Following administration of fluconazole 200 mg daily and Klarolid 500 mg twice daily to 21 healthy volunteers, the steady-state Klarolid Cmin and AUC increased 33% and 18%, respectively. Klarolid exposures were increased and steady-state concentrations of 14-OH Klarolid were not significantly affected by concomitant administration of fluconazole.
Klarolid 500 mg every 8 hours was given in combination with omeprazole 40 mg daily to healthy adult subjects. The steady-state plasma concentrations of omeprazole were increased (Cmax, AUC0-24, and t½ increases of 30%, 89%, and 34%, respectively), by the concomitant administration of Klarolid.
The plasma levels of Klarolid and 14–OH Klarolid were increased by the concomitant administration of omeprazole. For Klarolid, the mean Cmax was 10% greater, the mean Cmin was 27% greater, and the mean AUC0-8 was 15% greater when Klarolid was administered with omeprazole than when Klarolid was administered alone. Similar results were seen for 14–OH Klarolid, the mean Cmax was 45% greater, the mean Cmin was 57% greater, and the mean AUC0-8 was 45% greater. Klarolid concentrations in the gastric tissue and mucus were also increased by concomitant administration of omeprazole.
Klarolid Tissue Concentrations 2 hours after Dose (mcg/mL)/(mcg/g)
In two studies in which theophylline was administered with Klarolid (a theophylline sustained-release formulation was dosed at either 6.5 mg/kg or 12 mg/kg together with 250 or 500 mg q12h Klarolid), the steady-state levels of Cmax, Cmin, and the area under the serum concentration time curve (AUC) of theophylline increased about 20%.
When a single dose of midazolam was co-administered with Klarolid tablets (500 mg twice daily for 7 days), midazolam AUC increased 174% after intravenous administration of midazolam and 600% after oral administration.
For information about other drugs indicated in combination with BIAXIN, refer to their full prescribing information, CLINICAL PHARMACOLOGY section.
All-Cause Mortality In Patients With Coronary Artery Disease 1 To 10 Years After BIAXIN Exposure
In one clinical trial evaluating treatment with Klarolid on outcomes in patients with coronary artery disease, an increase in risk of all-cause mortality one year or more after the end of treatment was observed in patients randomized to receive Klarolid. 1 Klarolid for treatment of coronary artery disease is not an approved indication. The cause of the increased risk has not been established. Other epidemiologic studies evaluating this risk have shown variable results . Consider balancing this potential risk with the treatment benefits when prescribing BIAXIN in patients who have suspected or confirmed coronary artery disease.
Median survival time from trial entry (trial 1) was 249 days at the 500 mg twice daily dose compared to 215 days with the 1000 mg twice daily dose. However, during the first 12 weeks of therapy, there were 2 deaths in 53 patients in the 500 mg twice daily group versus 13 deaths in 51 patients in the 1000 mg twice daily group. The reason for this apparent mortality difference is not known. Survival in the two groups was similar beyond 12 weeks. The median survival times for these dosages were similar to recent historical controls with MAC when treated with combination therapies. 2
Median survival time from entry in trial 2 was 199 days for the 500 mg twice a day dose and 179 days for the 1000 mg twice a day dose. During the first four weeks of therapy, while patients were maintained on their originally assigned dose, there were 11 deaths in 255 patients taking 500 mg twice daily and 18 deaths in 214 patients taking 1000 mg twice daily.
Dosage-Ranging Monotherapy Trials In Pediatric AIDS Patients With MAC
Trial 4 was a pediatric trial of 3.75 mg/kg, 7.5 mg/kg, and 15 mg/kg of BIAXIN twice daily in patients with CDC-defined AIDS and CD4 counts less than 100 cells/mcL. The trial enrolled 25 patients between the ages of 1 to 20. The trial evaluated the same endpoints as in the adult trials 1 and 2. Results with the 7.5 mg/kg twice daily dose in the pediatric trial were comparable to those for the 500 mg twice daily regimen in the adult trials.
Combination Therapy In AIDS Patients With Disseminated MAC
Trial 5 compared the safety and efficacy of BIAXIN in combination with ethambutol versus BIAXIN in combination with ethambutol and clofazimine for the treatment of disseminated MAC (dMAC) infection. This 24-week trial enrolled 106 patients with AIDS and dMAC, with 55 patients randomized to receive BIAXIN and ethambutol, and 51 patients randomized to receive Klarolid, ethambutol, and clofazime. Baseline characteristics between treatment arms were similar with the exception of median CFU counts being at least 1 log higher in the BIAXIN, ethambutol, and clofazime arm.
Compared to prior experience with Klarolid monotherapy, the two-drug regimen of Klarolid and ethambutol extended the time to microbiologic relapse, largely through suppressing the emergence of Klarolid resistant strains. However, the addition of clofazimine to the regimen added no additional microbiologic or clinical benefit. Tolerability of both multidrug regimens was comparable with the most common adverse events being gastrointestinal in nature. Patients receiving the clofazimine-containing regimen had reduced survival rates; however, their baseline mycobacterial colony counts were higher. The results of this trial support the addition of ethambutol to Klarolid for the treatment of initial dMAC infections but do not support adding clofazimine as a third agent.
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“Klarolid.” The Merriam-Webster.com Medical Dictionary, Merriam-Webster Inc., https://www.merriam-webster.com/medical/Klarolid. Accessed 27 December 2019.
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