©TheCanadian Journal ofUrology™: International Supplement, April 2014
TABLE 1.
Administration and strategies tomanage side effectsof therapy
Toxicity (AFFIRM Strategy tomanage toxicity
enzalutamide
Dosede-escalation/discontinuationas clinically indicated
incidence)
Seizure (0.9%)
Avoidance inpatientsmeeting trial exclusion criteria, safetynotdetermined:
• Historyof seizure including febrile
• Lossof consciousnessor transient ischemicattack<12months
• Conditionswhichmaypredisposetoseizure–stroke,brainAVmalformation,headtrauma
with lossof consciousness.
• Brainmetastasis.
• Patientswhoexperienced seizureon studywerewithdrawn from study.
Avoidance/cautionwithuse of concomitantmedicationswhich can lower seizure threshold
(list not comprehensive):
• Bronchial agents: aminophylline, theophylline
• Antidepressants: tricyclics, buproprion (Wellbutrin,Aplenzin), doxepin (Silenor)
• Antipsychotics: chlorpromazine, haloperidol (Haldol), perphenazine, prochlorperazine
(Compazine), thioridazine, trifluoperazine (Terfluzine)
• Analgesics: fentanyl,meperidine, propoxyphene, tramadol
• Antibiotics: ampicillin, carbenicillin, cephalosporins, imipenem, isoniazid, lindane,
metronidazole, oxacillin, penicillin, ticarcillin, pyrimethamine
Hypertension (6.4%)
Optimizationof bloodpressurebeforeadministration.
PeriodicECGmonitoring, significant increases inQT intervalwerenot observed.
Overall incidenceof cardiacdisorderswasnotdifferent between the two treatment groups.
Fatigueand
High incidence inbothgroups, includinggrade3-4 fatigue/asthenia.
asthenia (50.6%)
• Considerstartingtreatmentat lowerdoseandquicklytitratetofulldoseaspatienttolerates.
4.6% of enzalutamide and 1.3% of placebo treated patients experienced falls on study.
Observe caution in this older population at risk, those with prior neuropathy, and at risk
for fracture.Considerationof exercise, physical therapyandother fallsprevention strategies.
Mental
1.6% incidenceofhallucinations inAFFIRM, themajoritywhomwereonconcomitantopioids.
impairment (4.3%)
Judicious reviewof concomitantmedications. These symptoms can improveover time.
Infections (19.4%)
Neutropenia reported in15%of enzalutamideand6%ofplacebo treatedpatients, death from
infection in1%and0.3% respectively.Consideration for routineevaluationofbloodcounts.
Diarrhea (21.8%)
Hydrationanduseof anti-diarrheal as supportivemeasureas indicated.Considerationof
volume statusas contribution to symptomsof fatigueandadverseoutcomes suchas falls.
Drug interactions
StrongCYP2C8inhibitorscanincreaseplasmaexposure,considerdosereductionofenzalutamide.
• Strong CYP2C8 inhibitors: abiraterone, gemfibrozil (increases enzalutamide AUC by
over 2x), ritonavir, sorafenib.
• ModerateCYP2C8inhibitors:celecoxib,deferasirox,felodipine,irbesartan,lapatinib,nilotinib,
pioglitazone,quinine,rabeprazole,rosiglitazone, tamoxifen, teriflunomide, trimethoprim.
Concomitant use of CYP3A4 or CYP2C8 inducers may decrease plasma concentration of
enzalutamide. Conduct additional INRmonitoringonwarfarin.
Enzalutamide
• Recommendeddose: 160mg (in40mg capsules) oral oncedaily.
administration
• Foodeffect: none, takewithorwithout food.
• Renal impairment:nosignificantdifferencesseenbetweenmenwithnormalorabnormal
renalfunction,effectinsevererenalimpairment(CrCl<30mL/min)orendstagerenaldisease
isnot known.
• Hepaticimpairment:effectinseverehepaticimpairment(Child-PughClassC)isnotknown
• Pharmacokinetics:medianpeakplasmaconcentration,1hour,steadystateat28daysfollowing
dailyadministration,metabolizedpredominantlyby liver, half-life5.8days.
66
Practical guide to theuseof enzalutamide
