imary rat hepatocytes, in Ames tests with Salmonella typhimurium (6 strains) andEscherichia coli, in the mouse lymphoma gene mutation tests, in a sex-linked recessive lethalmutation (Drosophila melanogaster) test, in chromosome aberration tests in human lymphocytes,in a cell transformation test with C3H/10T½ C18 mouse embryo fibroblasts cells, in a dominantlethal mutation test in male and female mice, and in micronucleus tests in mice and rats.
Impairment of Fertility
Itraconazole did not affect the fertility of male or female rats treated orally with dosage levels ofup to 40 mg/kg/day (6MRHD, based on mg/kg comparisons), even though parental toxicitywas present at this dosage level.
13.2 Animal Toxicology and/or Pharmacology
When itraconazole was administered intravenously to anesthetized dogs, a dose-related negativeinotropic effect was documented.
In three toxicology studies using rats, itraconazole (dosed in feed or via oral gavage) inducedbone defects at dosage levels as low as 20 mg/kg/day (3MRHD, based on mg/kg comparisons).
The induced defects included reduced bone plate activity, thinning of the zona compacta of thelarge bones, and increased bone fragility. At a dosage level of 80 mg/kg/day (12MRHD) over1 year or 160 mg/kg/day (25MRHD) for 6 months, itraconazole induced small tooth pulp withhypocellular appearance in some rats.
14 CLINICAL STUDIES
Overview of the Clinical Studies
Clinical studies in invasive mycoses listed in this section were conducted with itraconazole 100mg capsules. Dosage for TOLSURA is different from that of other itraconazole formulations.
TOLSURA is not interchangeable or substitutable with other itraconazole products [seeIndications and Usage (1), Dosage and Administration (2) and Clinical Pharmacology (12.3)]
14.1 Blastomycosis
Analyses were conducted on data from two open-label, non-concurrently controlled studies(N=73 combined) in patients with normal or abnormal immune status treated with the100 mgitraconazole capsules. The median dose was 200 mg/day (2 x 100 mg). A response for most signsand symptoms was observed within the first 2 weeks, and all signs and symptoms clearedbetween 3 and 6 months. Results of these two studies demonstrated substantial evidence of theeffectiveness of itraconazole for the treatment of blastomycosis compared with the naturalhistory of untreated cases.
14.2 Histoplasmosis
Analyses were conducted on data from two open-label, non-concurrently controlled studies(N=34 combined) in patients with normal or abnormal immune status (not including HIVinfectedpatients) treated with the 100 mg itraconazole capsules. The median dose was 200mg/day (2 x 100 mg). A response for most signs and symptoms was observed within the first 2weeks, and all signs and symptoms cleared between 3 and 12 months.
Results of these twostudies demonstrated substantial evidence of the effectiveness of itraconazole for the treatment ofhistoplasmosis, compared with the natural history of untreated cases.
14.3 Histoplasmosis in HIV-infected Patients
Data from a small number of HIV-infected patients treated with the 100 mg itraconazolecapsules suggested that the response rate of histoplasmosis in HIV-infected patients is similar tothat of non-HIV-infected patients. The clinical course of histoplasmosis in HIV-infected patientsis more severe and usually requires maintenance therapy to prevent relapse |
