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Background: Onychomycosis and dermatomycoses can result in serious complications in patients with underlying chronic diseases such as diabetes. To avoid these complications, these dermatological disorders need to be treated efficiently, for example with the triazole antifungal itraconazole. Itraconazole can inhibit the metabolism of drugs by CYP 3A4 and therefore might affect the efficacy of antidiabetic agents. Objective: To investigate this, we assessed the safety of itraconazole in diabetic patients with onychomycosis or dermatomycoses. Methods: We reviewed pharmacokinetic and safety data from clinical trials and postmarketing surveillance over the past 10 years. Results: Postmarketing surveillance (a review of all adverse-event reports in patients receiving itraconazole concomitantly with insulin or an oral antidiabetic agent) revealed 15 reports suggestive of hyperglycemia and 9 reports suggestive of hypoglycemia; in most patients, no change in antidiabetic effect was reported. From clinical trials including a total of 189 diabetic patients treated with itraconazole for various infections (mainly systemic infections and vaginal candidiasis), only one itraconazole-related adverse event was recorded; this was a case of aggravated diabetes in a renal transplant recipient who was also receiving cyclosporine. Adverse effects due to drug-drug interactions are not expected in diabetic patients receiving oral antidiabetic agents that are not metabolized through the CYP 3A4 system (e.g. tolbutamide, gliclazide, glibenclamide, glipizide and metformin). Conclusion: Itraconazole can be used safely and efficiently for the treatment of dermatological disorders in diabetic patients.

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A comparative post-marketing surveillance study of the safety and efficacy of flunarizine and propranolol in the treatment of migraine was carried out. General practitioners in Belgium and the Netherlands each recruited patients for whom they would prescribe one of the study medications in the normal course of their treatment and recorded all medical events on follow-up forms for up to 8 months. A total of 1601 migraine patients were enrolled; 838 in the flunarizine cohort and 763 in the propranolol cohort. Propranolol was somewhat better than flunarizine in reducing the severity of migraine attacks, although this may have been due to a selection bias. Discontinuations of therapy due to events considered likely to be treatment-related were mostly due to the recognized side effects of the two drugs. As regards the occurrence of depressions, a total of 58 patients had depressive events, 34 in the flunarizine cohort and 24 in the propranolol cohort. Whereas migraine itself appears to be associated with an increased risk of depression, the number of previous migraine treatments was shown to be an additional risk factor for the development of depression in patients receiving flunarizine as was a history of depression. Overall, there was no appreciable difference in the risk/benefit ratio between flunarizine and propranolol.

In the migraine study, treatment results with propranolol tended to be somewhat better than those with flunarizine, but a selection bias cannot be excluded. There was no clear difference regarding efficacy between flunarizine and betahistine in the vertigo study. The safety evaluation focused on extrapyramidal symptoms (EPS) and depression. Overall, EPS were noted in only four patients, two in the vertigo-betahistine and two in the migraine-flunarizine cohort. A total of 70 patients developed depressive symptoms (34 in the flunarizine and 24 in the propranolol migraine cohorts, but only 7 in the flunarizine and 5 in the betahistine vertigo cohorts). Patients with migraine were clearly more prone to depression than patients with vertigo, regardless of their treatment. Additional risk factors for depression were a history of depression, and, in the migraine flunarizine cohort, a high number of previous migraine treatments.

IntroductionWe evaluated cardiovascular disease (CVD) risk associated with darunavir treatment and examined the demographic/clinical characteristics of darunavir users based on data from Janssen-sponsored clinical trials, post-marketing pharmacovigilance databases, and administrative claims databases.MethodsFirst, selected CVD events [myocardial infarction, stroke, sudden death, invasive cardiovascular procedures (coronary artery angioplasty or bypass, or carotid endarterectomy)] were analyzed in 19 Janssen-sponsored phase 2–4 studies (incidence rates estimated from pooled data; 95% confidence intervals derived from Poisson distribution). Second, analyses were conducted to identify spontaneously reported CVD events in post-marketing pharmacovigilance databases and evaluate disproportional reporting of CVD events for darunavir (using Empirical Bayesian Geometric Mean scores). Third, baseline demographic/clinical characteristics of human immunodeficiency virus-1 (HIV-1)–infected patients in general and new users of darunavir and atazanavir were explored using three US administrative claims databases.ResultsAmong 19 Janssen-sponsored clinical trials (treatment durations ≤ 6 years), the CVD event rate (95% CI) per 1000 person-years (pooled population; n = 5713) was 6.15 (2.91–11.89), and was lower for patients who used once-daily darunavir/ritonavir 800/100 mg [0.71 (0.16–3.05); n = 1326] versus twice-daily darunavir/ritonavir 600/100 mg [9.21 (4.94–16.04); n = 3058]. Trend analysis of post-marketing pharmacovigilance data showed that cumulative CVD event reporting rates for darunavir users (any dose) generally declined over time. Spontaneously reported CVD events were not disproportionately reported with darunavir versus other protease inhibitors. Compared with the general HIV-1–infected population and atazanavir users, higher proportions of darunavir users were male, older, and had comorbidities associated with CVD risk based on results from US administrative claims databases.ConclusionsThis comprehensive review of Janssen-sponsored clinical trial, post-marketing, and epidemiological data does not suggest that CVD should be considered an important risk for users of darunavir.Electronic supplementary materialThe online version of this article (10.1007/s40268-018-0238-8) contains supplementary material, which is available to authorized users.

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