Is Mifepristone safe to use in patients taking Ranexa (Ranolazine)?

Mifepristone and Ranolazine: Significant Drug Interaction Risk

Mifepristone should be used with extreme caution or avoided in patients taking Ranexa (ranolazine) due to the high risk of drug-drug interactions, particularly given that both medications have complex metabolic profiles and ranolazine is a P-glycoprotein substrate with known interaction risks. 1

Critical Drug Interaction Concerns

Mifepristone's Complex Interaction Profile

• Mifepristone requires expert monitoring specifically because drug-drug interactions must be carefully considered when this medication is used 1
• The Lancet Diabetes and Endocrinology guidelines explicitly state that mifepristone should be used cautiously and only by clinicians with extensive experience, emphasizing that drug-drug interactions are a major concern 1
• Mifepristone has a long half-life, which compounds interaction risks and makes management of adverse effects more challenging 1

Ranolazine's Metabolic and Transport Characteristics

• Ranolazine is metabolized by cytochrome P450 isoenzymes CYP 3A4 and CYP 2D6 and is a P-glycoprotein substrate, creating high risk for pharmacokinetic interactions 2
• There is documented evidence of serious interactions between ranolazine and other P-glycoprotein substrates, as demonstrated in a case where ranolazine interacted with dabigatran (another P-glycoprotein substrate) causing dangerous overdose effects 3
• Ranolazine also carries risk of pharmacodynamic interactions with drugs that prolong the QT interval 2

Specific Risks in This Combination

Monitoring Challenges

• Mifepristone blocks cortisol measurements from being reliable for monitoring treatment response or adrenal insufficiency, eliminating a key safety parameter 1
• This monitoring limitation becomes particularly dangerous when combined with another medication that has unpredictable interaction potential
• If adverse effects occur, mifepristone's long half-life requires several days of stress-dose glucocorticoid replacement, preferably dexamethasone 1

Patient Risk Factors

• Patients with renal impairment are at particularly high risk when ranolazine is combined with interacting medications 3
• The combination should be especially avoided in elderly patients, as ranolazine doses greater than 500 mg twice daily are associated with serious neurologic adverse effects in patients over 80 years 4

Clinical Recommendation Algorithm

If mifepristone is being considered in a patient on ranolazine:

1. Consult an expert endocrinologist with extensive Cushing's disease experience before proceeding 1

2. Consider alternative medications:

   • For Cushing's disease: Use osilodrostat, metyrapone, or ketoconazole instead of mifepristone 1
   • For ranolazine: Evaluate if beta-blockers, ivabradine, nitrates, or amlodipine could substitute 1

3. If the combination cannot be avoided:

   • Use the lowest effective doses of both medications 3
   • Monitor closely for neurologic symptoms (dysarthria, dysmetria, hallucinations, tremors, word-finding difficulty) 4
   • Check renal function and adjust doses accordingly 3, 4
   • Counsel the patient extensively about the inability to use cortisol monitoring for safety 1
   • Have a plan for managing potential adrenal insufficiency with dexamethasone 1

Common Pitfalls to Avoid

• Do not assume standard monitoring will be adequate - mifepristone eliminates the ability to use cortisol levels for safety monitoring 1
• Do not use standard ranolazine doses in high-risk patients - dose reduction is essential in elderly or renally impaired patients when drug interactions are present 3, 4
• Do not prescribe this combination without specialist consultation - guidelines explicitly state mifepristone should only be used by experienced clinicians 1