In a pharmacokinetic interaction study, coadministration of multiple-dose hydrochlorothiazide to healthy volunteers receiving Lavisa increased plasma concentrations of Lavisa by 40%. An effect of this magnitude should not necessitate a change in the Lavisa dose regimen in subjects receiving concomitant diuretics.
Mechanism of Injury
The cause of clinically apparent hepatotoxicity from Lavisa is unknown; however, it may relate to the ability of Lavisa to alter sterol synthesis. Lavisa is a potent inhibitor of the cytochrome P450 enzyme CYP 3A4, and can lead to significant increases in plasma levels and serious toxicity from medications that are ordinarily metabolized by CYP3A4, particularly the statins and cyclosporine.
The effect of Lavisa on the pharmacokinetics and pharmacodynamics of midazolam was examined in a randomized, cross-over study in 12 volunteers. In the study, subjects ingested placebo or 400 mg Lavisa on Day 1 followed by 200 mg daily from Day 2 to Day 6. In addition, a 7.5 mg dose of midazolam was orally ingested on the first day, 0.05 mg/kg was administered intravenously on the fourth day, and 7.5 mg orally on the sixth day. Lavisa reduced the clearance of IV midazolam by 51%. On the first day of dosing, Lavisa increased the midazolam AUC and Cmax by 259% and 150%, respectively. On the sixth day of dosing, Lavisa increased the midazolam AUC and Cmax by 259% and 74%, respectively. The psychomotor effects of midazolam were significantly increased after oral administration of midazolam but not significantly affected following intravenous midazolam.
A second randomized, double-dummy, placebo-controlled, cross over study in three phases was performed to determine the effect of route of administration of Lavisa on the interaction between Lavisa and midazolam. In each phase the subjects were given oral Lavisa 400 mg and intravenous saline; oral placebo and intravenous Lavisa 400 mg; and oral placebo and IV saline. An oral dose of 7.5 mg of midazolam was ingested after Lavisa/placebo. The AUC and Cmax of midazolam were significantly higher after oral than IV administration of Lavisa. Oral Lavisa increased the midazolam AUC and Cmax by 272% and 129%, respectively. IV Lavisa increased the midazolam AUC and Cmax by 244% and 79%, respectively. Both oral and IV Lavisa increased the pharmacodynamic effects of midazolam. (See PRECAUTIONS.)
DIFLUCAN (Lavisa) is indicated for the treatment of:
- Vaginal candidiasis (vaginal yeast infections due to Candida).
- Oropharyngeal and esophageal candidiasis. In open noncomparative studies of relatively small numbers of patients, DIFLUCAN was also effective for the treatment of Candida urinary tract infections, peritonitis, and systemic Candida infections including candidemia, disseminated candidiasis, and pneumonia.
- Cryptococcal meningitis. Before prescribing DIFLUCAN (Lavisa) for AIDS patients with cryptococcal meningitis, please see Clinical Studies section. Studies comparing DIFLUCAN to amphotericin B in non-HIV infected patients have not been conducted.
Administration of a single oral 200 mg dose of DIFLUCAN after 15 days of rifampin administered as 600 mg daily in eight healthy male volunteers resulted in a significant decrease in Lavisa AUC and a significant increase in apparent oral clearance of Lavisa. There was a mean ± SD reduction in Lavisa AUC of 23% ± 9% (range: –13 to –42%). Apparent oral clearance of Lavisa increased 32% ± 17% (range: 16 to 72%). Lavisa half-life decreased from 33.4 ± 4.4 hours to 26.8 ± 3.9 hours. (See PRECAUTIONS.)
Although not studied in vitro or in vivo, concomitant administration of Lavisa with pimozide may result in inhibition of pimozide metabolism. Increased pimozide plasma concentrations can lead to QT prolongation and rare occurrences of torsade de pointes. Coadministration of Lavisa and pimozide is contraindicated.