Spironolactone and Atorvastatin Interaction: What Patients and Prescribers Need to Know

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Is there a direct interaction between spironolactone and atorvastatin?

Atorvastatin is taken once daily at any time of day, with or without food, at 10 mg to 80 mg [1]. It is a substrate of CYP3A4 and of the transporters OATP1B1/1B3, BCRP and P-gp, and the label warns that inhibitors of these pathways raise atorvastatin plasma levels and with them the risk of myopathy and rhabdomyolysis [1]. Clarithromycin and itraconazole can raise atorvastatin levels, and the Lipitor label limits atorvastatin to 20 mg daily when either is taken [1]. Concomitant use of cyclosporine or gemfibrozil with Lipitor is not recommended [1].

The Lipitor label identifies cyclosporine, gemfibrozil, certain antivirals, selected azole antifungals and macrolides, and large amounts of grapefruit juice as drugs or substances that can raise atorvastatin exposure. It separately links lipid-modifying niacin (1 g/day or more), other fibrates and colchicine with increased myopathy or rhabdomyolysis risk [1].

Spironolactone's own label describes rapid, extensive metabolism to canrenone and to sulfur-containing metabolites (7-alpha-thiomethylspironolactone and its 6-beta-hydroxy derivative) and names no cytochrome P450 enzyme [2].

What the spironolactone label warns about

Spironolactone is an aldosterone antagonist. It blocks aldosterone at the sodium-potassium exchange site in the distal renal tubule, so more sodium and water is excreted while potassium is retained [2]. The label warns that combining it with other potassium-sparing diuretics, ACE inhibitors, angiotensin II antagonists, aldosterone blockers, NSAIDs, heparin or low-molecular-weight heparin, potassium supplements, a potassium-rich diet or salt substitutes containing potassium may lead to severe hyperkalemia [2]. The current Aldactone label lists hyperkalemia, Addison's disease and concomitant eplerenone as contraindications. Impaired kidney function raises the risk of hyperkalemia [2]. Older-format generic labels state that hyperkalemia may be fatal in severe heart failure and that lithium generally should not be given with diuretics [2].

The current Aldactone label says to check serum potassium within 1 week of starting or changing the dose and regularly afterward. Older-format generic labels give a schedule for severe heart failure: potassium and creatinine one week after starting or increasing the dose, monthly for the first 3 months, quarterly for a year, and then every 6 months, with treatment stopped or interrupted if potassium is above 5 mEq/L or creatinine is above 4 mg/dL [2].

How large is the potassium risk when spironolactone is prescribed for acne?

Acne is not one of spironolactone's labeled indications; the labeled uses include heart failure, add-on therapy for hypertension, edema and primary hyperaldosteronism [2]. The SAFA trial enrolled 410 women with persistent facial acne and compared spironolactone, 50 mg daily to week 6 then 100 mg daily, with placebo while participants continued their usual topical treatments [3].

Potassium values in that population have been measured. In a retrospective study from two US tertiary care centers, 974 healthy young women taking spironolactone for acne had 13 abnormal potassium values in 1,802 measurements, a rate of 0.72%, against a 0.76% baseline rate among 1,165 comparison women; 6 of the 13 repeat values were normal [4]. Women with cardiovascular disease, renal failure, or drugs acting on the renin-angiotensin-aldosterone system were excluded from that study [4]. The Aldactone label itself still calls for potassium monitoring.

What are the muscle-risk factors with atorvastatin?

The Lipitor label lists the risk factors for myopathy and rhabdomyolysis as age 65 or older, uncontrolled hypothyroidism, renal impairment, interacting drugs, and higher atorvastatin doses [1]. The label says patients should be instructed to report unexplained muscle pain, tenderness or weakness promptly, particularly if accompanied by malaise or fever, and that atorvastatin should be discontinued if myopathy is diagnosed or suspected [1]. Rare cases of immune-mediated necrotizing myopathy, an autoimmune muscle condition, have also been reported with statins [1].

Both labels treat the kidney as a factor. Renal impairment is a listed myopathy risk factor for atorvastatin [1], and impaired kidney function raises the risk of hyperkalemia with spironolactone [2].

What else is worth checking in this combination

Grapefruit: the Lipitor label recommends avoiding large quantities, more than 1.2 liters a day; 240 mL of grapefruit juice daily raised the AUC of a single 40 mg atorvastatin dose 1.37-fold, with larger increases reported at 750 mL to 1.2 liters per day [1].

Combined oral contraceptives: atorvastatin 40 mg daily raised norethindrone AUC 1.28-fold and ethinyl estradiol AUC 1.19-fold, and the label says to consider this when choosing an oral contraceptive [1]. In a series of 403 women treated with spironolactone for acne, menstrual side effects were less common among those using combined oral contraception (odds ratio 0.23, 95% CI 0.11 to 0.50) [5].

Liver: persistent transaminase elevations above 3 times the upper limit of normal occurred in about 0.7% of atorvastatin-treated patients overall, and in 2.3% at 80 mg; the label suggests liver enzyme testing before starting and when clinically indicated [1].

Pregnancy: the Lipitor label does not list pregnancy as a contraindication and says to discontinue atorvastatin when pregnancy is recognized, or to weigh the patient's ongoing therapeutic needs [1]. The current Aldactone label advises avoiding the drug in pregnancy, or advising of the potential risk to a male fetus, because of its anti-androgenic properties and animal data showing feminization of male fetuses.