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Interactions between Osilodrostat and Rilzabrutinib

1 drug interaction and 11 additional warnings found for the following 2 drugs:

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Drug interactions

Moderate drug interactions

Moderate:

osilodrostat rilzabrutinib

Applies to: osilodrostat and rilzabrutinib
Monitor

Coadministration with 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 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

Caution is advised when osilodrostat is coadministered with CYP450 3A4 inhibitors. Dosage adjustments may be required 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.

References (3)
  1. (2024) "Product Information. Isturisa (osilodrostat)." Recordati Rare Diseases Australia Pty Ltd, 4.0
  2. (2025) "Product Information. Isturisa (osilodrostat)." Recordati Rare Diseases UK Ltd
  3. (2025) "Product Information. Isturisa (osilodrostat)." Recordati Rare Diseases Inc

Food/lifestyle interactions

Major food/lifestyle interactions

Major:

rilzabrutinib Food/Lifestyle

Applies to: rilzabrutinib
Generally avoid

Grapefruit, grapefruit juice, Seville oranges, and starfruit may increase the plasma concentrations of rilzabrutinib, which is primarily metabolized by CYP450 3A4. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in these fruits. Inhibition of hepatic CYP450 3A4 may also contribute. The interaction has not been studied with grapefruit, Seville oranges, or starfruit but has been studied with other CYP450 3A4 inhibitors. Based on clinical studies, concomitant use with the potent CYP450 3A4 inhibitor ritonavir increased rilzabrutinib peak plasma concentration (Cmax) and systemic exposure (AUC) by 5-fold and 8-fold at steady state, respectively. Based on model-informed approaches, coadministration of moderate CYP450 3A4 inhibitors (e.g., fluconazole, erythromycin, verapamil) is predicted to increase rilzabrutinib Cmax and AUC by 3-fold at steady state. 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. Increased exposure to rilzabrutinib may increase the risk of adverse effects such as infections, diarrhea, nausea, and headache.

Management

It may be advisable for patients to avoid the consumption of grapefruit, grapefruit juice, Seville oranges, starfruit or products that contain these fruits during treatment with rilzabrutinib.

References (34)
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  6. Sigusch H, Hippius M, Henschel L, Kaufmann K, Hoffmann A (1994) "Influence of grapefruit juice on the pharmacokinetics of a slow release nifedipine formulation." Pharmazie, 49, p. 522-4
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  9. (1995) "Grapefruit juice interactions with drugs." Med Lett Drugs Ther, 37, p. 73-4
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  12. Majeed A, Kareem A (1996) "Effect of grapefruit juice on cyclosporine pharmacokinetics." Pediatr Nephrol, 10, p. 395
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  16. Ozdemir M, Aktan Y, Boydag BS, Cingi MI, Musmul A (1998) "Interaction between grapefruit juice and diazepam in humans." Eur J Drug Metab Pharmacokinet, 23, p. 55-9
  17. Bailey DG, Malcolm J, Arnold O, Spence JD (1998) "Grapefruit juice-drug interactions." Br J Clin Pharmacol, 46, p. 101-10
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  19. Garg SK, Kumar N, Bhargava VK, Prabhakar SK (1998) "Effect of grapefruit juice on carbamazepine bioavailability in patients with epilepsy." Clin Pharmacol Ther, 64, p. 286-8
  20. Lilja JJ, Kivisto KT, Neuvonen PJ (1998) "Grapefruit juice-simvastatin interaction: Effect on serum concentrations of simvastatin, simvastatin acid, and HMG-CoA reductase inhibitors." Clin Pharmacol Ther, 64, p. 477-83
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  27. Gunston GD, Mehta U (2000) "Potentially serious drug interactions with grapefruit juice." S Afr Med J, 90, p. 41
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  34. (2025) "Product Information. Wayrilz (rilzabrutinib)." Genzyme Corporation

Disease interactions

10 potential interactions Applies to: 8 conditions, including Heart Failure, Arrhythmia, Hypokalemia, Adrenal Insufficiency, and Liver Disease.

Adrenal Insufficiency

Moderate:

osilodrostat

Osilodrostat has a moderate potential interaction with Adrenal Insufficiency.

Osilodrostat lowers cortisol levels and can lead to hypocortisolism and sometimes life-threatening adrenal insufficiency. Patients should be evaluated for precipitating causes of hypocortisolism. Serum/plasma cortisol, 24-hour urine free cortisol, and patient's signs/symptoms should be monitored periodically during treatment. Osilodrostat should be decreased or temporarily discontinued if urine free cortisol levels fall below the target range, there is a rapid decrease in cortisol levels, and/or patients report hypocortisolism symptoms. Therapy should be stopped and exogenous glucocorticoid replacement therapy should be administered if serum/plasma cortisol levels are below the target range and patients have symptoms of adrenal insufficiency. Osilodrostat should be restarted at a lower dose when urine free cortisol and serum/plasma cortisol levels are within the target range, and/or patient symptoms have resolved.

Arrhythmia

Moderate:

osilodrostat

Osilodrostat has a moderate potential interaction with Arrhythmia.

The use of osilodrostat is associated with a dose-dependent QT interval prolongation, which may cause cardiac arrhythmias. It is recommended to perform an ECG to obtain a baseline QTc interval measurement before starting therapy and to monitor for an effect on the QTc interval thereafter. Temporary discontinuation of osilodrostat should be considered in the case of an increase in QTc interval greater than 480 milliseconds. Hypokalemia and hypomagnesemia should be corrected before initiating treatment and monitored regularly during treatment. Electrolyte abnormalities should be corrected if indicated. Care should be exercised when using this agent in patients with risk factors for QT prolongation and more frequent ECG monitoring should be considered.

Electrolyte Abnormalities

Moderate:

osilodrostat

Osilodrostat has a moderate potential interaction with Electrolyte Abnormalities.

The use of osilodrostat is associated with a dose-dependent QT interval prolongation, which may cause cardiac arrhythmias. It is recommended to perform an ECG to obtain a baseline QTc interval measurement before starting therapy and to monitor for an effect on the QTc interval thereafter. Temporary discontinuation of osilodrostat should be considered in the case of an increase in QTc interval greater than 480 milliseconds. Hypokalemia and hypomagnesemia should be corrected before initiating treatment and monitored regularly during treatment. Electrolyte abnormalities should be corrected if indicated. Care should be exercised when using this agent in patients with risk factors for QT prolongation and more frequent ECG monitoring should be considered.

Heart Failure

Moderate:

osilodrostat

Osilodrostat has a moderate potential interaction with Heart Failure.

The use of osilodrostat is associated with a dose-dependent QT interval prolongation, which may cause cardiac arrhythmias. It is recommended to perform an ECG to obtain a baseline QTc interval measurement before starting therapy and to monitor for an effect on the QTc interval thereafter. Temporary discontinuation of osilodrostat should be considered in the case of an increase in QTc interval greater than 480 milliseconds. Hypokalemia and hypomagnesemia should be corrected before initiating treatment and monitored regularly during treatment. Electrolyte abnormalities should be corrected if indicated. Care should be exercised when using this agent in patients with risk factors for QT prolongation and more frequent ECG monitoring should be considered.

Hypokalemia

Moderate:

osilodrostat

Osilodrostat has a moderate potential interaction with Hypokalemia.

The use of osilodrostat is associated with a dose-dependent QT interval prolongation, which may cause cardiac arrhythmias. It is recommended to perform an ECG to obtain a baseline QTc interval measurement before starting therapy and to monitor for an effect on the QTc interval thereafter. Temporary discontinuation of osilodrostat should be considered in the case of an increase in QTc interval greater than 480 milliseconds. Hypokalemia and hypomagnesemia should be corrected before initiating treatment and monitored regularly during treatment. Electrolyte abnormalities should be corrected if indicated. Care should be exercised when using this agent in patients with risk factors for QT prolongation and more frequent ECG monitoring should be considered.

Liver Disease

Moderate:

osilodrostat

Osilodrostat has a moderate potential interaction with Liver Disease.

Dosage adjustment of osilodrostat is required for patients with moderate to severe liver dysfunction. The recommended starting dose for patients with moderate liver dysfunction is 1 mg orally twice a day, and for patients with severe liver dysfunction is 1 mg orally once a day in the evening. No dose adjustment is required in patients with mild liver dysfunction. More frequent monitoring of adrenal function may be needed during dose titration in all patients with liver dysfunction.

Moderate:

rilzabrutinib

Rilzabrutinib has a moderate potential interaction with Liver Disease.

Rilzabrutinib is not recommended for use in patients with moderate or severe hepatic dysfunction (Child-Pugh B or C). Cmax and AUC increased by approximately 4.5-fold in patients with moderate hepatic dysfunction. Patients with severe hepatic dysfunction were not studied.

Magnesium Imbalance

Moderate:

osilodrostat

Osilodrostat has a moderate potential interaction with Magnesium Imbalance.

The use of osilodrostat is associated with a dose-dependent QT interval prolongation, which may cause cardiac arrhythmias. It is recommended to perform an ECG to obtain a baseline QTc interval measurement before starting therapy and to monitor for an effect on the QTc interval thereafter. Temporary discontinuation of osilodrostat should be considered in the case of an increase in QTc interval greater than 480 milliseconds. Hypokalemia and hypomagnesemia should be corrected before initiating treatment and monitored regularly during treatment. Electrolyte abnormalities should be corrected if indicated. Care should be exercised when using this agent in patients with risk factors for QT prolongation and more frequent ECG monitoring should be considered.

Renal Dysfunction

Moderate:

osilodrostat

Osilodrostat has a moderate potential interaction with Renal Dysfunction.

No dosage adjustment of osilodrostat is required for patients with impaired renal function. However, in patients with moderate to severe renal dysfunction, urinary free cortisol (UFC) levels should be interpreted with caution due to reduced UFC excretion.

Moderate:

rilzabrutinib

Rilzabrutinib has a moderate potential interaction with Renal Dysfunction.

Rilzabrutinib is not recommended for use in patients with severe renal dysfunction (CrCl less than 46 mL/min). Patients with severe renal dysfunction were not studied.

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osilodrostat

A total of 607 drugs are known to interact with osilodrostat.

rilzabrutinib

A total of 574 drugs are known to interact with rilzabrutinib.

Drug Interaction Classification

These classifications are only a guideline. The relevance of a particular drug interaction to a specific individual is difficult to determine. Always consult your healthcare provider before starting or stopping any medication.
Major Highly clinically significant. Avoid combinations; the risk of the interaction outweighs the benefit.
Moderate Moderately clinically significant. Usually avoid combinations; use it only under special circumstances.
Minor Minimally clinically significant. Minimize risk; assess risk and consider an alternative drug, take steps to circumvent the interaction risk and/or institute a monitoring plan.
Unknown No interaction information available.

Further information

Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.

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