Tacrolimus + SSRIs and related antidepressants - Drug Interactions

Marked increases in tacrolimus levels and toxicity were observedwhen three patients were also given nefazodone. In theory,fluvoxamine may increase tacrolimus levels. Paroxetine and sertraline may not interact, but situation is not clear.

A kidney transplant patient taking tacrolimus 5mg daily developed delirium and renal failure 4 weeks after starting to take nefazodone 150mg daily. The tacrolimus levels had been 9.4 nanograms/mL some 3 months earlier when he was taking a dose of 6mg daily, but in presence of nefazodone tacrolimus level increased to 46.4 nanograms/mL with a tacrolimus dose of 5mg daily. His serum creatinine had doubled. The tacrolimus level fell to 29.6 nanograms/mL within 2 days of dose being reduced to 3mg daily. Nefazodone was then replaced by paroxetine 20mg daily. After 3 days tacrolimus dose was increased to 5mg daily and satisfactory levels of 12.4 nanograms/mL were observed (See reference number 1).

A kidney transplant patient taking prednisone,azathioprine and tacrolimus 5mg daily for 2 years experienced headache, confusion and grey areas in her vision within one week of starting nefazodone 50mg twice daily in place of sertraline, for depression. Her serum creatinine had risen from 132 to 195 micromol/Land her trough tacrolimus level was greater than 30 nanograms/mL. Nefazodone was replaced by sertraline,and tacrolimus was withheld for 4 days. Signs of tacrolimus-induced neurotoxicity disappeared within 36 hrs and serum creatinine and tacrolimus levels returned to pretreatment levels within 2 weeks (See reference number 2).

Another patient developed raised liver enzymes and raised tacrolimus levels after taking nefazodone and tacrolimus for 2 weeks. When nefazodone was stopped his liver enzymes normalised over next 5 days, and his tacrolimus levels fell from 23 to 9.5 nanograms/mL over 10 days (See reference number 3).

Tacrolimus is metabolised by cytochrome P450 isoenzyme CYP3A4, which is inhibited by nefazodone, concurrent use therefore results in increased levels of tacrolimus. Paroxetine and sertraline do not have significant effects on CYP3A4 and are therefore not expected to interact with tacrolimus.

Information appears to be limited but what is known indicates that tacrolimus levels or at least signs of toxicity should be well monitored if nefazodone is also given. In view of narrow therapeutic index of tacrolimus, it may be advisable to avoid concurrent nefazodone.

Fluvoxamine is an inhibitor of CYP3A4(See reference number 4) and so theoretically could affect metabolism of tacrolimus. Close monitoring of tacrolimus levels is therefore advised. Paroxetine and sertraline and possibly other SSRIs may be suitable alternative antidepressants, but evidence is slim, so additional monitoring may still be warranted (See reference number 1). Further study on use of antidepressants with tacrolimus is needed.

Campo JV,Smith C, Perel JM. Tacrolimus toxic reaction associated with the use of nefazodone: paroxetine as an alternative agent. Arch Gen Psychiatry (1998) 55, 1050–2.

Olyaei AJ,deMattos AM, Norman DJ, Bennett WM. Interaction between tacrolimus and nefazodone in a stable renal transplant recipient. Pharmacotherapy (1998) 18, 1356–9.

Garton T,Nefazodone and CYP450 3A4 interactions with cyclosporine and tacrolimus. Transplantation (2002) 74, 745.

Faverin (Fluvoxamine). Solvay Healthcare Ltd. UK Summary of product characteristics,June2006.