OSILODROSTAT Drug Interactions: What You Need to Know

INTERACTIONS CYP3A4 Inhibitor: Reduce the dose of ISTURISA by half with concomitant use of a strong CYP3A4 inhibitor ( 7.1 ) CYP3A4 and CYP2B6 Inducers: An increase of ISTURISA dosage may be needed if ISTURISA is used concomitantly with strong CYP3A4 and CYP2B6 inducers. A reduction in ISTURISA dosage may be needed if strong CYP3A4 and CYP2B6 inducers are discontinued while using ISTURISA ( 7.1 )

7.1 Effect of Other Drugs on ISTURISA The effect of other drugs on ISTURISA can be found in Table 3.

Table

3: Effect of Other Drugs on ISTURISA CYP3A4 Inhibitors Clinical Impact: Concomitant use of ISTURISA with a strong CYP3A4 inhibitor (e.g., itraconazole, clarithromycin) may cause an increase in osilodrostat concentration and may increase the risk of ISTURISA-related adverse reactions [see Clinical Pharmacology (12.3) ] . Intervention : Reduce the dose of ISTURISA by half with concomitant use of a strong CYP3A4 inhibitor. CYP3A4 and CYP2B6 Inducers Clinical Impact: Concomitant use of ISTURISA with strong CYP3A4 and/or CYP2B6 inducers (e.g., carbamazepine, rifampin, phenobarbital) may cause a decrease in osilodrostat concentration and may reduce the efficacy of ISTURISA [see Clinical Pharmacology (12.3) ] . Discontinuation of strong CYP3A4 and/or CYP2B6 inducers while using ISTURISA may cause an increase in osilodrostat concentration and may increase the risk of ISTURISA-related adverse reactions [see Clinical Pharmacology (12.3) ] . Intervention: During concomitant use of ISTURISA with strong CYP3A4 and CYP2B6 inducers, monitor cortisol concentration and patient's signs and symptoms. An increase in ISTURISA dosage may be needed. Upon discontinuation of strong CYP3A4 and CYP2B6 inducers during ISTURISA treatment, monitor cortisol concentration and patient's signs and symptoms. A reduction in ISTURISA dosage may be needed.

7.2 Effect of ISTURISA on Other Drugs ISTURISA should be used with caution when coadministered with CYP1A2 and CYP2C19 substrates with a narrow therapeutic index, such as theophylline, tizanidine, and S-mephenytoin <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span> .

None. None ( 4 )

AND PRECAUTIONS Hypocortisolism : Monitor patients closely for hypocortisolism and potentially life-threatening adrenal insufficiency. Dosage reduction or interruption may be necessary. After interruption or discontinuation of ISTURISA, cortisol suppression may persist and patients should be regularly monitored ( 5.1 ) QTc Prolongation : Perform electrocardiogram in all patients Use with caution in patients with risk factors for QTc prolongation ( 5.2 ) Elevations in Adrenal Hormone Precursors and Androgens: Monitor for hypokalemia, worsening of hypertension, edema, and hirsutism ( 5.3 )

5.1 Hypocortisolism ISTURISA lowers cortisol levels and can lead to hypocortisolism and sometimes life-threatening adrenal insufficiency. Lowering of cortisol can cause nausea, vomiting, fatigue, abdominal pain, loss of appetite, dizziness. Significant lowering of serum cortisol may result in hypotension, abnormal electrolyte levels, and hypoglycemia <span class="opacity-50 text-xs">[see Adverse Reactions (6) ]</span> . Hypocortisolism can occur at any time during ISTURISA treatment. Evaluate patients for precipitating causes of hypocortisolism (infection, physical stress, etc.).

Monitor

24-hour urine free cortisol, serum or plasma cortisol, and patient's signs and symptoms periodically during ISTURISA treatment. Decrease or temporarily discontinue ISTURISA if urine free cortisol levels fall below the target range, there is a rapid decrease in cortisol levels, and/or patients report symptoms of hypocortisolism. Stop ISTURISA and administer exogenous glucocorticoid replacement therapy if serum or plasma cortisol levels are below target range and patients have symptoms of adrenal insufficiency. After interruption or discontinuation of ISTURISA, cortisol suppression may persist beyond the 4 hour half-life. Monitor patients regularly and re-initiate ISTURISA at a lower dose when urine free cortisol, serum or plasma cortisol levels are within target range, and/or patient symptoms have resolved. Educate patients on the symptoms associated with hypocortisolism and advise them to contact a healthcare provider if they occur.

5.2 QTc Prolongation ISTURISA is associated with a dose-dependent QT interval prolongation (maximum mean estimated QTcF increase of up to 5.3 ms at 30 mg), which may cause cardiac arrhythmias <span class="opacity-50 text-xs">[see Adverse Reactions (6) , Clinical Pharmacology (12.2) ]</span>. Perform an ECG to obtain a baseline QTc interval measurement prior to initiating therapy with ISTURISA and monitor for an effect on the QTc interval thereafter. Correct hypokalemia and/or hypomagnesemia prior to ISTURISA initiation and monitor periodically during treatment with ISTURISA. Correct electrolyte abnormalities if indicated. Consider temporary discontinuation of ISTURISA in the case of an increase in QTc interval &gt; 480 ms. Use caution in patients with risk factors for QT prolongation, (such as congenital long QT syndrome, congestive heart failure, bradyarrhythmias, uncorrected electrolyte abnormalities, and concomitant medications known to prolong the QT interval) and consider more frequent ECG monitoring.

5.3 Elevations in Adrenal Hormone Precursors and Androgens ISTURISA blocks cortisol synthesis and may increase circulating levels of cortisol and aldosterone precursors (11-deoxy cortisol and 11-deoxycorticosterone) and androgens.

Elevated

11-deoxycorticosterone levels may activate mineralocorticoid receptors and cause hypokalemia, edema and hypertension [see Adverse Reactions (6) ] . Hypokalemia should be corrected prior to initiating ISTURISA. Monitor patients treated with ISTURISA for hypokalemia, worsening of hypertension and edema. ISTURISA-induced hypokalemia should be treated with intravenous or oral potassium supplementation based on event severity. If hypokalemia persists despite potassium supplementation, consider adding mineralocorticoid antagonists. ISTURISA dose reduction or discontinuation may be necessary. Accumulation of androgens may lead to hirsutism, hypertrichosis and acne (in females). Inform patients of the symptoms associated with hyperandrogenism and advise them to contact a healthcare provider if they occur.