Drug Interactions between aliskiren / valsartan and licorice

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.

GENERALLY AVOID: Licorice use has been associated with hypertension and may antagonize the effects of antihypertensive agents or effects of agents with hypotensive properties. Glycyrrhizic acid, a component of licorice, is hydrolyzed in the intestine to a metabolite (glycyrrhetinic acid) that causes mineralocorticoid and renin-suppressing effects. In one study, licorice was found to increase blood pressure in a dose-dependent manner. Healthy volunteers who consumed licorice 50 to 200 g/day (corresponding to 75 to 540 mg/day of glycyrrhetinic acid) for two to four weeks had a 3.1 to 14.4 mmHg increase in their systolic blood pressure. Even the lowest dosage demonstrated a significant effect. In another study, plasma potassium levels decreased by 0.3 to 1.5 mEq/L in 12 out of 14 healthy volunteers who ingested licorice 100 or 200 g/day (equivalent to 700 to 1400 mg/day of glycyrrhizic acid) for one to four weeks, including four who had to be withdrawn from the study because of hypokalemia. Two more subjects were withdrawn due to edema of the face, hands, and ankles. Other side effects reported include mild, transient generalized edema; headache; sodium retention; and weight gain (1 to 4 kg, mean 1.5 kg). Signs of renin-angiotensin-aldosterone suppression were observed in all subjects, especially plasma renin activity and urinary aldosterone concentrations, which fell to subnormal or undetectable levels in the majority of subjects. There have been various published case reports of refractory hypertension, severe hypokalemia (life-threatening hypokalemic paralysis, myopathy, arrhythmia, or cardiac arrest), and hypertensive encephalopathy in association with licorice intoxication. Hypertension and hypokalemia have also been reported with moderate doses of licorice in the form of licorice-flavored chewing gum or candy, chewing tobacco, or licorice-based foods and beverages consumed on a chronic basis. Prolonged use of licorice has led to a hypermineralocorticoid (pseudohyperaldosteronism) syndrome characterized by hypertension, hypernatremia, hypokalemia, metabolic alkalosis, renin-angiotensin-aldosterone suppression, and edema. In studies and case reports, licorice toxicity has generally been completely reversible within one to several weeks of licorice discontinuation. However, renin-angiotensin-aldosterone axis may be suppressed for up to several months.

MANAGEMENT: Patients receiving antihypertensive therapy or agents with hypotensive properties should avoid or limit the consumption of licorice-containing products. Even relatively moderate doses of licorice may be problematic in susceptible patients when ingested regularly for prolonged periods.

GENERALLY AVOID: Licorice use has been associated with hypertension and may antagonize the effects of antihypertensive agents or effects of agents with hypotensive properties. Glycyrrhizic acid, a component of licorice, is hydrolyzed in the intestine to a metabolite (glycyrrhetinic acid) that causes mineralocorticoid and renin-suppressing effects. In one study, licorice was found to increase blood pressure in a dose-dependent manner. Healthy volunteers who consumed licorice 50 to 200 g/day (corresponding to 75 to 540 mg/day of glycyrrhetinic acid) for two to four weeks had a 3.1 to 14.4 mmHg increase in their systolic blood pressure. Even the lowest dosage demonstrated a significant effect. In another study, plasma potassium levels decreased by 0.3 to 1.5 mEq/L in 12 out of 14 healthy volunteers who ingested licorice 100 or 200 g/day (equivalent to 700 to 1400 mg/day of glycyrrhizic acid) for one to four weeks, including four who had to be withdrawn from the study because of hypokalemia. Two more subjects were withdrawn due to edema of the face, hands, and ankles. Other side effects reported include mild, transient generalized edema; headache; sodium retention; and weight gain (1 to 4 kg, mean 1.5 kg). Signs of renin-angiotensin-aldosterone suppression were observed in all subjects, especially plasma renin activity and urinary aldosterone concentrations, which fell to subnormal or undetectable levels in the majority of subjects. There have been various published case reports of refractory hypertension, severe hypokalemia (life-threatening hypokalemic paralysis, myopathy, arrhythmia, or cardiac arrest), and hypertensive encephalopathy in association with licorice intoxication. Hypertension and hypokalemia have also been reported with moderate doses of licorice in the form of licorice-flavored chewing gum or candy, chewing tobacco, or licorice-based foods and beverages consumed on a chronic basis. Prolonged use of licorice has led to a hypermineralocorticoid (pseudohyperaldosteronism) syndrome characterized by hypertension, hypernatremia, hypokalemia, metabolic alkalosis, renin-angiotensin-aldosterone suppression, and edema. In studies and case reports, licorice toxicity has generally been completely reversible within one to several weeks of licorice discontinuation. However, renin-angiotensin-aldosterone axis may be suppressed for up to several months.

MANAGEMENT: Patients receiving antihypertensive therapy or agents with hypotensive properties should avoid or limit the consumption of licorice-containing products. Even relatively moderate doses of licorice may be problematic in susceptible patients when ingested regularly for prolonged periods.