Drug Interactions between finerenone and Synthroid

GENERALLY AVOID: Grapefruit juice may increase the plasma concentrations of finerenone. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit. Inhibition of hepatic CYP450 3A4 may also contribute. The interaction has not been studied with grapefruit juice, but has been reported for other CYP450 3A4 inhibitors. Pharmacokinetic modeling simulations suggest that concomitant use of finerenone with 200 mg twice daily itraconazole, a potent CYP450 3A4 inhibitor, increases finerenone peak plasma concentration (Cmax) and systemic exposure (AUC) by 137% and 531%, respectively. Clarithromycin, another potent CYP450 3A4 inhibitor, given at 500 mg twice daily is predicted to increase finerenone Cmax by 125% and AUC by 428%. Additionally, drug interaction studies showed that concomitant use of finerenone with 500 mg thrice daily erythromycin, a moderate CYP450 3A4 inhibitor, increased mean finerenone Cmax and AUC by 88% and 248%, respectively. Verapamil, another moderate CYP450 3A4 inhibitor, given as a 240 mg controlled-release tablet once daily increased mean finerenone Cmax by 120% and AUC by 170%. In general, the effect of grapefruit juice is concentration-, dose- and preparation-dependent, and can vary widely among brands. Certain preparations of grapefruit juice (e.g., high dose, double strength) have sometimes demonstrated potent inhibition of CYP450 3A4, while other preparations (e.g., low dose, single strength) have typically demonstrated moderate inhibition. Pharmacokinetic interactions involving grapefruit juice are also subject to a high degree of interpatient variability, thus the extent to which a given patient may be affected is difficult to predict. High exposure to finerenone may potentiate the risk of hyperkalemia, and the risk may be further increased with decreasing kidney function and higher baseline potassium levels.

MONITOR CLOSELY: Dietary intake of excess potassium, especially via salt substitutes, may increase the risk of hyperkalemia in patients who are using finerenone. Patients with diabetes, heart failure, dehydration, or renal insufficiency have a greater risk of developing hyperkalemia.

Administration of finerenone with high-fat, high-calorie food decreased finerenone Cmax by 19%, increased AUC by 21%, and prolonged the time to reach Cmax to 2.5 hours. These changes are not considered clinically relevant.

MANAGEMENT: Patients receiving finerenone therapy should be instructed to avoid consumption of grapefruit or grapefruit juice. In addition, patients should receive dietary counseling and be advised not to use potassium-containing salt substitutes or over-the-counter potassium supplements without consulting their physician. If salt substitutes or supplements are used concurrently, more frequent monitoring of serum potassium levels is recommended. Patients should also be advised to seek medical attention if they experience signs and symptoms of hyperkalemia such as nausea, vomiting, weakness, listlessness, tingling of the extremities, paralysis, confusion, weak pulse, and a slow or irregular heartbeat. Finerenone may be taken with or without food.

ADJUST DOSING INTERVAL: Consumption of certain foods as well as the timing of meals relative to dosing may affect the oral absorption of T4 thyroid hormone (i.e., levothyroxine). T4 oral absorption is increased by fasting and decreased by foods such as soybean flour (e.g., infant formula), cotton seed meal, walnuts, dietary fiber, calcium, and calcium fortified juices. Grapefruit or grapefruit products may delay the absorption of T4 thyroid hormone and reduce its bioavailability. The mechanism of this interaction is not fully understood.

MANAGEMENT: Some manufacturers recommend administering oral T4 as a single daily dose, on an empty stomach, one-half to one hour before breakfast. In general, oral preparations containing T4 thyroid hormone should be administered on a consistent schedule with regard to time of day and relation to meals to avoid large fluctuations in serum levels. Foods that may affect T4 absorption should be avoided within several hours of dosing if possible. Consult local guidelines for the administration of T4 in patients receiving enteral feeding.

ADJUST DOSING INTERVAL: Concurrent administration of calcium-containing products may decrease the oral bioavailability of levothyroxine by one-third in some patients. Pharmacologic effects of levothyroxine may be reduced. The exact mechanism of interaction is unknown but may involve nonspecific adsorption of levothyroxine to calcium at acidic pH levels, resulting in an insoluble complex that is poorly absorbed from the gastrointestinal tract. In one study, 20 patients with hypothyroidism who were taking a stable long-term regimen of levothyroxine demonstrated modest but significant decreases in mean free and total thyroxine (T4) levels as well as a corresponding increase in mean thyrotropin (thyroid-stimulating hormone, or TSH) level following the addition of calcium carbonate (1200 mg/day of elemental calcium) for 3 months. Four patients had serum TSH levels that were higher than the normal range. Both T4 and TSH levels returned to near-baseline 2 months after discontinuation of calcium, which further supported the likelihood of an interaction. In addition, there have been case reports suggesting decreased efficacy of levothyroxine during calcium coadministration. It is not known whether this interaction occurs with other thyroid hormone preparations.

MANAGEMENT: Some experts recommend separating the times of administration of levothyroxine and calcium-containing preparations by at least 4 hours. Monitoring of serum TSH levels is recommended. Patients with gastrointestinal or malabsorption disorders may be at a greater risk of developing clinical or subclinical hypothyroidism due to this interaction.