SSRIs + Protease inhibitors - Drug Interactions

Fluoxetine modestly raised levels of ritonavir, and ritonavir ispredicted to raise levels of fluoxetine, paroxetine and sertraline. Afew cases of serotonin syndrome have been attributed to theuse of fluoxetine and ritonavir. The concurrent use of escitalopram and ritonavir do not appear to affect pharmacokineticsof either drug.

Clinical evidence,mechanism, importance and management

In a single-dose study involving 18 healthy subjects,no significant pharmacokinetic interaction was seen when ritonavir was given with escitalopram (See reference number 1).

Ritonavir 600mg was given to 16 healthy subjects before and after 8 days of treatment with fluoxetine 30mg twice daily. The maximum plasma levels of ritonavir were unaffected,but its AUC rose by 19%. These changes were not considered large enough to warrant changing dose of ritonavir (See reference number 2). The study was criticised for not achieving steady state before assessing pharmacokinetics and thus possibly underestimating interaction (See reference number 3). However, authors point out that fluoxetine levels were equivalent to those seen at steady state, and multiple dosing of ritonavir is likely to induce its own metabolism, so if anything, interaction would be lessened at steady state (See reference number 4).

The UK manufacturers of ritonavir predict that it may raise levels of SSRIs (fluoxetine, paroxetine, sertraline) due to inhibitory effect of ritonavir on cytochrome P450 isoenzymes CYP2D6 (See reference number 5). The US manufacturers do not mention any specific SSRIs (See reference number 6). Both manufacturers suggest careful monitoring of adverse effects when these drugs are used with ritonavir; a dose reduction of SSRI may be required (See reference number 5,6).

Two cases of serotonin syndrome were attributed to adding ritonavir to established fluoxetine treatment. In one patient this was managed by halving fluoxetine dose, and in other ritonavir was withdrawn. Other cases of serotonin syndrome have been seen in patients taking ritonavir or indinavir with fluoxetine. One involved additional use of trazodone, , and other involved large quantities of grapefruit, .

Gutierrez,MM, Rosenberg J, Abramowitz W. An evaluation of the potential for pharmacokinetic interaction between escitalopram and the cytochrome P450 3A4 inhibitor ritonavir. Clin Ther (2003) 25, 1200–10.

Ouellet D,Hsu A, Qian J, Lamm JE, Cavanaugh JH, Leonard JM, Granneman GR. Effect offluoxetine on the pharmacokinetics of ritonavir. Antimicrob Agents Chemother (1998) 42, 3107–12.

Bellibas SE. Ritonavir-fluoxetine interaction. Antimicrob Agents Chemother (1999) 43,1815.

Ouellet D,Hsu A. Ritonavir-fluoxetine interaction. Antimicrob Agents Chemother (1999) 43, 1815.

Norvir (Ritonavir). Abbott Laboratories Ltd. UK Summary of product characteristics,May2007.

Norvir (Ritonavir). Abbott Laboratories. US Prescribing information,January 2006.