Drug Interactions between aliskiren / valsartan and fosinopril

GENERALLY AVOID: Coadministration of angiotensin converting enzyme inhibitors (ACEIs) with angiotensin II receptor blockers (ARBs) may increase the risk of hyperkalemia, severe hypotension, and renal failure due to additive or synergistic effects on the renin-angiotensin system, particularly in patients with diabetes and/or renal impairment. A multicenter double-blind, randomized, controlled study evaluating the efficacy of combination-therapy with losartan (an ARB) and lisinopril (an ACEI) in slowing the progression of proteinuric diabetic nephropathy was stopped early on account of safety concerns due to increased rates of serious adverse events in the combination-therapy treatment group (hyperkalemia and acute kidney injury). Hyperkalemia occurred in 9.9% of patients in the combination-therapy group compared to 4.4% in the monotherapy group, and acute kidney injury events occurred in 18% of the combination-group compared to 11% in the monotherapy group.

MANAGEMENT: Coadministration of angiotensin converting enzyme inhibitors (ACEIs) with angiotensin II receptor blockers (ARBs) should generally be avoided, especially in patients with diabetic nephropathy and/or moderate to severe renal impairment (GFR <60 mL/min/1.73 m2). Some authorities consider this combination contraindicated in such patients. However, if the combination is considered medically necessary, serum electrolytes, blood pressure, and renal function should be closely monitored particularly in the elderly, patients with worsening heart failure, or those at risk for dehydration. Additionally, potassium supplementation should generally be avoided unless potassium levels are closely monitored. Patients and their caregivers should be advised to seek medical attention if they experience signs and symptoms of hyperkalemia (e.g., weakness, tingling of the extremities, irregular heartbeat) and/or acute kidney injury (e.g., reduced urine output, lower extremity edema). Individual product labeling should be consulted for further guidance.

CONTRAINDICATED: In patients with type 2 diabetes and renal impairment, coadministration of aliskiren with ACE inhibitors or angiotensin receptor blockers (ARBs) has been associated with an increased risk of adverse events including renal complications, hyperkalemia, and hypotension. Interim review of data from the ALTITUDE study after 18 to 24 months revealed no additional benefit and a higher incidence of adverse events when aliskiren 300 mg daily, as opposed to placebo, was added to optimal cardiovascular treatment including an ACE inhibitor or ARB. Another preliminary finding was a slight excess of death or stroke in the aliskiren group; however, the relationship to aliskiren treatment has not been established. ALTITUDE was a multinational study in 8,606 patients from 36 countries evaluating the potential benefits of aliskiren to reduce the risk of cardiovascular and renal events in patients with type 2 diabetes and renal impairment, who are known to be at high risk of cardiovascular and renal events. The trial was halted in December 2011 per recommendation of the independent data monitoring committee overseeing the study.

GENERALLY AVOID: In patients without diabetes, coadministration of aliskiren with ACE inhibitors or ARBs may also be associated with increased risk of symptomatic hypotension, hyperkalemia, and changes in renal function including acute renal failure. All drugs inhibiting the renin-angiotensin system (RAS) can have these effects, which may be additive during concomitant administration. The risk of symptomatic hypotension is increased in the presence of marked volume and/or salt depletion. Elevations in serum potassium levels to greater than 5.5 mEq/L were infrequent with aliskiren alone (0.9% compared to 0.6% with placebo), but increased to 5.5% when used in combination with an ACE inhibitor in a diabetic population. Patients whose renal function may depend in part on the activity of the RAS, including those with renal artery stenosis, severe heart failure, postmyocardial infarction or volume depletion, may be at particular risk for developing acute renal failure with these drugs.

MANAGEMENT: The use of aliskiren with ACE inhibitors or ARBs is considered contraindicated in patients with diabetes and should be avoided in general, particularly in patients with moderate to severe renal impairment (i.e., creatinine clearance (CrCl) < 60 mL/min). Prescribers should not initiate aliskiren in diabetic patients who are taking an ACE inhibitor or an ARB, and should stop any aliskiren-containing treatment if these patients are already receiving the combination. Alternative antihypertensive treatment should be considered as necessary. Most patients do not obtain any additional benefit from combination therapy relative to monotherapy; therefore, the potential risks should be thoroughly assessed when aliskiren is prescribed with ACE inhibitors or ARBs for the treatment of essential hypertension in patients without diabetes. Volume or salt depletion should be corrected prior to initiation of treatment. Routine monitoring of blood pressure, electrolytes, and renal function are recommended, particularly in the elderly or patients with worsening heart failure or a risk for dehydration. Potassium supplementation should generally be avoided unless it is closely monitored, and patients should be advised to seek medical attention if they experience signs and symptoms of hyperkalemia such as weakness, listlessness, confusion, tingling of the extremities, and irregular heartbeat.

CONTRAINDICATED: In patients with type 2 diabetes and renal impairment, coadministration of aliskiren with ACE inhibitors or angiotensin receptor blockers (ARBs) has been associated with an increased risk of adverse events including renal complications, hyperkalemia, and hypotension. Interim review of data from the ALTITUDE study after 18 to 24 months revealed no additional benefit and a higher incidence of adverse events when aliskiren 300 mg daily, as opposed to placebo, was added to optimal cardiovascular treatment including an ACE inhibitor or ARB. Another preliminary finding was a slight excess of death or stroke in the aliskiren group; however, the relationship to aliskiren treatment has not been established. ALTITUDE was a multinational study in 8,606 patients from 36 countries evaluating the potential benefits of aliskiren to reduce the risk of cardiovascular and renal events in patients with type 2 diabetes and renal impairment, who are known to be at high risk of cardiovascular and renal events. The trial was halted in December 2011 per recommendation of the independent data monitoring committee overseeing the study.

GENERALLY AVOID: In patients without diabetes, coadministration of aliskiren with ACE inhibitors or ARBs may also be associated with increased risk of symptomatic hypotension, hyperkalemia, and changes in renal function including acute renal failure. All drugs inhibiting the renin-angiotensin system (RAS) can have these effects, which may be additive during concomitant administration. The risk of symptomatic hypotension is increased in the presence of marked volume and/or salt depletion. Elevations in serum potassium levels to greater than 5.5 mEq/L were infrequent with aliskiren alone (0.9% compared to 0.6% with placebo), but increased to 5.5% when used in combination with an ACE inhibitor in a diabetic population. Patients whose renal function may depend in part on the activity of the RAS, including those with renal artery stenosis, severe heart failure, postmyocardial infarction or volume depletion, may be at particular risk for developing acute renal failure with these drugs.

MANAGEMENT: The use of aliskiren with ACE inhibitors or ARBs is considered contraindicated in patients with diabetes and should be avoided in general, particularly in patients with moderate to severe renal impairment (i.e., creatinine clearance (CrCl) < 60 mL/min). Prescribers should not initiate aliskiren in diabetic patients who are taking an ACE inhibitor or an ARB, and should stop any aliskiren-containing treatment if these patients are already receiving the combination. Alternative antihypertensive treatment should be considered as necessary. Most patients do not obtain any additional benefit from combination therapy relative to monotherapy; therefore, the potential risks should be thoroughly assessed when aliskiren is prescribed with ACE inhibitors or ARBs for the treatment of essential hypertension in patients without diabetes. Volume or salt depletion should be corrected prior to initiation of treatment. Routine monitoring of blood pressure, electrolytes, and renal function are recommended, particularly in the elderly or patients with worsening heart failure or a risk for dehydration. Potassium supplementation should generally be avoided unless it is closely monitored, and patients should be advised to seek medical attention if they experience signs and symptoms of hyperkalemia such as weakness, listlessness, confusion, tingling of the extremities, and irregular heartbeat.