VA Pharmacy Benefit Management Service (PBM) continually issues or revises its guidances for hematology and oncology care providers on a number of cancer care medications. Below are excerpts from recently released Criteria for Use documents. The complete documents, including the inclusion criteria, dosage and administration guidance, monitoring information, and discontinuation criteria should be consulted and can be found at www.pbm.va.gov or vaww.cmopnational.va.gov/cmop/PBM/default.aspx.
ENZALUTAMIDE (XTANDI) Criteria for Use, January 2017
Exclusion Criteria: If the answer to ANY item below is met, then the patient should NOT receive enzalutamide.
- Brain metastases or active epidural disease
- Severe renal impairment (creatinine clearance < 30 mL/min)
- History of seizure (including febrile seizure, loss of consciousness, or transient ischemic attack within the previous 12 months, any condition predisposing to seizure: prior stroke, brain AV malformation, head trauma with loss of consciousness requiring hospitalization)
- ECOG Performance Status > 2
- Inability to swallow capsules
Issues for Consideration
- Enzalutamide is not indicated for use in women. Based on the mechanism of action, can cause fetal harm if used during pregnancy. Pregnancy Category X—use contraindicated during pregnancy. Exclude pregnancy before prescribing enzalutamide, discuss risks if pregnancy occurs, and provide contraceptive counseling.
- Use in patients taking concomitant medications that may lower the seizure threshold was not studied; caution patients about the risk of activities where the sudden loss of consciousness could cause serious harm if concomitant use cannot be avoided.
- Use in patients at risk for or with a strong history of falls: in the phase 3 clinical trial, falls or injuries from falls occurred in 4.6% of enzalutamide patients vs 1.3% of placebo patients.
- Avoid strong inhibitors of CYP2C8 (eg, gemfibrozil); if concomitant use of a strong CYP2C8 inhibitor cannot be avoided, reduce the dose of enzalutamide to 80 mg once daily according to the package insert.
- Co-administration with strong or moderate inducers of CYP3A4 (eg, carbamazepine, phenobarbital, phenytoin, rifampin, bosentan, efavirenz, modafinil, nafcillin, St. John’s Wort) or CYP2C8 (eg, rifampin) should be avoided if possible. If patient must be co-administered a strong CYP3A4 inducer, increase enzalutamide dose from 160 mg to 240 mg once daily.
- Drugs that are substrates of CYP3A4 (eg, alfentanil, cyclosporine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, tacrolimus), CYP2C9 (eg, phenytoin, warfarin), or CYP2C19 (eg, S-mephenytoin) with a narrow therapeutic index should be avoided. If enzalutamide is co-administered with warfarin, additional INR testing should be conducted.
- Use in patients with hepatic impairment: Pharmacokinetics of enzalutamide and its metabolite were examined in volunteers with normal, Child-Pugh Class A, Child-Pugh Class B, and Child-Pugh Class C hepatic impairment. The composite AUC for enzalutamide and its metabolite after a single 160-mg dose was similar across all levels of hepatic impairment compared with normal volunteers.
- There have been postmarketing reports of posterior reversible encephalopathy syndrome (PRES) in patients receiving enzalutamide. PRES is a neurologic disorder presenting with rapidly evolving symptoms including seizure, headache, lethargy, confusion, blindness, and other visual/neurological disturbances with or without associated hypertension. Diagnosis of PRES requires brain imaging, preferably by MRI. Enzalutamide should be discontinued in patients developing PRES.
- Sequencing of enzalutamide and abiraterone has been evaluated in several small retrospective analyses; the majority of the analyses are in the post chemotherapy setting. From this limited observational data, it is unclear if there is a preferred sequencing of abiraterone and enzalutamide. There is some evidence for cross-resistance. There are ongoing investigations into mechanisms of resistance to enzalutamide and abiraterone.