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

Does spironolactone interact with levothyroxine?

No interaction between the two is described on either label. Spironolactone is not named among the drugs the levothyroxine labels identify as interfering with absorption or metabolism, and levothyroxine is not named among spironolactone's labelled interactions [2][1].

The levothyroxine labels are specific about what does interfere. Calcium carbonate may form an insoluble chelate with levothyroxine and ferrous sulfate likely forms a ferric-thyroxine complex; the label says to give levothyroxine at least 4 hours apart from them. Bile acid sequestrants and ion exchange resins such as colesevelam, cholestyramine, colestipol, sodium polystyrene sulfonate and sevelamer reduce absorption, and the label says to take levothyroxine at least 4 hours before them or monitor TSH. Antacids, sucralfate and proton pump inhibitors may reduce absorption by lowering gastric acidity; the label gives no fixed spacing for them and says to monitor [2]. Spironolactone falls in none of those groups.

On the spironolactone side, the Aldactone label's interaction warnings concern potassium-raising drugs (potassium supplements, potassium-containing salt substitutes, ACE inhibitors, angiotensin receptor blockers, NSAIDs, heparin and low molecular weight heparin, trimethoprim), lithium, NSAIDs and aspirin, digoxin immunoassays, cholestyramine, abiraterone and mitotane [1]. Spironolactone is rapidly and extensively metabolized, and the label names no cytochrome P450 enzyme and lists no CYP-based interactions [1].

Why timing comes up anyway

Both labels give food instructions, and they differ.

The levothyroxine tablet and capsule labels say to take it as a single daily dose on an empty stomach, one-half to one hour before breakfast, and at least 4 hours before or after drugs known to interfere with absorption. The label also advises evaluating the need for dose adjustments when levothyroxine is regularly taken within an hour of foods that affect absorption [2]. For Tirosint-SOL, the oral solution, the label says 15 minutes before breakfast instead [2]. Soybean flour (infant formula), cottonseed meal, walnuts and dietary fiber may bind and decrease absorption, and grapefruit juice may delay absorption and reduce bioavailability [2].

For spironolactone, the Aldactone label says to take it consistently with respect to food; food raised its bioavailability by about 95% [1].

The 4-hour rule in the levothyroxine labels applies to calcium carbonate, ferrous sulfate, the bile acid sequestrants and the ion exchange resins [2]. Spironolactone is not on that list.

Adrenal insufficiency: where the two labels meet

Spironolactone is contraindicated in Addison's disease [1]. The levothyroxine labels contraindicate use in uncorrected adrenal insufficiency and say adrenal insufficiency should be treated with glucocorticoids before levothyroxine is started, because of the risk of acute adrenal crisis [2]. The overlap is about the patient's adrenal status, not a reaction between the two drugs.

Potassium and TSH: what gets checked

Potassium is the spironolactone check. The Aldactone label lists hyperkalemia as a risk increased by impaired renal function, potassium supplements, potassium-containing salt substitutes, ACE inhibitors and angiotensin receptor blockers, and says to monitor serum potassium within 1 week of starting or changing the dose and regularly afterwards; if hyperkalemia occurs, it says to reduce the dose or stop and treat [1]. In heart failure, the label says to discontinue potassium supplements when starting spironolactone [1].

In healthy young women taking spironolactone for acne, abnormal potassium was uncommon: 13 abnormal values in 1,802 measurements (0.72%) among 974 women, against a 0.76% baseline rate in 1,165 comparison women, with 6 of the 13 values normal on repeat. That study excluded women with heart or kidney disease and those taking drugs acting on the renin-angiotensin system, and its authors concluded routine potassium monitoring has low usefulness in this group [4]. The Aldactone label itself still calls for monitoring [1].

TSH is the levothyroxine check. In euthyroid adults the half-life is 6 to 7 days (3 to 4 days in hyperthyroidism, 9 to 10 days in hypothyroidism), the peak effect of a dose may take 4 to 6 weeks, and the label adjusts the dose in 12.5 to 25 mcg steps every 4 to 6 weeks until TSH is normal [2]. The Synthroid label tells patients to stop biotin and biotin-containing supplements at least 2 days before TSH or T4 testing, because of assay interference [2].

Doses you may see

Acne is not a labelled spironolactone indication; the labelled uses are NYHA Class III-IV heart failure with reduced ejection fraction, add-on therapy for hypertension, edema in cirrhosis or nephrotic syndrome, and primary hyperaldosteronism [1]. In the SAFA randomised trial, 410 women with facial acne took spironolactone 50 mg daily for 6 weeks, then 100 mg daily to week 24, or placebo, and the spironolactone group improved more on acne-specific quality of life and on investigator-rated success [3]. For levothyroxine, the label's average full replacement dose in adult primary hypothyroidism is about 1.6 mcg per kg per day [2].