Drug Interactions between doxycycline / salicylic acid topical and finerenone

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.

GENERALLY AVOID: The oral bioavailability of quinolone and tetracycline antibiotics may be reduced by concurrent administration of preparations containing polyvalent cations such as aluminum, calcium, iron, magnesium, and zinc. Therapeutic failure may result. The proposed mechanism is chelation of quinolone and tetracycline antibiotics by di- and trivalent cations, forming an insoluble complex that is poorly absorbed from the gastrointestinal tract. Reduced gastrointestinal absorption of the cations should also be considered.

MANAGEMENT: Concomitant administration of oral quinolone and tetracycline antibiotics with preparations containing aluminum, calcium, iron, magnesium, and/or zinc salts should generally be avoided. Otherwise, the times of administration should be staggered by as much as possible to minimize the potential for interaction. Quinolones should typically be dosed either 2 to 4 hours before or 4 to 6 hours after polyvalent cation preparations, depending on the quinolone and formulation. Likewise, tetracyclines and polyvalent cation preparations should typically be administered 2 to 4 hours apart. The prescribing information for the antibiotic should be consulted for more specific dosing recommendations.

Chronic alcohol consumption may enhance the elimination of doxycycline. The mechanism is induction of hepatic microsomal enzymes by alcohol. In one study, the half-life of doxycycline in six alcoholics was 10.5 hours, compared with 14.7 hours in six control patients. In addition, half the alcoholic patients had serum concentrations below what is generally considered the minimum therapeutic concentration (0.5 mcg/mL) at 12 to 24 hours after the dose. The investigators suggest that twice-a-day dosing may be indicated in these patients, especially if additional inducing drugs are used. The elimination of other tetracyclines probably is not affected by alcohol consumption.