Xtandi ^TM

/ Astellas

The recommended dose is 160 mg enzalutamide (four 40 mg film-coated tablets or two 80 mg film-coated tablets) as a single oral daily dose.
Medical castration with an LHRH analogue should be continued during treatment of patients not surgically castrated.
If a patient misses taking enzalutamide at the usual time, the prescribed dose should be taken as close as possible to the usual time. If a patient misses a dose for a whole day, treatment should be resumed the following day with the usual daily dose.
If a patient experiences a ≥ Grade 3 toxicity or an intolerable adverse reaction, dosing should be withheld for one week or until symptoms improve to ≤ Grade 2, then resumed at the same or a reduced dose (120 mg or 80 mg) if warranted.
Concomitant use with strong CYP2C8 inhibitors: The concomitant use of strong CYP2C8 inhibitors should be avoided if possible. If patients must be co-administered a strong CYP2C8 inhibitor, the dose of enzalutamide should be reduced to 80 mg once daily. If co-administration of the strong CYP2C8 inhibitor is discontinued, the enzalutamide dose should be returned to the dose used prior to initiation of the strong CYP2C8 inhibitor.
Elderly: No dose adjustment is necessary for older elderly.
Hepatic impairment: No dose adjustment is necessary for patients with mild, moderate, or severe hepatic impairment (Child-Pugh Class A, B, or C, respectively). An increased drug half-life has however been observed in patients with severe hepatic impairment.
Renal impairment: No dose adjustment is necessary for patients with mild or moderate renal impairment. Caution is advised in patients with severe renal impairment or end-stage renal disease.
Paediatric population: There is no relevant use of enzalutamide in the paediatric population in the indication of treatment of adult men with CRPC.
Method of administration: This drug is for oral use. The capsules should be swallowed whole with water, and can be taken with or without food.

The treatment of adult men with high-risk non-metastatic castration-resistant prostate cancer (CRPC).
The treatment of adult men with metastatic CRPC who are asymptomatic or mildly symptomatic after failure of androgen deprivation therapy in whom chemotherapy is not yet clinically indicated.
The treatment of adult men with metastatic CRPC whose disease has progressed on or after docetaxel therapy.
Treatment of patients with metastatic castration-sensitive prostate cancer mHSPC.

Hypersensitivity to the active substance(s) or to any of the excipients.
Women who are or may become pregnant.

Risk of seizure: Use of enzalutamide has been associated with seizure. The decision to continue treatment in patients who develop seizure should be taken case by case.
Posterior reversible encephalopathy syndrome: There have been rare reports of posterior reversible encephalopathy syndrome (PRES) in patients receiving Enzalutamide. PRES is a rare, reversible, neurological disorder which can present with rapidly evolving symptoms including seizure, headache, confusion, blindness, and other visual and neurological disturbances, with or without associated hypertension. A diagnosis of PRES requires confirmation by brain imaging, preferably magnetic resonance imaging (MRI). Discontinuation of Enzalutamide in patients who develop PRES is recommended.
Concomitant use with other medicinal products: Enzalutamide is a potent enzyme inducer and may lead to loss of efficacy of many commonly used medicinal products.  A review of concomitant medicinal products should therefore be conducted when initiating enzalutamide treatment. Concomitant use of enzalutamide with medicinal products that are sensitive substrates of many metabolising enzymes or transporters should generally be avoided if their therapeutic effect is of large importance to the patient, and if dose adjustments cannot easily be performed based on monitoring of efficacy or plasma concentrations.
Co-administration with warfarin and coumarin-like anticoagulants should be avoided. If this drug is co-administered with an anticoagulant metabolised by CYP2C9 (such as warfarin or acenocoumarol), additional International Normalised Ratio (INR) monitoring should be conducted.
Renal impairment: Caution is required in patients with severe renal impairment as enzalutamide has not been studied in this patient population.
Severe hepatic impairment: An increased drug half-life has been observed in patients with severe hepatic impairment, possibly related to increased tissue distribution. The clinical relevance of this observation remains unknown. A prolonged time to reach steady state concentrations is however anticipated, and the time to maximum pharmacological effect as well as time for onset and decline of enzyme induction may be increased.
Recent cardiovascular disease: The phase 3 studies excluded patients with recent myocardial infarction (in the past 6 months) or unstable angina (in the past 3 months), New York Heart Association Class (NYHA) III or IV heart failure except if Left Ventricular Ejection Fraction (LVEF) ≥ 45%, bradycardia or uncontrolled hypertension. This should be taken into account if this drug is prescribed in these patients.
Androgen deprivation therapy may prolong the QT interval: In patients with a history of or risk factors for QT prolongation and in patients receiving concomitant medicinal products that might prolong the QT interval physicians should assess the benefit risk ratio including the potential for Torsade de pointes prior to initiating this drug.
Use with chemotherapy: The safety and efficacy of concomitant use of Enzalutamide with cytotoxic chemotherapy has not been established. Co-administration of enzalutamide has no clinically relevant effect on the pharmacokinetics of intravenous docetaxel: however, an increase in the occurrence of docetaxel-induced neutropenia cannot be excluded.
Excipients: The drug contains sorbitol (E420). Patients with rare hereditary problems of fructose intolerance should not take this medicinal product.
Hypersensitivity reactions: Hypersensitivity reactions manifested by symptoms including, but not limited to, rash, or face, tongue, lip, or pharyngeal oedema, have been observed with enzalutamide.

The most common adverse reactions are asthenia/fatigue, hot flush, fractures, and hypertension. Other important adverse reactions include fall, cognitive disorder, and neutropenia.
Seizure occurred in 0.4% of enzalutamide-treated patients, 0.1% of placebo-treated patients, and 0.3% in bicalutamide-treated patients.
Rare cases of posterior reversible encephalopathy syndrome have been reported in enzalutamide-treated patients
See prescribing information for full details.

Potential for other medicinal products to affect enzalutamide exposures:
CYP2C8 inhibitors: CYP2C8 plays an important role in the elimination of enzalutamide and in the formation of its active metabolite. Following oral administration of the strong CYP2C8 inhibitor gemfibrozil (600 mg twice 4 daily) to healthy male subjects, the AUC of enzalutamide increased by 326% while Cmax of enzalutamide decreased by 18%. For the sum of unbound enzalutamide plus the unbound active metabolite, the AUC increased by 77% while Cmax decreased by 19%. Strong inhibitors (e.g. gemfibrozil) of CYP2C8 are to be avoided or used with caution during enzalutamide treatment. If patients must be co-administered a strong CYP2C8 inhibitor, the dose of enzalutamide should be reduced to 80 mg once daily.
CYP3A4 inhibitors: CYP3A4 plays a minor role in the metabolism of enzalutamide. Following oral administration of the strong CYP3A4 inhibitor itraconazole (200 mg once daily) to healthy male subjects, the AUC of enzalutamide increased by 41% while Cmax was unchanged. For the sum of unbound enzalutamide plus the unbound active metabolite, the AUC increased by 27% while Cmax was again unchanged. No dose adjustment is necessary when Xtandi™ is co-administered with inhibitors of CYP3A4.
CYP2C8 and CYP3A4 inducers: Following oral administration of the moderate CYP2C8 and strong CYP3A4 inducer rifampin (600 mg once daily) to healthy male subjects, the AUC of enzalutamide plus the active metabolite decreased by 37% while Cmax remained unchanged. No dose adjustment is necessary when Xtandi™ is co-administered with inducers of CYP2C8 or CYP3A4.
Potential for enzalutamide to affect exposures to other medicinal products: 
Enzyme induction: Enzalutamide is a potent enzyme inducer and increases the synthesis of many enzymes and transporters; therefore, interaction with many common medicinal products that are substrates of enzymes or transporters is expected. The reduction in plasma concentrations can be substantial, and lead to lost or reduced clinical effect. There is also a risk of increased formation of active metabolites. Enzymes that may be induced include CYP3A in the liver and gut, CYP2B6, CYP2C9, CYP2C19, and uridine 5′-diphospho-glucuronosyltransferase (UGTs – glucuronide conjugating enzymes). The transport protein P-gp may also be induced, and probably other transporters as well, e.g. multidrug resistance-associated protein 2 (MRP2), breast cancer resistance protein (BCRP) and the organic anion transporting polypeptide 1B1 (OATP1B1).  Interactions with certain medicinal products that are eliminated through metabolism or active transport are expected. If their therapeutic effect is of large importance to the patient, and dose adjustments are not easily performed based on monitoring of efficacy or plasma concentrations, these medicinal products are to be avoided or used with caution. The risk for liver injury after paracetamol administration is suspected to be higher in patients concomitantly treated with enzyme inducers.
Groups of medicinal products that can be affected include, but are not limited to:
• Analgesics (e.g. fentanyl, tramadol)
• Antibiotics (e.g. clarithromycin, doxycycline)
• Anticancer agents (e.g. cabazitaxel)
• Antiepileptics (e.g. carbamazepine, clonazepam, phenytoin, primidone, valproic acid)
• Antipsychotics (e.g. haloperidol)
• Antithrombotics (e.g. acenocoumarol, warfarin, clopidogrel)
• Betablockers (e.g. bisoprolol, propranolol)
• Calcium channel blockers (e.g. diltiazem, felodipine, nicardipine, nifedipine, verapamil)
• Cardiac glycosides (e.g. digoxin)
• Corticosteroids (e.g. dexamethasone, prednisolone)
• HIV antivirals (e.g. indinavir, ritonavir)
• Hypnotics (e.g. diazepam, midazolam, zolpidem)
• Immunosuppressant (e.g. tacrolimus)
• Proton pump inhibitor (e.g. omeprazole)
• Statins metabolized by CYP3A4 (e.g. atorvastatin, simvastatin)
• Thyroid agents (e.g. levothyroxine)
The full induction potential of enzalutamide may not occur until approximately 1 month after the start of treatment, when steady-state plasma concentrations of enzalutamide are reached, although some induction effects may be apparent earlier. Patients taking medicinal products that are substrates of CYP2B6, CYP3A4, CYP2C9, CYP2C19, or UGT1A1 should be evaluated for possible loss of pharmacological effects (or increase in effects in cases where active metabolites are formed) during the first month of enzalutamide treatment, and dose adjustment should be considered as appropriate. In consideration of the long half-life of enzalutamide, effects on enzymes may persist for one month or longer after stopping enzalutamide. A gradual dose reduction of the concomitant medicinal product may be necessary when stopping enzalutamide treatment.
CYP1A2 and CYP2C8 substrates: Enzalutamide (160 mg once daily) did not cause a clinically relevant change in the AUC or Cmax of caffeine (CYP1A2 substrate) or pioglitazone (CYP2C8 substrate). The AUC of pioglitazone increased by 20% while Cmax decreased by 18%. The AUC and Cmax of caffeine decreased by 11% and 4% respectively. No dose adjustment is indicated when a CYP1A2 or CYP2C8 substrate is co-administered with Xtandi™.
P-gp substrates: In vitro data indicate that enzalutamide may be an inhibitor of the efflux transporter P-gp. The effect of enzalutamide on P-gp substrates has not been evaluated in vivo; however, under conditions of clinical use, enzalutamide may be an inducer of P-gp via activation of the nuclear pregnane receptor (PXR). Medicinal products with a narrow therapeutic range that are substrates for P-gp (e.g. colchicine, dabigatran etexilate, digoxin) should be used with caution when administered concomitantly with This drug and may require dose adjustment to maintain optimal plasma concentrations.
BCRP, MRP2, OAT3 and OCT1 substrates: Based on in vitro data, inhibition of BCRP and MRP2 (in the intestine), as well as organic anion transporter 3 (OAT3) and organic cation transporter 1 (OCT1) (systemically) cannot be excluded. Theoretically, induction of these transporters is also possible, and the net effect is presently unknown.
Medicinal products which prolong the QT interval: Since androgen deprivation treatment may prolong the QT interval, the concomitant use of Enzalutamide with medicinal products known to prolong the QT interval or medicinal products able to induce Torsade de pointes such as class IA (e.g. quinidine, disopyramide) or class III (e.g. amiodarone, sotalol, dofetilide, ibutilide) antiarrhythmic medicinal products, methadone, moxifloxacin, antipsychotics, etc. should be carefully evaluated.
Effect of food on enzalutamide exposures: Food has no clinically significant effect on the extent of exposure to enzalutamide. In clinical trials, Xtandi™ was administered without regard to food.

Pregnancy: Enzalutamide is not for use in women. Enzalutamide is contraindicated in women who are or may become pregnant.
Lactation: Enzalutamide is not for use in women. It is not known if enzalutamide is present in human milk.
See prescribing information for full details. 

There is no antidote for enzalutamide. In the event of an overdose, treatment with enzalutamide should be stopped and general supportive measures initiated taking into consideration the half-life of 5.8 days. Patients may be at increased risk of seizures following an overdose.