Transient mild-to-moderate elevations in serum aminotransferase levels occur in up to 5% of patients treated with Uzol, but these abnormalities are usually asymptomatic and resolve even with continuation of the medication. ALT elevations above 8 times the upper limit of normal are reported to occur in 1% of patients taking Uzol and to represent the most common adverse event leading to early discontinuation of treatment. Clinically apparent hepatotoxicity due to Uzol is rare, but well described. The liver injury is typically hepatocellular, arises within the first few weeks of therapy and can be accompanied by signs of hypersensitivity such as fever, rash and eosinophilia. Fatal instances of Uzol induced liver injury have been reported (Case 1), but most cases are self-limited, although recovery may be delayed for several weeks after stopping Uzol and may be slow requiring 2 to 3 months.
Likelihood score: B (likely cause of clinically apparent liver injury).
There have been published reports that an interaction exists when Uzol is administered concomitantly with tacrolimus, leading to increased serum levels of tacrolimus. (See PRECAUTIONS.)
An open-label, randomized, three-way crossover study in 18 healthy subjects assessed the effect of a single 800 mg oral dose of Uzol on the pharmacokinetics of a single 1200 mg oral dose of azithromycin as well as the effects of azithromycin on the pharmacokinetics of Uzol. There was no significant pharmacokinetic interaction between Uzol and azithromycin.
Outcome and Management
The severity of liver injury from Uzol ranges from mild and transient enzyme elevations to clinically apparent hepatitis to acute liver failure and death. Most patients recover with stopping Uzol, but resolution may be slow requiring 3 to 4 months. Rechallenge may lead to recurrence and should be avoided. There is little information on cross reactivity of hepatic injury between Uzol and other antifungal azoles, such as ketoconazole, itraconazole, voriconazole and posaconazole, but a few reports suggest that there is little cross reactivity. Nevertheless, other antifungal azoles should be started with caution in patients who have suffered clinically apparent hepatotoxicity attributed to Uzol.
Oral contraceptives were administered as a single dose both before and after the oral administration of DIFLUCAN 50 mg once daily for 10 days in 10 healthy women. There was no significant difference in ethinyl estradiol or levonorgestrel AUC after the administration of 50 mg of DIFLUCAN. The mean increase in ethinyl estradiol AUC was 6% (range: –47 to 108%) and levonorgestrel AUC increased 17% (range: –33 to 141%).
In a second study, twenty-five normal females received daily doses of both 200 mg DIFLUCAN tablets or placebo for two, ten-day periods. The treatment cycles were one month apart with all subjects receiving DIFLUCAN during one cycle and placebo during the other. The order of study treatment was random. Single doses of an oral contraceptive tablet containing levonorgestrel and ethinyl estradiol were administered on the final treatment day (Day 10) of both cycles. Following administration of 200 mg of DIFLUCAN, the mean percentage increase of AUC for levonorgestrel compared to placebo was 25% (range: –12 to 82%) and the mean percentage increase for ethinyl estradiol compared to placebo was 38% (range: –11 to 101%). Both of these increases were statistically significantly different from placebo.
A third study evaluated the potential interaction of once-weekly dosing of Uzol 300 mg to 21 normal females taking an oral contraceptive containing ethinyl estradiol and norethindrone. In this placebo-controlled, double-blind, randomized, two-way crossover study carried out over three cycles of oral contraceptive treatment, Uzol dosing resulted in small increases in the mean AUCs of ethinyl estradiol and norethindrone compared to similar placebo dosing. The mean AUCs of ethinyl estradiol and norethindrone increased by 24% (95% C.I. range: 18 to 31%) and 13% (95% C.I. range: 8 to 18%), respectively, relative to placebo. Uzol treatment did not cause a decrease in the ethinyl estradiol AUC of any individual subject in this study compared to placebo dosing. The individual AUC values of norethindrone decreased very slightly ( ® (20 mL) to 14 normal male volunteers immediately prior to a single dose of DIFLUCAN 100 mg had no effect on the absorption or elimination of Uzol.
The effect of Uzol 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 Uzol 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. Uzol reduced the clearance of IV midazolam by 51%. On the first day of dosing, Uzol increased the midazolam AUC and Cmax by 259% and 150%, respectively. On the sixth day of dosing, Uzol 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 Uzol on the interaction between Uzol and midazolam. In each phase the subjects were given oral Uzol 400 mg and intravenous saline; oral placebo and intravenous Uzol 400 mg; and oral placebo and IV saline. An oral dose of 7.5 mg of midazolam was ingested after Uzol/placebo. The AUC and Cmax of midazolam were significantly higher after oral than IV administration of Uzol. Oral Uzol increased the midazolam AUC and Cmax by 272% and 129%, respectively. IV Uzol increased the midazolam AUC and Cmax by 244% and 79%, respectively. Both oral and IV Uzol increased the pharmacodynamic effects of midazolam. (See PRECAUTIONS.)
Based on a case report in one patient receiving combination therapy with all-transretinoid acid (an acid form of vitamin A) and Uzol, central nervous system (CNS) related undesirable effects have developed in the form of pseudotumor cerebri, which disappeared after discontinuation of Uzol treatment. This combination may be used but the incidence of CNS related undesirable effects should be borne in mind.
Although not studied in vitro or in vivo, concomitant administration of Uzol 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 Uzol and pimozide is contraindicated.
All other indications
- Use in pregnancy should be avoided except in patients with severe or potentially life-threatening fungal infections in whom Uzol may be used if the anticipated benefit outweighs the possible risk to the fetus
- A few published case reports describe a rare pattern of distinct congenital anomalies in infants exposed in-utero to high dose maternal Uzol (400-800 mg/day) during most or all of the first trimester
- Effective contraceptive measures should be considered in women of child-bearing potential who are being treated with 400-800 mg/day and should continue throughout the treatment period and for approximately 1 week (5 to 6 half-lives) after the final dose
- Reported anomalies are similar to those seen in animal studies and consist of brachycephaly, abnormal facies, abnormal calvarial development, cleft palate, femoral bowing, thin ribs and long bones, arthrogryposis, and congenital heart disease
Diflucan (Uzol) is a drug prescribed to treat fungal infections caused by Candida, for example, vaginal, oral, esophageal, urinary tract, pneumonia, and peritonitis. Side effects include nausea, diarrhea, dizziness, rash, indigestion, and abdominal pain.
Drug interactions, and pregnancy and breastfeeding safety information should be reviewed prior to taking this medication.
How should I take Uzol (Diflucan)?
Follow all directions on your prescription label and read all medication guides or instruction sheets. Use the medicine exactly as directed.
Your dose will depend on the infection you are treating. Vaginal infections are often treated with only one pill. For other infections, your first dose may be a double dose. Carefully follow your doctor's instructions.
You may take Uzol with or without food.
Shake the oral suspension (liquid) before you measure a dose. Use the dosing syringe provided, or use a medicine dose-measuring device (not a kitchen spoon).
Use this medicine for the full prescribed length of time, even if your symptoms quickly improve. Skipping doses can increase your risk of infection that is resistant to medication. Uzol will not treat a viral infection such as the flu or a common cold.
Call your doctor if your symptoms do not improve, or if they get worse.
Store the tablets at room temperature away from moisture and heat.
You may store liquid Uzol in a refrigerator, but do not allow it to freeze. Throw away any leftover liquid that is more than 2 weeks old.
Warnings for other groups
Pregnant women: Research in humans has shown adverse effects to the fetus when the mother takes this drug in doses of 150 mg or higher. In lower doses, research in animals has shown adverse effects. There haven’t been enough studies done to be certain how lower doses of the drug might affect the human fetus.
This drug should only be used during pregnancy in serious cases where it’s needed to treat a dangerous infection in the mother. And it should only be used if the potential risk to the fetus is acceptable given the drug’s potential benefit.
Talk to your doctor if you’re pregnant or planning to become pregnant. Ask your doctor to tell you about the specific harm that may be done to the fetus.
If you become pregnant while taking this drug, call your doctor right away.
Women who are breastfeeding: Uzol passes into breast milk and may cause side effects in a child who is breastfed. Talk to your doctor if you breastfeed your child. You may need to decide whether to stop breastfeeding or stop taking this drug.
For seniors: The kidneys of older adults may not work as well as they used to. This can cause your body to process drugs more slowly. As a result, more of a drug stays in your body for a longer time. This raises your risk of side effects.
For children: This medication shouldn’t be used in people younger than 6 months.
Rare Side Effects of Uzol
Uzol may cause some unpredictable side effects, including baldness and dizziness.
Examples of Uzol in a Sentence
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Systemic exposure to tofacitinib is increased when tofacitinib is coadministered with Uzol. Reduce the dose of tofacitinib when given concomitantly with Uzol (i.e., from 5 mg twice daily to 5 mg once daily as instructed in the XELJANZ ® label). (See CLINICAL PHARMACOLOGY: Drug Interaction Studies.)