Pregnancy outcome after in utero exposure to itraconazole: a prospective cohort study.

OBJECTIVE: This study was undertaken to determine whether itraconazole use during the first trimester of pregnancy was associated with increased risks of major malformations, spontaneous abortions, premature deliveries, and neonatal complications. STUDY DESIGN: In a prospective cohort study pregnant women exposed to oral itraconazole were matched with control subjects not exposed to any known teratogens. Primary outcome was the rate of major malformations. Secondary outcomes were live birth rate, rates of spontaneous abortion and therapeutic abortion, gestational age at delivery, birth weight, and neonatal complications. RESULTS: A total of 229 women exposed to itraconazole were reported to the manufacturer, 198 of whom used the drug during the first trimester of pregnancy. The rate of major malformations in the study group (156 live births) was 3.2%, compared with 4.8% in the control group (187 live births; relative risk, 0.67; 95% confidence interval, 0. 23-1.95). The rate of any pregnancy loss was higher in the exposed group (relative risk, 1.75; 95% confidence interval, 1.47-2.09). Birth weight was lower in the itraconazole group, although that difference may not be clinically significant. Gestational age at birth, rate of preterm delivery, Apgar scores at 1 and 5 minutes, and neonatal complications were comparable between the groups. CONCLUSION: Our study supports the hypothesis that the use of itraconazole during pregnancy is safe. Further surveillance and reporting of pregnancy outcomes will help to support this conclusion.

Safety of itraconazole pulse therapy for onychomycosis. An update.

After experience with more than 34 million patients over 10 years, the safety of itraconazole and its potential drug-drug interactions are well known. In clinical trials, the average incidence of adverse events with a 1-week pulse regimen was 18% in pooled safety data (n = 2,867); only 2.2% of patients dropped out. In direct comparative trials, the incidence of mild and reversible adverse effects was comparable for itraconazole and terbinafine (31% and 28%, respectively) during treatment. The rate of permanent withdrawal because of adverse events was 3.6% for itraconazole and 7.5% for terbinafine (P < .05). Itraconazole was significantly better tolerated as evaluated by the investigator and patients. The analysis of the elderly subpopulation showed that patients 65 and older tolerated itraconazole pulse well, with only 20% experiencing mild and reversible side effects (total group). In direct comparative trials, itraconazole also produced fewer adverse effects than terbinafine (13% vs 32%, respectively). As newer oral antifungal agents gain widespread use, clinicians need to be aware of their potential drug-drug interactions and their possibly serious adverse events. However, pooled data from the 1-week itraconazole pulse regimen indicated a favorable safety profile, and a dose increase to 400 mg had no impact on safety.

Safety of itraconazole in diabetic patients.

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.

Post-marketing cohort study comparing the safety and efficacy of flunarizine and propranolol in the prophylaxis of migraine.

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.

Postmarketing study of the use of flunarizine in vestibular vertigo and in migraine.

OBJECTIVE: This international postmarketing observational study of flunarizine was designed to evaluate, in routine clinical practice, the risk/benefit ratio of flunarizine in its approved indications, namely prophylaxis of migraine and treatment of vertigo. Comparator drugs were propranolol in migraine and betahistine in vertigo. The study was carried out by 498 general practitioners in Belgium, The Netherlands and Germany, whose participation had been requested by mail. In total 3186 patients were entered: 1601 in the two migraine cohorts and 1585 in the two vertigo cohorts. RESULTS: 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.

Risk of selected serious cardiac events among new users of antihistamines.

This retrospective cohort study examined the risk of selected serious cardiac events in new users of either astemizole or sedating antihistamines identified from the COMPASS Ohio Medicaid population of approximately 1 million active lives per year (1986-1992). (COMPASS is an automated claims database.) There were 15,585 patients in the astemizole group and 30,105 in the sedating antihistamines group. Reports of ventricular arrhythmia or sudden death occurring within 30 days of the first antihistamine claim were identified from Medicaid claims. Medical records were obtained and reviewed by a clinician for validity of diagnoses. Records for patients without a full 30 days of follow-up were sought in the National Death Index. Death certificates were obtained for all patients who died within 30 days of the first antihistamine claim. Of 53 cases identified, 6 were in the astemizole group and 47 in the sedating antihistamines group. The relative risk for all selected cardiac events among astemizole users compared with sedating antihistamine users was 0.25 (95% confidence interval: 0.11 to 0.58), and this estimate did not change substantially when adjusted for age; sex; race; recent history of cardiovascular disease, arrhythmias, asthma/pulmonary disease, or malignant neoplasms; or concomitant prescription of other drugs. This study provided no evidence that astemizole users are at increased risk for cardiac events in the first month of use when compared with users of sedating antihistamines.