Drug Interactions between Omeclamox-Pak and osilodrostat

ADJUST DOSE: Coadministration with potent inhibitors of CYP450 3A4 may increase the plasma concentrations of osilodrostat, which is partially metabolized by the isoenzyme. According to the product labeling, multiple CYP450 isoenzymes (CYP450 3A4, 2B6, and 2D6) and UDP-glucuronosyltransferases contribute to osilodrostat metabolism, and no single pathway contributes greater than 25% to the total clearance. Pharmacokinetic data for osilodrostat in combination with a potent CYP450 3A4 inhibitor have not been reported. Clinically, high plasma levels of osilodrostat may increase the risk of adverse effects such as hypocortisolism (which may lead to life-threatening adrenal insufficiency), QT prolongation (which may increase the risk of ventricular arrhythmias including torsade de pointes and sudden death), and elevated androgen and 11-deoxycorticosterone levels (the latter of which may activate mineralocorticoid receptors and cause hypokalemia, edema, and hypertension).

MANAGEMENT: The manufacturer recommends reducing the dosage of osilodrostat by one-half during concomitant use of a potent CYP450 3A4 inhibitor. Further dosage adjustments should be based on clinical response and tolerance. Patients should have regular monitoring of 24-hour urine free cortisol and serum or plasma cortisol during treatment, as well as regular evaluations for signs and symptoms of hypocortisolism such as nausea, vomiting, abdominal pain, loss of appetite, fatigue, dizziness, hypotension, abnormal electrolyte levels, and hypoglycemia. Decrease dosing or temporarily discontinue osilodrostat if patients experience symptoms of hypocortisolism or if urine free cortisol levels fall below the target range or there is a rapid decrease in cortisol levels. Stop osilodrostat and administer exogenous glucocorticoid replacement therapy if patients have symptoms of adrenal insufficiency and serum or plasma cortisol levels are below target range. Osilodrostat therapy may be restarted at a lower dosage when symptoms have resolved and cortisol values are within target range. Additionally, an electrocardiogram and serum electrolyte levels should also be obtained prior to initiating osilodrostat, with ECG repeated within one week after starting treatment and periodically thereafter. Correct hypokalemia and/or hypomagnesemia before starting treatment and as indicated during treatment, as they may be risk factors for ventricular arrhythmias. If QTc interval exceeds 480 msec at any point, temporary dose reduction, interruption, or discontinuation of osilodrostat may be necessary.

Switch to consumer interaction data

MONITOR: Coadministration with osilodrostat may increase the plasma concentrations of drugs that are metabolized by CYP450 1A2, 2C19, 2D6, and/or 3A4. Osilodrostat has been shown to be a moderate inhibitor of CYP450 1A2, a mild to borderline moderate inhibitor of CYP450 2C19, and a weak inhibitor of CYP450 2D6 and 3A4. In a pharmacokinetic study with 20 healthy volunteers using a single 50 mg dose of osilodrostat and a probe drug cocktail, osilodrostat increased the exposures to caffeine (CYP450 1A2 substrate), omeprazole (CYP450 2C19 substrate), dextromethorphan (CYP450 2D6 substrate), and midazolam (CYP450 3A4/5 substrate) by 2.5-, 1.9-, 1.5- and 1.5-fold, respectively.

MANAGEMENT: Caution is advised when osilodrostat is used concurrently with drugs that are substrates of CYP450 1A2, 2C19, 2D6 and/or 3A4, particularly those with a narrow therapeutic range. Dosage adjustments as well as clinical and laboratory monitoring may be appropriate for some drugs whenever osilodrostat is added to or withdrawn from therapy.

Switch to consumer interaction data

Although some in vitro data indicate synergism between macrolide antibiotics and penicillins, other in vitro data indicate antagonism. When these drugs are given together, neither has predictable therapeutic efficacy. Data are available for erythromycin, although theoretically this interaction could occur with any macrolide. Except for monitoring of the effectiveness of antibiotic therapy, no special precautions appear to be necessary.

Switch to consumer interaction data

Clarithromycin may increase and prolong the omeprazole plasma concentration. The mechanism may be related to clarithromycin inhibition of hepatic cytochrome P450 enzymes responsible for omeprazole metabolism. Coadministration of omeprazole may result in an increase in clarithromycin and 14-(R)-hydroxyclarithromycin plasma concentrations. These increases may be due to the effect of omeprazole on gastric pH.

Switch to consumer interaction data