Spironolactone and Acetaminophen Interaction: What Patients and Clinicians Need to Know

Is There a Real Interaction Between Spironolactone and Acetaminophen?

The spironolactone label warns that potassium supplements, potassium-containing salt substitutes, ACE inhibitors and ARBs can lead to severe hyperkalemia, and it also names NSAIDs, heparin and low molecular weight heparin, and trimethoprim as drugs that can raise potassium [1]. Acetaminophen is not on that list. Absence from a warning list does not prove the pair is harmless, and no study of the combination is available here.

The two drugs are handled differently by the body. Spironolactone is rapidly and extensively metabolized into canrenone and sulfur-containing metabolites (7-alpha-thiomethylspironolactone and its 6-beta-hydroxy form), and the label names no cytochrome P450 enzyme for its metabolism [1]. Acetaminophen is metabolized by glucuronidation, sulfation and CYP2E1 oxidation; CYP2E1 makes a reactive metabolite, NAPQI, that is cleared at normal doses by conjugation with glutathione.

What the Spironolactone Label Does Warn About

Potassium is the central safety issue. The label says to check serum potassium within one week of starting or changing the dose and regularly afterward, and that if hyperkalemia occurs the dose should be reduced or the drug stopped and treated [1].

The label also lists lithium, because spironolactone reduces lithium renal clearance and raises the risk of lithium toxicity, and it notes that spironolactone and its metabolites interfere with digoxin radioimmunoassays [1]. Cholestyramine has been reported with hyperkalemic metabolic acidosis, and the label says combining spironolactone with abiraterone is not recommended and that mitotane should be avoided [1]. None of these entries involves acetaminophen.

Acne is not among the labeled uses of spironolactone. The labeled uses are heart failure, add-on treatment of hypertension, edema in cirrhosis or nephrotic syndrome, and primary hyperaldosteronism [1].

The Liver Warnings

The Tylenol labels carry a liver warning: severe liver damage may occur if an adult takes more than 4,000 mg in 24 hours, takes it with another drug containing acetaminophen, or has 3 or more alcoholic drinks every day while using it [2].

The printed maximum on each over-the-counter Tylenol product is lower than that 4,000 mg ceiling. The labels allow 6 caplets (3,000 mg) of Extra Strength 500 mg in 24 hours, 10 tablets (3,250 mg) of Regular Strength 325 mg, and 6 caplets (3,900 mg) of 8 HR Arthritis Pain 650 mg [2]. The intravenous acetaminophen label sets 4,000 mg a day as the limit from all routes and all acetaminophen-containing products for adults and adolescents weighing 50 kg or more [2].

In a prospective US study of 662 patients with acute liver failure at 22 centers, 275 (42%) were attributed to acetaminophen. The median dose taken was 24 g, and 48% of those cases were unintentional; within that group, 38% had taken two or more acetaminophen preparations and 63% had used narcotic-containing products [3].

Alcohol is the other variable. In a randomized trial of 201 alcoholic patients entering detox, acetaminophen 1,000 mg four times daily for two days produced a day-4 mean AST of 38.0 U/L versus 37.5 U/L on placebo, with no evidence of liver injury [5]. In a second randomized trial, people who drank 1 to 3 alcoholic beverages a day and took 4 g of acetaminophen daily for 10 days had a mean ALT rise of 8.7 IU/L at day 11, without symptoms or predefined hepatotoxicity [6]. Neither trial tested long courses or heavy ongoing drinking.

Does Spironolactone Cause Liver Damage on Its Own?

Rarely. The label's adverse reaction list includes a very few cases of mixed cholestatic/hepatocellular toxicity, with one reported fatality [1]. The label also says that in people with cirrhosis and ascites, treatment should start in hospital because spironolactone can precipitate encephalopathy and coma [1].

In the SAFA trial of 410 women with facial acne, no serious adverse reactions were reported, and adverse reactions were otherwise similar between groups apart from headache, which occurred in 20.4% of the spironolactone group versus 12.0% on placebo [4].

What the Label Says About NSAIDs and Aspirin

The spironolactone label names NSAIDs among the drugs that can raise potassium, and says NSAIDs can reduce the diuretic, natriuretic and antihypertensive effect of spironolactone [1]. It also says acetylsalicylic acid may reduce spironolactone's efficacy; 600 mg of aspirin blunted the natriuretic effect, possibly by blocking tubular secretion of the active metabolite canrenone [1].

Practical Points for People Taking Both

Using more than one acetaminophen-containing product can lead to unintentional overdosing. Acetaminophen is an ingredient in many over-the-counter cold and flu products and in prescription opioid combinations such as Percocet and Norco, and the Tylenol labels say never to use it with another acetaminophen drug, prescription or over-the-counter [2]. In the US acute liver failure study, 38% of the unintentional cases had taken two or more acetaminophen preparations at once [3].

On the spironolactone side, the label lists hyperkalemia, Addison's disease and concomitant use of eplerenone as contraindications [1].