Drug Interaction Report

MONITOR: The use of mTOR (mammalian target of rapamycin) inhibitors has been associated with the development of angioedema, and coadministration with other drugs that are also known to cause angioedema such as ACE inhibitors, angiotensin II receptor antagonists, and renin inhibitors may increase the risk. In a pooled analysis of everolimus oncology clinical trials, the incidence of angioedema in patients taking everolimus with an ACE inhibitor was 6.8% compared to 1.3% in the control arm with an ACE inhibitor. The onset of angioedema may sometimes be delayed. According to the product labeling for temsirolimus, angioneurotic edema-type reactions have occurred two months after initiation of therapy in some patients who received concomitant ACE inhibitors.

MANAGEMENT: Clinicians and patients should be aware of the potential for increased risk of angioedema when mTOR inhibitors are prescribed with other drugs that are also known to cause angioedema. Patients should be advised to promptly discontinue these medications and seek medical attention if they develop signs or symptoms suggestive of angioedema such as swelling of the face, extremities, eyes, lips, or tongue, and difficulty swallowing or breathing.

GENERALLY AVOID: Moderate-to-high dietary intake of potassium can cause hyperkalemia in some patients who are using angiotensin converting enzyme (ACE) inhibitors. In some cases, affected patients were using a potassium-rich salt substitute. ACE inhibitors can promote hyperkalemia through inhibition of the renin-aldosterone-angiotensin (RAA) system.

MANAGEMENT: It is recommended that patients who are taking ACE inhibitors be advised to avoid moderately high or high potassium dietary intake. Particular attention should be paid to the potassium content of salt substitutes.

GENERALLY AVOID: Grapefruit juice may significantly increase the plasma concentrations of orally administered everolimus. The mechanism is inhibition of CYP450 3A4 and P-glycoprotein activity in the gut wall by certain compounds present in grapefruit.

MANAGEMENT: Patients treated with everolimus should avoid consumption of grapefruit and grapefruit juice.