sirolimus – kdc

CLINICAL USE

Immunosuppressant:Prophylaxis of transplant allograft rejection

DOSE IN NORMAL RENAL FUNCTION

6 mg loading dose followed by 2 mg daily, adjusted according to levels – see ‘Other Information’

PHARMACOKINETICS

Molecular weight :914.2

%Protein binding :92

%Excreted unchanged in urine : 2.2

Volume of distribution (L/kg) :4–20

half-life – normal/ESRD (hrs) :48–78/Unchanged

DOSE IN RENAL IMPAIRMENT

GFR (mL/MIN)

20 to 50 : Dose as in normal renal function

10 to 20 : Dose as in normal renal function

<10 : Dose as in normal renal function

DOSE IN PATIENTS UNDERGOING RENAL REPLACEMENT THERAPIES

CAPD :Unlikely to be dialysed. Dose as in normal renal function

HD :Not dialysed. Dose as in normal renal function

HDF/high flux :Unknown dialysability. Dose as in normal renal function

CAV/VVHD :Unlikely to be dialysed. Dose as in normal renal function

IMPORTANT DRUG INTERACTIONS

Potentially hazardous interactions with other drugs

Antibacterials: concentration increased by clarithromycin and telithromycin – avoid; concentration of both drugs increased with erythromycin; concentration reduced by rifampicin and rifabutin – avoid

Antifungals: concentration increased by itraconazole, ketoconazole, miconazole, posaconazole and voriconazole

Antivirals: concentration possibly increased by atazanavir and lopinavir

Calcium-channel blockers: concentration increased by diltiazem; concentration of both drugs increased with verapamil

Ciclosporin: increased absorption of sirolimus – give sirolimus 4 hours after ciclosporin; sirolimus concentration increased; long-term concomitant administration may be associated with a deterioration in renal function

Grapefruit juice: concentration of sirolimus increased – avoid concomitant useMycophenolate: concomitant use of mycophenolate and sirolimus increases plasma levels of both sirolimus and mycophenolic acid

ADMINISTRATION

Reconstition

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Route

Oral

Rate of Administration

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Comments

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OTHER INFORMATION

Aim for trough levels of 4–12 ng/mL where sirolimus is used in combination with low dose ciclosporinIn cases of delayed graft function or where a calcineurin inhibitor is not tolerated or contraindicated, sirolimus may be used with steroids alone. A loading dose of 10–15 mg may be given, followed by maintenance dose of 3–6 mg daily and adjust according to levels. Aim for trough levels of 8–20 ng/mLMay be used in combination with MMF, but can lead to delayed wound healing post surgery. Sirolimus can increase levels of mycophenolate mofetil leading to anaemiaSome centres successfully using level- controlled sirolimus in conjunction with low dose tacrolimus
Anecdotally, has been used for encapsulating sclerosing peritonitis in a CAPD patient at Guy’s Hospital, London. Acts by interfering with various growth factors and their effect on impairing wound healing.
Pneumonitis appears to be more common with sirolimus than initially thought, especially if the trough levels are on the high side.
If changing from tablets to solution, give the same dose and monitor trough levels 1–2 weeks laterTablet has a 27% increased bioavailability compared with the solutionSirolimus has been associated with anaphylactic/anaphylactoid reactions, angioedema and hypersensitivity vasculitis.

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