Tacrolimus observational study

Observational studies In a study of seven patients with lupus nephritis who failed on mycophenolate mofetil monotherapy, toxicity hmited the use of combination therapy with tacrolimus - - mycophenolate mofetil [84 ]. One patient achieved complete renal remission, and three achieved partial remission with reduced proteinuria. Four of seven patients stopped taking combination therapy because of diabetic ketoacidosis (n = 1), pneumonia ( = 1) and muscle pain (n = 2). Four patients had infectious complications, pneumonia (n = 2), herpes zoster (n = l), and septic arthritis ( = 1). There were no severe nephrotoxic adverse reactions, although there was a small increase in serum creatinine in two patients. 

Observational studies Adverse events have been studied in a 2-year, non-placebo-controlled trial in 164 children and adolescents undergoing renal transplantation [151, who were randomized to tacrolimus, azathioprine, and glucocorticoids or tacrolimus, azathioprine, glucocorticoids, and two doses of basiliximab. Basiliximab conferred no additional benefit. There were no differences between the groups in mean eGFR, blood pressure, or serum cholesterol concentrations, and no differences in the incidences of infections or malignancies. 

Observational studies In a retrospective study in 42 patients who took tacrolimus for a mean of 288 days, tacrolimus was withdrawn in 28 patients, because of adverse reactions in 21 cases [72 ]. Gastrointestinal symptoms were the most common adverse reactions (19/42 patients), followed by infections and hyperglycemia, nausea and vomiting led to withdrawal in seven... 

Observational studies In a retrospective study of the effects of telaprevir based triple therapy (telaprevir in combination with peg interferon alfa (peg IFNa) + RBV on nine patients) four patients were hospitalised because of adverse events (bacterial pneumonia, tacrolimus overdosing with renal failure, infectious enteritis, exacerbated diabetes mellitus and raised liver enzymes) [76=]. Anaemia (n=4), thrombocytopenia (n=4) and skin reactions (n = 3) were also reported. 

In a randomized, double-blind, placebo-controlled study at 23 centers in the USA, children with moderate to severe atopic dermatitis applied the vehicle, tacrolimus ointment 0.03%, or tacrolimus ointment 0.1% for 12 weeks (94). Burning and pruritus were the main adverse effects. Varicella infection and vesiculobullous rashes on non-application areas occurred, but with a low incidence (below 5%). Since they occurred in those who used tacrolimus 0.03%, it is likely that they were random events rather than drug-related. Regardless of dose, there were some age-related differences in the incidence of individual adverse events. For example, otitis media was more common in younger children (2-6 years). Tacrolimus ointment had no age-selective effect that was not also observed with the vehicle. Each of the adverse events resolved without sequelae. 

In the U.S. double-blind study in which NSAID use was unrestricted, a dose-dependent increase in serum creatinine from baseline was observed. In contrast, although slight increases were seen in the Japanese study, most patients creatinine levels remained within the normal range. Whether the concomitant use of NSAIDs was a confounding factor in the development of increased creatinine is not clear. It is important to note that the antirheumatic effect of tacrolimus becomes clear within the first 4 weeks after treatment initiation and, therefore, the potential exists to reduce the dose of NSAIDs at that time. Further clinical studies are currently under way to confirm these results in a larger cohort of patients who have failed at least one DMARD in the United States and Japan, using a double-blind, placebo-controlled paradigm. This study should also better define the safety profile of tacrolimus in this patient population. 

Kawashima, M., and the Japanese FK506 Ointment Study Group (2000). Long-term treatment with FK506 (tacrolimus) ointment in patients with atopic dermatitis—analysis at the time of 2-year observation. Presented at Clinical Dermatology 2000 (May 17-20, Vienna). Abstr. No. 235. 

There are other reports of this interaction between tacrolimus and alcohol. The reaction is usually confined to the face and the intensity may be related to the amount of alcohol ingested. In an open study of 316 patients, alcohol intolerance (facial flushing) was observed in 19% of the patients using tacrolimus 0.1% ointment and in a controlled study, 6.9% of patients experienced the reaction with tacrolimus 0.1% ointment, and 3.4% of patients experienced the reaction with tacrolimus 0.03% ointment. ... 

In rats orally administered 1.5 mg/kg of tacrolimus (a substrate of CYP3A4) with or without 2 g/kg of a decoction of the unripe fruits or an article described as the ripe peel of bitter orange, a 72% decrease in the maximum plasma concentration of tacrolimus was observed in rats administered the decoction of the unripe fruits of bitter orange. No change in tacrolimus levels was observed in the rats administered a decoction of the ripe peels. A related in vitro study with the same plant materials indicated that the unripe fruit... 

Initial studies of tacrolimus conversion from the immediate to the extended-release form (1 mg l mg) in stable transplant recipients showed 5-15% reductions in total drug exposure. Reduced exposure to tacrolimus (AUC ) of approximately 30-40% has been observed in de novo transplant recipients [45]. These situations yield evidence that dosage form conversions require vigilant therapeutic monitoring and dose intensification of extended-release tacrolimus. 

Thirteen renal transplant recipients who had received ertapenem 500 mg IV once daily for a UTl were retrospectively reviewed to evaluate the interaction between ertapenem and tacrolimus. The mean dose of tacrolimus to achieve therapeutic concentration was 0.079 0.03 mg/kg before ertapenem and 0.043 + 0.02 mg/kg after ertapenem (P = 0.005). Although the mechanism by which ertapenem affects tacrolimus levels is unknown, a significant decrease in the dose required to achieve the therapeutic effect was observed in this study. Patients who are receiving this combination should be monitored closely [81 ]. 

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