have reviewed the proposed clinical trial design and have agreed to provide enzalutamide for the trial. 11.4.3 Storage Store enzalutamide capsules at 20°C to 25°C (68°F to 77°F) in a dry place and keep the container tightly closed. Excursions permitted from 15°C to 30°C (59°F to 86°F). 11.4.4 Stability The company providing the IND drug will also provide the expiration date for each lot allocated to this study. Version Date: 12/5/17 Abbreviated Title : Enzalutamide in non-met CSPC 6911.4.5 Dosage and Administration Enzalutamide 160 mg (four 40 mg capsule s) administered orally once daily. Swallow capsules whole. Enzalutamide can be taken with or without food. 11.4.6 Adverse EffectsSeizure In the randomized clinical trial, 7 of 800 (0.9%) patients treated with enzalutamide 160 mg once daily experienced a seizure. No seizures occurr ed in patients treated with placebo. Seizures occurred from 31 to 603 days after initiation of enzalutamide. Patients experiencing seizure were permanently discontinued from therapy and all seizures resolved. There is no clinical trial experience re-administering enzalutamide to patie nts who experienced seizures. The safety of enzalutamide in patients with predisposing factors for seizure is not known because these patients were excluded from the trial. These exclusion criteria included a history of seizure, underlying brain injury with loss of consciousness, transient ischemic attack within the past 12 months, cerebral vascular accident , brain metastases, brain arteriovenous malformation or the use of concomitant medications that may lower the seizure threshold. Because of the risk of seizure associated with enzalutamide use, patients should be advised of the risk of engaging in any activity where sudden loss of consciousness could cause serious harm to themselves or others. Other adverse events 7KHPRVWFRPPRQDGYHUVHGUXJU HDFWLRQV  UHSRUWHGLQSDWLH QWVUHFHLYLQJHQ]DOXWDPLGHLQ the randomized clinical trial were asthenia/fatigue, back pain, diarrhea, arthralgia, hot flush, peripheral edema, musculoskele tal pain, headache, upper resp iratory infection, muscular weakness, dizziness, insomnia, lower respiratory infection, spinal cord compression and cauda equina syndrome, hematuria, paresthesia, anxiety, and hypertension. Grade 3 and higher adverse reactions were reported among 47% of enzalutamide-treated patients and 53% of placebo-treated patients. Disconti nuations due to adverse events were reported for 16% of enzalutamide-treated patients and 18% of placebo-treated patients. The most common adverse reaction leading to treatment discontinuation was seizure, which occurred in 0.9% of the enzalutamide-treated patients compared to none (0%) of the placebo-treated patients. Laboratory Abnormalities In the randomized clinical trial, Grade 1- 4 neutropenia occurred in 15% of patients on enzalutamide (1% Grade 3-4) and in 6% of patie nts on placebo (no Grade 3-4). The incidence of Grade 1-4 thrombocytopenia was similar in both arms; 0.5% of patients on enzalutamide and 1% on placebo experienced Grade 3-4 thrombocytopenia. Grade 1-4 elevations in ALT occurred in 10% of patients on enzalutamide (0.3% Grade 3-4) and 18% of patients on placebo (0.5% Grade 3-4). Grade 1-4 elevations in bilirubin occurred in 3% of patients on enzalutamide and 2% of patients on placebo. Infections In the randomized clinical trial, 1.0% of patients trea ted with enzalutamide compared to 0.3% of patients on placebo died from infections or sepsis. Infection-relate d serious adverse events were reported in approximately 6% of the patients on both treatment arms. Version Date: 12/5/17 Abbreviated Title : Enzalutamide in non-met CSPC 70Falls and Fall-related Injuries In the randomized clinical trial, falls or injuries related to falls occurred in 4.6% of patients treated with enzalutamide compared to 1.3% of patients on placebo. Falls were not associated with loss of consciousness or seizur e. Fall-related injuries were more severe in patients treated with enzalutamide and included non-pathologic fractures, joint injuries, and hematomas. HallucinationsIn the randomized clinical trial, 1.6% of patients treated with en zalutamide were reported to have Grade 1 or 2 hallucinations compared to 0.3% of patients on placebo. Of the patients with hallucinations, the majority were on opioid-containing medications at the time of the event. Hallucinations were visu al, tactile, or undefined. 11.4.7 Drug Interactions Drugs that Inhibit or Induce CYP2C8 Co-administration of a strong CYP2C8 inhib itor (gemfibrozil) increased the composite area under the plasma concentration-time curve (AUC) of enzalutamide plus N-desmethyl enzalutamide in healthy volunteers. Co-administr ation of enzalutamide with strong CYP2C8 inhibitors should be avoided if possible. If co-administration of enzalutamide with a strongCYP2C8 inhibitor cannot be avoide d, reduce the dose of enzalutamide . The effects of CYP2C8 inducers on the pharm acokinetics of enzalutamide have not been evaluated in vivo . Co-administration of enzalutamide with strong or moderate CYP2C8 inducers (e.g., rifampin) may alter the plasma exposure of enzalutamide and should be avoided if possible. Selection of a concomitant medicati on with no or minimal CYP2C8 induction potential is recommended. Drugs that Inhibit or Induce CYP3A4Co-administration of a strong CYP3A4 inhibito r (itraconazole) increased the composite AUC of enzalutamide plus Ndesmethyl enzaluta mide by 1.3 fold in healthy volunteers The effects of CYP3A4 inducers on the pharm acokinetics of enzalutamide have not been evaluated in vivo . Co-administration of enzalutamide with strong CYP3A4 inducers (e.g., carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, rifapentine) may decr ease the plasma exposure of enzalutamide and should be avoided if possible. Selection of a concomita nt medication with no or minimal CYP3A4 induction potential is r ecommended. Moderate CYP3A4 inducers (e.g., bosentan, efavirenz, etravirine, modafinil, nafcillin) and St. John’s Wort may also reduce the plasma exposure of enzalutamide a nd should be avoided if possible. Effect of Enzalutamide on Drug Metabolizing Enzymes Enzalutamide is a strong CYP3A4 inducer and a moderate CYP2C9 and CYP2C19 inducer in humans. At steady state, enzalutamide reduced the plasma exposure to midazolam (CYP3A4 substrate), warfarin (CYP2C9 substrate), and omeprazole (CYP2C19 substrate). Concomitant use of enzalutamide with narrow therapeutic index drugs that are metabolized by CYP3A4 (e.g., alfentanil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus Version Date: 12/5/17 Abbreviated Title : Enzalutamide in non-met CSPC 71and tacrolimus), CYP2C9 (e.g., phenytoin, warfarin) and CYP2C19 (e.g., proton pump inhibitors (lansoprazole, omeprazole, pant oprazole, rabeprazole) and clopidogrel.) should be avoided, as enzalutamide may decrease their exposure. If co -administration with wa rfarin cannot be avoided, conduct additional INR monitoring.