Amlodipine Liver Function Impact: What the Clinical Evidence Actually Shows

How much of amlodipine does the liver handle?

The Norvasc label states that about 90% of amlodipine is converted to inactive metabolites by hepatic metabolism, and that 10% of the parent drug and 60% of the metabolites are excreted in urine [1]. About 93% is protein bound. Peak plasma concentration arrives 6 to 12 hours after a dose, absolute bioavailability is 64% to 90% and is not altered by food, and the terminal elimination half-life is about 30 to 50 hours, with steady state after 7 to 8 days of daily dosing [1].

The label's interaction data point to CYP3A involvement. Diltiazem 180 mg daily given with amlodipine 5 mg in elderly hypertensive patients raised amlodipine exposure by 60%, erythromycin did not significantly change exposure, and strong inhibitors such as itraconazole and clarithromycin may raise concentrations to a greater extent [1]. Amlodipine is also a weak CYP3A inhibitor: multiple doses of amlodipine 10 mg with simvastatin 80 mg raised simvastatin exposure by 77%, and the label limits simvastatin to 20 mg daily in patients taking amlodipine [1]. Co-administered amlodipine does not affect exposure to atorvastatin, digoxin or ethanol, or the warfarin prothrombin response time [1].

What the label says about liver disease

On dosing, the label says patients with hepatic insufficiency may be started on 2.5 mg once daily, and for angina it suggests the lower end of the 5 to 10 mg range in hepatic insufficiency [1]. Routine titration waits 7 to 14 days between steps unless faster titration is clinically warranted [1]. On safety, the label says to titrate slowly in severe hepatic impairment, and gives as its reason that amlodipine is extensively metabolized by the liver and the plasma elimination half-life is 56 hours in patients with impaired hepatic function [1].

Exposure is higher in this group. The label reports decreased clearance and about 40% to 60% higher AUC in hepatic insufficiency, similar to the increase seen in moderate to severe heart failure, and notes that a lower starting dose may be needed [1].

Liver-related drug interactions

Moderate and strong CYP3A inhibitors raise amlodipine exposure and may require dose reduction, and the label advises monitoring for hypotension and edema [1]. An Ontario cohort followed older adults (mean age 76) on a calcium-channel blocker who were newly given clarithromycin (n=96,226) or azithromycin (n=94,083); amlodipine accounted for more than half of calcium-channel blocker use. Within 30 days of the new prescription, hospitalization with acute kidney injury occurred in 0.44% versus 0.22% (OR 1.98, 95% CI 1.68-2.34), hospitalization with hypotension in 0.12% versus 0.07% (OR 1.60), and all-cause mortality in 1.02% versus 0.59% (OR 1.74) [2].

For CYP3A inducers, the label says no quantitative information is available and that blood pressure should be monitored closely [1].

The label states that grapefruit juice has no impact on amlodipine exposure [1]. One small study of 12 healthy men found about 15% higher peak concentration and exposure when a single 5 mg dose was taken with 250 mL of juice (Cmax 115% and AUC(0-72h) 116% of water values), with no significant difference in blood pressure or heart rate [3]. Another study of 20 healthy men given juice daily for 9 days found no marked change in amlodipine exposure [4].

If liver enzymes rise while taking amlodipine

The label places jaundice and hepatic enzyme elevations, mostly consistent with cholestasis or hepatitis and in some cases severe enough to require hospitalization, in its postmarketing section [1]. Those reports come from a population of uncertain size, so the label says it is not always possible to reliably estimate frequency or establish a causal relationship [1]. Amlodipine carries no boxed warning, and known sensitivity to amlodipine is its only contraindication [1].

The American College of Gastroenterology guideline on idiosyncratic drug-induced liver injury treats DILI as a diagnosis of exclusion, with careful assessment for other causes of liver disease before the drug is implicated [7]. The guideline notes mortality up to 10% when hepatocellular jaundice is present, and states that patients with progressive jaundice, with or without coagulopathy, should be referred to a tertiary care center [7].