4. Drug-Drug Interactions

Patient profiles will be assessed to identify those drug regimens, which may result in clinically significant drug-drug interactions. Drug-drug interactions considered clinically relevant for ARBs are summarized in Table 5. Only those drug-drug interactions classified as clinical significance of contraindicated or those considered life-threatening which have not yet been classified will be reviewed.

Table 5.  ARB Drug-Drug Interactions [1]

Target Drug	Interacting Drug	Interaction	Recommendation	Clinical Significance Level #
ARBs, nebivolol/ valsartan, sacubitril/valsartan	aliskiren	increased risk for renal impairment, hyperkalemia, and hypotension with adjunctive administration most likely due to additive effects; documented in ALTITUDE trial (type 2 diabetics with renal impairment had increased stroke, renal complications, hypotension when given ARBs and aliskiren concurrently)	combined administration in diabetics contraindicated by manufacturer; avoid combination in patients with CrCl less than 60 ml/min; use cautiously together in other patients and closely monitor renal function, serum potassium levels	major
ARBs, nebivolol/ valsartan, sacubitril/valsartan	lithium	potential for enhanced lithium pharmacologic/adverse effects with combined administration; speculated that ARBs augment lithium reabsorption by decreasing lithium renal excretion	monitor patients for increased signs/symptoms of lithium toxicity and adjust lithium doses as necessary; may select alternate cardiovascular therapy that does not interact with lithium	moderate
ARBs, nebivolol/valsartan, sacubitril/valsartan	nonsteroidal anti-inflammatory drugs	combined administration may increase risk for renal function deterioration and alter response to antihypertensives, especially in volume-depleted, elderly, or renally compromised patients, due to vasodilatory prostaglandin inhibition	monitor renal function, antihypertensive efficacy when combined administration required	moderate
ARBs, nebivolol/ valsartan, sacubitril/valsartan	potassium-sparing diuretics (e.g., amiloride, spironolactone, triamterene), potassium supplements	combined therapy may increase risk for hyperkalemia as ARBs reduce circulating aldosterone concentrations, resulting in potassium retention; elderly as well as patients with impaired renal function, diabetes,  or high potassium diets may be at greater risk	measure serum potassium concentrations, monitor for signs and symptoms of hyperkalemia when administered concurrently, especially in patients with predisposing factors	major
ARBs	sparsentan	concomitant use is contraindicated due to the additive risk for serious adverse events such as hypotension, syncope, hyperkalemia, and renal dysfunction	concomitant use is contraindicated	contraindicated
ARBs	tranylcypromine	concomitant use may increase the effects of hypotensive agents	concomitant use is contraindicated	contraindicated
sacubitril/valsartan	ACE inhibitors	concomitant use increases the risk of angioedema	concomitant use is contraindicated	contraindicated
telmisartan	clopidogrel	concomitant use may reduce the antiplatelet effect of clopidogrel by inhibiting metabolism to active clopidogrel metabolite	concomitant use should be monitored for reduced efficacy of clopidogrel	major
telmisartan	digoxin	concomitant use may increase digoxin peak concentrations	increase serum digoxin monitoring and adjust digoxin dosing	major