Sirolimus dosage

In 119 patients taking sirolimus, thrombocjdopenia (defined as a platelet count below 150 x 10 /1) and leukopenia (white blood cell count below 5.0 x 10 /I) occurred in 78 and 63% respectively (9). The incidence, but not the severity, of these effects correlated with sirolimus whole-blood trough concentrations. Most cases occurred within the first 4 weeks of treatment and the severity was usually limited. There was spontaneous resolution in 89% of the patients and sirolimus dosage reduction or temporary withdrawal was necessary in only 7% and 4% of the patients respectively. None of the patients required permanent withdrawal. 

A case report describes 2 patients taking sirolimus who were also given erythromycin 1 g three times daily for suspected Legionella pneumonia. Despite reductions in the sirolimus dosage, the sirolimus levels of both patients rose fivefold. ... 

Monitor patients receiving sirolimus or nifedipine in combination with micafungin for sirolimus or nifedipine toxicity, and reduce sirolimus or nifedipine dosage if necessary. 

Drug/Food interactions To minimize variability, sirolimus should be taken consistently with or without food (see Administration and Dosage). 

The most striking consequence of treatment with sirolimus is dose-dependent hyperlipidemia with significant increases in both cholesterol and triglyceride serum concentrations, which resolve after dosage reduction or sirolimus withdrawal (1065). 

In a 1-year follow-up of 40 renal transplant patients treated with various dosages of sirolimus (0.5-7 mg/m2/ day) in addition to a ciclosporin-based regimen, there were significant increases in serum cholesterol and triglycerides, and significant falls in white blood cell and platelet counts, compared with historical controls (1066). These effects correlated with sirolimus trough concentrations but not dosages. One patient had to discontinue sirolimus because of hyperlipidemia refractory to treatment. 

Hypertriglyceridemia due to sirolimus often does not respond to dosage reduction or hypolipidemic drugs. After liver transplantation (n — 6), significant hyperlipidemia improved after withdrawal of sirolimus (1070). The incidence of sirolimus-associated hyperlipidemia is up to 44%. After liver transplantation, there was hypercholesterolemia in 15% and hypertriglyceridemia in 10% of recipients. Sirolimus in combination with tacrolimus... 

Sirolimus is a substrate and inhibitor of CYP3A4 with a narrow therapeutic index and is associated with cognitive impairment and nephrotoxicity. There is a synergistic effect when it is co-administered with ciclosporin, possibly because both are substrates of CYP3A4 (and thus compete at metabolic sites) and are P-gp substrates that may competitively inhibit each other at the efflux pump. There is considerable interindividual variability, with a 10-fold range in plasma concentration in renal transplant recipients when it is given at a dosage of 5 mg per day. 

Bronchiohtis obliterans with organizing pneumonia has been attributed to sirolimus in two renal transplant patients (6). Both improved rapidly after sirohmus withdrawal or dosage reduction. 

There are few data on clinical strategies to avoid or minimize TAC-induced chronic nephrotoxicity. Patients with biopsy proved chronic allograft nephropathy or TAC chronic nephrotoxicity showed renal function improvement after switch from TAC to sirolimus or reduction of TAC dosage and introduc-... 

The concurrent use of sirolimus is contraindicated by the manufacturers of voriconazole. The rises in sirolimus levels caused by voriconazole are probably too large to be easily accommodated by reducing the dosage of the sirolimus. One study found that an initial empiric reduction in... 

Diltiazem and verapamil raise sirolimus levels, and dosage adjustments may be necessaiy. Nicardipine is predicted to interact similarly. Nifedipine appears not to interact with sirolimus. 

Mouth In four Japanese heart transplant recipients treated with everolimus, aphthous stomatitis necessitated dosage reductions in three and complete withdrawal in the other after a switch from mycophenolate mofetil [43 ]. Everolimus trough concentrations had not exceeded the target range at any time. They all recovered after dosage reduction or withdrawal. Aphthous stomatitis has been reported as an adverse reaction to sirolimus. 

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