drug-induced LCV associated with LER only. Thus, this is the first reported case of LCV induced by LER.The drug-induced LCV therapeutic approach is based on antigen removal and the treatment of the cutaneous lesions. Withdrawal of the precipitating drug and minimization of stasis by compression, elevation, and use of non steroidal anti-inflammatory drugs are employed. Antihistamines, systemic corticosteroids or other immunosuppressant may be required when the cutaneous lesions are progressive (6,8).This report is, to the best of our knowledge, the first case of LCV induced by LER. Considering the wide use of LER in hypertensive population, prescribers should be aware of the possibility of occurrence of cutaneous LCV as a side effect of this drug.References:1) Goeser MR, Laniosz V, Wetter DA. A Practical Approach to the Diagnosis, Evaluation, and Management of Cutaneous Small-Vessel Vasculitis. Am J ClinDermatol 2014;15(4):299-306.(2) Baigrie D, Bansal P, Goyal A, et al. LeukocytoclasticVasculitis (Hypersensitivity Vasculitis. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2020.(3) del Río Fernández MC, Plagaro Cordero ME, de FrutosArribas JF, del PozoRomán T, Martín Escudero JC. Leukocytoclasticvasculitis in relation to amlodipine administration. Rev ClinEsp 1995;195(10):738-9.(4) Sheehan-Dare RA, Goodfield MJ. Severe cutaneous vasculitis induced bydiltiazem. Br J Dermatol 1988;119(1):134.(5) Lachapelle J-M, Ramelet A-A. Exercise-induced vasculitis and amlodipine. Louvain Med 2014;133:103-6.(6) Ha YJ, Han YJ, Choi YW, Myung KB, Choi HY. Sibutramine (Reductil®)-Induced Cutaneous LeukocytoclasticVasculitis: A Case Report. Ann Dermatol 2011;23(4):544-7.(7) Merkel PA. Drug-induced vasculitis. Rheum Dis Clin North Am. 2001;27(4):849-862.(8) Gupta M. Levetiracetam-induced leukocytoclasticvasculitis. Indian J Pharmacol. 2017;49(1):124-6.(9) Naranjo CA, Busto U, Sellars EM, et al. A method for estimating the probability of adverse drug reactions. ClinPharmacolTher 1981; 30: 239-45(10) Ouni B, Fathallah N, Ben‐Sayed N, Slim R, Abdessayed N, Anoun J, et al. Enalapril‐lercanidipine combination induced leukocytoclasticvasculitis: A case report. Br J ClinPharmacol 2020; 10.1111/bcp.14346.