Drug Interactions between amiloride and Exforge HCT

MONITOR CLOSELY: Concomitant use of angiotensin II receptor blockers (ARBs) and potassium-sparing diuretics may increase the risk of hyperkalemia. Inhibition of angiotensin II results in decreased aldosterone secretion, which can lead to increases in serum potassium that may be additive with that induced by potassium-sparing diuretics. Life-threatening and fatal hyperkalemia can occur, especially when the combination is used in patients with risk factors such as renal impairment, diabetes, advanced age, severe or worsening heart failure, dehydration, and concomitant use of other agents that block the renin-angiotensin-aldosterone system or otherwise increase serum potassium levels. Individually, both ARBs and potassium-sparing diuretics have been associated with hyperkalemia in patients with renal impairment. ARBs may also cause deterioration of renal function in patients with chronic heart failure, and the risk is increased if they are sodium-depleted or dehydrated secondary to excessive diuresis. In a meta-analysis of 20 randomized controlled studies evaluating serum potassium changes in individuals taking ARBs and/or angiotensin converting enzyme inhibitors (ACEIs) with spironolactone (n=570) versus controls on ARBs and/or ACEIs alone (n=547), mean serum potassium concentration was shown to increase by 0.19 mEq/L with the addition of spironolactone. However, a total of 27 patients from eleven studies were withdrawn from participation due to the occurrence of an acute hyperkalemic event (defined as serum potassium >= 5.5 mEq/L), and their data did not contribute to these findings, which could have led to an under-estimation of the result. A retrospective analysis of evaluating the incidence of hyperkalemia in the CHARM study (Candesartan in Heart Failure-Assessment of Reduction in Mortality and Morbidity) found that the addition of candesartan to standard medical therapy for heart failure was associated with a 2- to 3-fold increase in risk of hyperkalemia, which was further amplified by cotreatment with spironolactone or ACE inhibitors. In a case series conducted over approximately 4 years, 44 patients with congestive heart failure who were receiving spironolactone (mean dosage = 88 mg, range 25-200 mg daily) plus an ACEI or ARB experienced life threatening hyperkalemia, with death occurring in 2 patients. Additionally, authors identified several possible conditions (e.g., advanced age, a daily spironolactone dose of >25 mg, reduced renal function and diabetes mellitus type 2) that may lead to the development of severe hyperkalemia in patients with heart failure who are taking spironolactone with an ACE or ARB.

MANAGEMENT: Caution and close monitoring are advised if angiotensin II receptor blockers (ARBs) and potassium-sparing diuretics are used concurrently due to the risk of potentially life-threatening hyperkalemia. Some authorities advise against combining certain ARBs with potassium-sparing diuretics unless the anticipated benefits substantially outweigh the potential risks. Particular caution is advised in older patients and those with certain disease states (e.g., renal impairment, diabetes, severe or worsening heart failure, dehydration) or when additional agents that increase serum potassium (e.g., potassium-containing salt substitutes, nonsteroidal anti-inflammatory drugs, beta-blockers, cyclosporine, heparin, tacrolimus, trimethoprim) are prescribed. For patients with heart failure, local guidelines should be consulted for specific therapy recommendations, as these may differ from general product labeling. For instance, the AHA/ACC/HFSA Guideline for the Management of Heart Failure advise that individuals with heart failure and reduced ejection fraction (HFrEF) should be treated with a combination of an ACEI or an ARB, along with a potassium-sparing diuretic (also known as a mineralocorticoid receptor antagonist or MRA), as part of a combination therapy regimen. If after careful consideration and/or consultation with local treatment guidelines both an ARB and a potassium-sparing diuretic are deemed necessary, serum potassium and renal function should be checked prior to initiating therapy and at frequent intervals thereafter, including after any dosage increases. In addition, if spironolactone is coadministered with an ARB, some investigators recommend that its dosage not exceed 25 mg/day in high-risk patients (e.g., advanced age, reduced renal function and type 2 diabetes). Patients and their caregivers should be given counseling on the appropriate levels of potassium and fluid intake, and advised to seek medical attention if they experience signs and symptoms of hyperkalemia such as nausea, vomiting, weakness, listlessness, tingling of the extremities, paralysis, confusion, weak pulse, and a slow or irregular heartbeat. Individual product labeling should be consulted for further guidance.

The antihypertensive effect of amlodipine and thiazide diuretics may be additive. Management consists of monitoring blood pressure during coadministration, especially during the first 1 to 3 weeks of therapy.