Can methadone be co‑administered with apalutamide, and what monitoring or dose adjustments are required?

Methadone and Apalutamide Co-Administration

Direct Answer

Methadone should NOT be co-administered with apalutamide without significant dose adjustments and intensive monitoring, as apalutamide is a potent CYP3A4 and CYP2C8 inducer that will substantially reduce methadone levels, potentially precipitating opioid withdrawal. 1

Mechanism of Interaction

Apalutamide causes profound enzyme induction that reduces exposure to CYP3A4 substrates by 92% and CYP2C8 substrates by 18%. 1 Since methadone is metabolized predominantly by CYP2C8 and to a lesser extent by CYP3A4, co-administration with apalutamide will dramatically decrease methadone plasma concentrations. 2, 1

• Apalutamide reduces systemic exposure to midazolam (a CYP3A4 substrate) by 92%, demonstrating its potent induction effect 1
• The magnitude of this interaction is severe enough to cause complete loss of therapeutic activity for affected medications 1
• Methadone's complex pharmacokinetics (half-life 8 to >120 hours) make dose adjustments particularly challenging 2, 3

Required Management Strategy

If Co-Administration is Unavoidable:

Increase the methadone dose by 2-3 fold when initiating apalutamide, with close monitoring for withdrawal symptoms. 2 This recommendation is based on rifampin interaction data, which shows similar CYP enzyme induction patterns requiring 2-3 fold dose increases. 2

• Monitor patients daily during the first week for signs of opioid withdrawal (anxiety, sweating, tachycardia, mydriasis, piloerection, nausea, diarrhea) 2
• Provide short-acting opioid breakthrough medications during the titration period 2
• Obtain baseline and follow-up ECGs, as both high-dose methadone (≥100-120 mg/day) and dose escalation increase QTc prolongation risk 2, 4
• QTc ≥450 msec requires dose reduction or discontinuation; QTc >500 msec is an absolute contraindication to continuing methadone 5

Cardiac Monitoring Protocol:

Obtain ECG at baseline, after each significant methadone dose increase, and if methadone doses exceed 100 mg/day. 2, 5, 4

• High methadone doses (≥120 mg) significantly increase risk of torsades de pointes and sudden cardiac death 2, 4
• Apalutamide itself does not prolong QTc, but the required methadone dose escalation will 6
• Monitor for other QTc-prolonging medications that may compound the risk 2

Alternative Approaches

Consider switching to fentanyl or buprenorphine before initiating apalutamide, as these have fewer drug-drug interactions. 4

• Fentanyl has no active metabolites and is not significantly affected by CYP enzyme induction 4
• Buprenorphine may be preferable in patients with opioid use disorder, though it requires specialized prescribing 2
• If switching from methadone, consult a pain management or addiction medicine specialist due to complex conversion ratios 2

Critical Warnings

Never abruptly discontinue methadone when starting apalutamide—this will precipitate severe withdrawal. 2, 4

• Methadone maintenance doses prevent withdrawal but provide no analgesia 4
• Patients on methadone maintenance have developed significant opioid tolerance and require higher analgesic doses than opioid-naïve patients 4, 3
• Coordinate with the patient's opioid treatment program (OTP) before making any changes 5, 4

Documentation Requirements

Obtain signed release forms to communicate with the patient's OTP and verify exact methadone dosing before prescribing apalutamide. 5, 4

• Document baseline methadone dose, indication (pain vs. opioid use disorder), and prescribing provider 4
• Establish clear monitoring plan with defined withdrawal assessment intervals 5
• Notify the OTP of the planned apalutamide initiation and anticipated methadone dose increases 4

Special Populations

Patients with cardiac disease, renal impairment, or concurrent QTc-prolonging medications require even more intensive monitoring. 2, 5

• Methadone is preferred in renal failure (no active metabolites), but QTc monitoring becomes even more critical 4
• Tricyclic antidepressants, commonly used in this population, also prolong QTc 2
• Consider cardiology consultation for patients with baseline QTc 450-500 msec 5