Consumer medicine information

Xtandi

Enzalutamide

BRAND INFORMATION

Brand name

Xtandi

Active ingredient

Enzalutamide

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Xtandi.

What is in this leaflet

This leaflet answers some common questions about XTANDI.

It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you taking XTANDI against the benefits they expect it will have for you.

If you have any concerns about taking this medicine, ask your doctor or pharmacist.

Keep this leaflet with the medicine. You may need to read it again.

What XTANDI is used for

XTANDI contains enzalutamide, an androgen receptor inhibitor, which is used to treat adult men with prostate cancer that no longer responds to androgen deprivation therapy and has spread to other parts of the body. XTANDI is also used to treat prostate cancer that has not yet spread to other parts of the body in patients that no longer responds to androgen deprivation therapy.

This medicine works by blocking the activity of hormones called androgens (such as testosterone). By blocking androgens, XTANDI stops prostate cancer cells from growing and dividing.

Ask your doctor if you have any questions about why this medicine has been prescribed for you. Your doctor may have prescribed it for another reason.

XTANDI is not for use in children and adolescents.

Safety and effectiveness in children and adolescents have not been established.

Before you take XTANDI

When you must not take it

Do not take XTANDI if you have an allergy to:

  • any medicine containing enzalutamide
  • any of the ingredients listed at the end of this leaflet

Some of the symptoms of an allergic reaction may include:

  • shortness of breath
  • wheezing or difficulty breathing
  • swelling of the face, lips, tongue or other parts of the body
  • rash, itching or hives on the skin.

Do not take this medicine after the expiry date printed on the pack or if the packaging is torn or shows signs of tampering. If it has expired or is damaged, return it to your pharmacist for disposal.

XTANDI is not for use in women.

This medicine may cause harm to the unborn child or potential loss of pregnancy if it is taken by women who are pregnant. It must not be taken by women who are pregnant, may become pregnant, or who are breast feeding.

This medicine could possibly have an effect on male fertility.

If you are having sex with a woman who can become pregnant, you must use a condom and another effective birth control method, during treatment and for 3 months after stopping treatment with this medicine. Men who are sexually active with a pregnant woman must use a condom during and for 3 months after stopping treatment with XTANDI to protect the unborn child.

Talk with your doctor if you have questions about birth control. Your doctor can discuss with you the risks and benefits involved.

If you are not sure whether you should start taking this medicine, talk to your doctor.

Before you start to take it

Tell your doctor if you have allergies to any other medicines, foods, preservatives or dyes.

Tell your doctor if you have or have had any of the following medical conditions:

  • a history of seizures
  • a serious head injury or a history of head trauma
  • a stroke
  • a brain tumour, or cancer which has spread to the brain
  • drink very large amounts of alcohol either regularly or from time to time
  • are taking a medicine that can cause seizures or that increases risks for having seizures (see Taking other medicines)

In some of these situations you may have a higher risk of having a seizure.

Tell your doctor if you have:

  • heart or blood pressure problems
  • kidney problems
  • a partner who is pregnant or is planning to become pregnant.

If you have not told your doctor about any of the above, tell him/ her before you start taking XTANDI.

Taking other medicines

Tell your doctor if you are taking any of the following medicines.

When taken at the same time as XTANDI, these medicines may increase the risk of a seizure:

  • certain medicines used to treat asthma and other respiratory diseases (e.g. aminophylline, theophylline)
  • medicines used to treat certain psychiatric disorders such as depression and schizophrenia (e.g. clozapine, olanzapine, risperidone, ziprasidone, bupropion, lithium, chlorpromazine, thioridazine, amitriptyline, desipramine, doxepin, imipramine, mirtazapine)
  • certain medicines for the treatment of pain (e.g. pethidine)

Tell your doctor or pharmacist if you are taking any other medicines, including any that you get without a prescription from your pharmacy, supermarket or health food shop.

Some medicines and XTANDI may interfere with each other. These include certain medicines used to:

  • treat pain (e.g. fentanyl, tramadol, paracetamol)
  • thin the blood, or to prevent blood clots (e.g. warfarin, clopidogrel)
  • lower cholesterol (e.g. gemfibrozil, atorvastatin, simvastatin)
  • treat cancer (e.g. cabazitaxel)
  • treat epilepsy (e.g. carbamazepine, clonazepam, phenytoin, primidone, valproic acid)
  • treat certain psychiatric disorders such as severe anxiety or schizophrenia (e.g. diazepam, midazolam, haloperidol)
  • treat sleep disorders (eg. Zolpidem)
  • treat heart conditions or lower blood pressure (e.g. bisoprolol, digoxin, diltiazem, felodipine, nicardipine, nifedipine, propanolol, verapamil)
  • treat serious disease related to inflammation (e.g. dexamethasone, prednisolone)
  • lower your immunity (e.g. cyclosporin, tacrolimus)
  • treat HIV infection (e.g. indinavir, ritonavir)
  • treat bacterial infections (e.g. clarithromycin, doxycycline, rifampicin)
  • treat thyroid disorders (e.g. levothyroxine)
  • treat gout (e.g. colchicine)
  • prevent heart conditions or strokes (dabigatran etexilate).
  • treat reflux disease or peptic ulcers (e.g. omeprazole)

These medicines may be affected by XTANDI or may affect how well it works. You may need different amounts of your medicines, or you may need to take different medicines.

Your doctor and pharmacist have more information on medicines to be careful with or avoid while taking this medicine.

How to take XTANDI

Follow all directions given to you by your doctor or pharmacist carefully. They may differ from the information contained in this leaflet.

If you do not understand the instructions on the box, ask your doctor or pharmacist for help.

XTANDI should not be handled by persons other than the patient and his caregivers, and especially not by women who are or may become pregnant.

How much to take

The usual dose is four 40 mg capsules taken at the same time once a day. Your doctor may reduce your dose depending on your medical conditions.

Reduced dose:

If you are taking a reduced dose of XTANDI, you may use the remaining capsules in the open dose compartment for your next scheduled dose, provided that the capsules have been otherwise stored under the conditions described below (see After Taking XTANDI, Storage).

How to take it

Swallow the capsules whole with a full glass of water. Do not chew, dissolve or open the capsules before swallowing.

You can take XTANDI with or without food.

When to take it

Take your medicine at about the same time each day. Taking it at the same time each day will have the best effect. It will also help you remember when to take it.

How long to take it

Continue taking your medicine for as long as your doctor tells you.

It is important to keep taking your medicine even if you feel well.

Do not stop treatment with XTANDI unless your doctor tells you to.

If you forget to take it

Take it as soon as you remember, and then go back to taking your medicine as you would normally.

If you forget to take XTANDI for the whole day, take your usual dose the following day.

If you forget to take XTANDI for more than one day, talk to your doctor immediately.

Do not take a double dose to make up for the dose that you missed. This may increase the chance of you getting an unwanted side effect.

If you are not sure what to do, ask your doctor or pharmacist.

If you have trouble remembering to take your medicine, ask your pharmacist for some hints.

If you take too much (overdose)

Immediately telephone your doctor or the Poisons Information Centre (telephone 13 11 26) for advice, or go to Accident and Emergency at the nearest hospital, if you think that you or anyone else may have taken too much XTANDI. Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

You may be at increased risk of experiencing a seizure.

While you are taking XTANDI

Things you must do

If you are about to be started on any new medicine, remind your doctor and pharmacist that you are taking XTANDI.

Tell any other doctors, dentists, and pharmacists who treat you that you are taking this medicine.

If you are going to have surgery, tell the surgeon or anaesthetist that you are taking this medicine.

If your partner becomes pregnant while taking this medicine, tell your doctor immediately.

Keep all of your doctor's appointments so that your progress can be checked.

Things you must not do

Do not take XTANDI to treat any other complaints unless your doctor tells you to.

Do not give your medicine to anyone else, even if they have the same condition as you.

Do not stop taking your medicine or alter the dosage without checking with your doctor.

Do not drive or operate machinery until you know how XTANDI affects you. XTANDI may have a moderate effect on your ability to drive or use any tools or machinery as the side effects for XTANDI includes seizures.

Side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking XTANDI.

All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical attention if you get some of the side effects.

Do not be alarmed by the following lists of side effects. You may not experience any of them.

Ask your doctor or pharmacist to answer any questions you may have.

Tell your doctor or go to Accident and Emergency at your nearest hospital immediately if you have a seizure. Seizures are more likely if you take more than the recommended dose of this medicine. If you have a seizure during treatment, stop taking XTANDI and see your doctor as soon as possible.

Posterior Reversible Encephalopathy Syndrome (PRES)
There have been rare reports of PRES, a rare, reversible condition involving the brain, in patients treated with XTANDI. If you have a seizure, worsening headache, confusion, blindness or other vision problems, please contact your doctor as soon as possible.

Tell your doctor or pharmacist if you notice or experience any of the following:

  • headache
  • weakness
  • tiredness
  • dizziness
  • breathlessness
  • chest pain
  • swelling of the hands, ankles or feet
  • rash
  • pain in back, muscles or joints
  • hot flushes
  • falls
  • broken bones
  • hallucinations
  • feeling anxious
  • dry skin
  • itching
  • high blood pressure
  • constipation
  • diarrhoea
  • feeling sick
  • decreased appetite
  • difficulty remembering things
  • difficulty thinking clearly
  • forgetfulness
  • reduced concentration.
  • cancer as a result of previous treatment with radiation or chemotherapy

Tell your doctor or pharmacist if you notice anything that is making you feel unwell.

The above list includes the more common side effects of your medicine.

Other side effects not listed above may also occur in some people.

After taking XTANDI

Storage

Keep your capsules in the pack until it is time to take them. If you take the capsules out of the pack they may not keep as well.

If you are taking a reduced dose of XTANDI, you may store the remaining capsules in the open dose compartment until the next dose, provided that the capsules have been otherwise stored under the conditions described below.

Keep your capsules in the original packaging in a cool dry place where the temperature stays below 25°C.

Do not store XTANDI or any other medicine in the bathroom or near a sink. Do not leave it on a window sill or in the car. Heat and dampness can destroy some medicines.

Do not take any capsule that is leaking, damaged, or shows signs of tampering.

Keep it where children cannot reach it. A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Disposal

If your doctor tells you to stop taking this medicine or the expiry date has passed, ask your pharmacist what to do with any medicine that is left over.

Do not throw away any medicines via wastewater or household waste.

Product description

What it looks like

XTANDI capsules are white to off-white, oblong soft gelatin capsules with "ENZ" written on one side in black ink.

XTANDI is available in packs of 112 capsules (in 4 wallets of 28 capsules each).

Ingredients

XTANDI contains 40 mg of enzalutamide as the active ingredient.

Each capsule also contains:

  • caprylocaproyl macrogolglycerides
  • butylated hydroxyanisole
  • butylated hydroxytoluene
  • gelatin
  • sorbitol sorbitan solution
  • glycerol
  • titanium dioxide
  • purified water
  • OPACODE WB monogramming ink NSP-78-17827 BLACK

Supplier

XTANDI is distributed in Australia by:

Astellas Pharma Australia Pty Ltd
6 Eden Park Drive
Macquarie Park, NSW 2113

Medical Information: 1800 751 755

® = Registered Trademark

Australian registration number: AUST R 210494

This leaflet was prepared in September 2019.

Published by MIMS October 2019

BRAND INFORMATION

Brand name

Xtandi

Active ingredient

Enzalutamide

Schedule

S4

 

1 Name of Medicine

Enzalutamide.

6.7 Physicochemical Properties

Enzalutamide is a white crystalline non-hygroscopic solid. It is practically insoluble in water.
Chemical name: 4-{3-[4-cyano-3-(trifluoromethyl)phenyl]- 5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl}-2-fluoro- N-methylbenzamide. Molecular formula: C21H16F4N4O2S.

Chemical structure.


CAS number.

915087-33-1.

2 Qualitative and Quantitative Composition

Xtandi is provided as liquid-filled soft gelatin capsules for oral administration. Each soft capsule contains 40 mg of enzalutamide as a solution in caprylocaproyl macrogolglycerides.

Excipient(s) with known effect.

Each soft capsule contains 57.8 mg of sorbitol.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Capsule, soft.
Supplied as white to off-white oblong soft gelatin capsules imprinted with "ENZ" in black ink on one side.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Enzalutamide is an androgen receptor signalling inhibitor that blocks the androgen receptor signalling pathway. Enzalutamide competitively inhibits androgen binding to androgen receptors, and consequently, inhibits nuclear translocation of these receptors and inhibits the binding of androgen receptor to DNA. In vitro, enzalutamide treatment decreased proliferation and induced prostate cancer cell death. Decreased tumour growth was seen in a mouse prostate cancer xenograft model. In preclinical studies enzalutamide lacked androgen receptor agonist activity against several prostate cancer cell lines. The active metabolite, N-desmethyl enzalutamide, exhibited similar in vitro activity to enzalutamide in the inhibition of testosterone binding to the androgen receptor.

Clinical trials.

Efficacy of enzalutamide was established in three randomised placebo-controlled multicentre phase 3 clinical studies [MDV3100-14 (PROSPER), CRPC2 (AFFIRM), MDV3100-03 (PREVAIL)] of patients with progressive metastatic prostate cancer who had failed androgen deprivation therapy [luteinising hormone-releasing hormone (LHRH) analogue or after bilateral orchiectomy]. The PREVAIL study enrolled metastatic CRPC chemotherapy-naïve patients; whereas the AFFIRM study enrolled metastatic CRPC patients who had received prior docetaxel; and the PROSPER study enrolled patients with non-metastatic CRPC. All patients continued on a LHRH analogue or had prior bilateral orchiectomy. In the active treatment arm, Xtandi was administered orally at a dose of 160 mg daily. In the three clinical trials, patients received placebo in the control arm and patients were allowed, but not required, to take prednisone (maximum daily dose allowed was 10 mg prednisone or equivalent).
Changes in prostate specific antigen (PSA) serum concentration independently do not always predict clinical benefit. Therefore, in the three studies it was recommended that patients be maintained on their study treatments until discontinuation criteria were met as specified below for each study.

PROSPER study (patients with non-metastatic CRPC).

The PROSPER study enrolled 1401 patients with asymptomatic, high-risk non-metastatic CRPC who continued on androgen deprivation therapy (ADT; defined as LHRH analogue or prior bilateral orchiectomy). Patients were required to have a PSA doubling time ≤ 10 months, PSA ≥ 2 ng/mL, and confirmation of non-metastatic disease by blinded independent central review (BICR).
Patients with a history of mild to moderate heart failure (NYHA Class I or II), and patients taking medicinal products associated with lowering the seizure threshold were allowed. Patients were excluded with a previous history of seizure, a condition that might predispose them to seizure, or certain prior treatments for prostate cancer (i.e., chemotherapy, ketoconazole, abiraterone acetate, aminoglutethimide and/or enzalutamide).
Patients were randomised 2:1 to receive either enzalutamide at a dose of 160 mg once daily (N = 933) or placebo (N = 468). Patients were stratified by Prostate Specific Antigen (PSA) Doubling Time (PSADT) (< 6 months or ≥ 6 months) and the use of bone-targeting agents (yes or no).
The demographic and baseline characteristics were well-balanced between the two treatment arms. The median age at randomisation was 74 years in the enzalutamide arm and 73 years in the placebo arm. Most patients (approximately 71%) in the study were Caucasian; 16% were Asian and 2% were Black. Eighty-one percent (81%) of patients had an ECOG performance status score of 0 and 19% patients had an ECOG performance status of 1.
Metastasis-free survival (MFS) was the primary endpoint defined as the time from randomisation to radiographic progression or death within 112 days of treatment discontinuation without evidence of radiographic progression, whichever occurred first. Key secondary endpoints assessed in the study were time to PSA progression, time to first use of new antineoplastic therapy (TTA), overall survival (OS). Additional secondary endpoints included time to first use of cytotoxic chemotherapy and chemotherapy-free survival. See results below (Table 6).
Enzalutamide demonstrated a statistically significant 71% reduction in the relative risk of radiographic progression or death compared to placebo [HR = 0.29 (95% CI: 0.24, 0.35), p < 0.0001]. Median MFS was 36.6 months (95% CI: 33.1, NR) on the enzalutamide arm versus 14.7 months (95% CI: 14.2, 15.0) on the placebo arm. Consistent MFS results were also observed in all pre-specified patient sub-groups including PSADT (< 6 months or ≥ 6 months), demographic region (North America, Europe, rest of world), age (< 75 or ≥ 75), use of a prior bone-targeting agent (yes or no). See Figure 1.
Overall survival was evaluated at two prespecified interim analyses to date; the first at the time of final MFS (n = 165) [HR = 0.80 (95% CI: 0.58, 1.09), p = 0.1519], and the second interim analysis (n = 288) [HR = 0.83 (95% CI: 0.65, 1.06), p = 0.1344]. The median was not reached in either treatment group and neither analysis showed a statistically significant difference between treatment arms.
Enzalutamide demonstrated a statistically significant 93% reduction in the relative risk of PSA progression compared to placebo [HR = 0.07 (95% CI: 0.05, 0.08), p < 0.0001]. Median time to PSA progression was 37.2 months (95% CI: 33.1, NR) on the enzalutamide arm versus 3.9 months (95% CI: 3.8, 4.0) on the placebo arm.
Enzalutamide demonstrated a statistically significant delay in the time to first use of new antineoplastic therapy compared to placebo [HR = 0.21 (95% CI: 0.17, 0.26), p < 0.0001]. Median time to first use of new antineoplastic therapy was 39.6 months (95% CI: 37.7, NR) on the enzalutamide arm versus 17.7 months (95% CI: 16.2, 19.7) on the placebo arm. See Figure 2.

STRIVE study (chemotherapy-naïve patients with non-metastatic/metastatic CRPC).

The STRIVE study enrolled 396 non-metastatic or metastatic CRPC patients who had serologic or radiographic disease progression despite primary androgen deprivation therapy who were randomized to receive either enzalutamide at a dose of 160 mg once daily (N = 198) or bicalutamide at a dose of 50 mg once daily (N = 198). PFS was the primary endpoint defined as the time from randomization to the earliest objective evidence of PSA progression, radiographic progression, or death on study. Median PFS was 19.4 months (95% CI: 16.5, not reached) in the enzalutamide group versus 5.7 months (95% CI: 5.6, 8.1) in the bicalutamide group [HR = 0.24 (95% CI: 0.18, 0.32), p < 0.0001]. Consistent benefit of enzalutamide over bicalutamide on PFS was observed in all prespecified patient subgroups. See Figure 3.

TERRAIN study (chemotherapy-naïve patients).

TERRAIN enrolled 375 chemotherapy- and anti-androgen-therapy naïve patients who were randomised to receive either enzalutamide orally at a dose of 160 mg once daily (N = 184) or bicalutamide orally at a dose of 50 mg once daily (N = 191). Median progression-free survival (PFS) was 15.7 months for patients on enzalutamide vs. 5.8 months for patients on bicalutamide [HR = 0.44 (95% CI: 0.34, 0.57), P < 0.0001] (Figure 4). PFS was defined as objective evidence of radiographic disease progression by independent central review, skeletal-related events, initiation of new antineoplastic therapy or death by any cause, whichever occurred first. Consistent PFS benefit was observed across all pre-specified patient subgroups.

PREVAIL study (chemotherapy-naïve patients with metastatic CRPC).

A total of 1717 asymptomatic or mildly symptomatic chemotherapy-naïve patients were randomised 1:1 to receive either enzalutamide orally at a dose of 160 mg once daily (N = 872) or placebo orally once daily (N = 845). Patients with visceral disease, patients with a history of mild to moderate heart failure (NYHA Class 1 or 2), and patients taking medications associated with lowering the seizure threshold were allowed. Patients with a previous history of seizure or a condition that might predispose to seizure and patients with moderate or severe pain from prostate cancer were excluded. Study treatment continued until disease progression (evidence of radiographic progression, a skeletal related event, or clinical progression) and the initiation of either a cytotoxic chemotherapy or an investigational agent, or until unacceptable toxicity.
Patient demographics and baseline disease characteristics were balanced between the treatment arms. The median age was 71 years (range 42 - 93) and the racial distribution was 77% Caucasian, 10% Asian, 2% Black and 11% other or unknown races. Sixty-eight percent (68%) of patients had an ECOG performance status score of 0 and 32% of patients had an ECOG performance status of 1. Baseline pain assessment was 0 - 1 (asymptomatic) in 66.2% of patients and 2 - 3 (mildly symptomatic) in 31.1% of patients as defined by the Brief Pain Inventory Short Form (worst pain over past 24 hours on a scale of 0 to 10). Approximately 45% of patients had measurable soft tissue disease at study entry, and 12% of patients had visceral (lung and/or liver) metastases.
Co-primary efficacy endpoints were overall survival and radiographic progression-free survival (rPFS). In addition to the co-primary endpoints, benefit was also assessed using time to initiation of cytotoxic chemotherapy, best overall soft tissue response, time to first skeletal-related event, PSA response (≥ 50% decrease from baseline), time to PSA progression, and time to FACT-P total score degradation.
Radiographic progression was assessed with the use of sequential imaging studies as defined by Prostate Cancer Clinical Trials Working Group 2 (PCWG2) criteria (for bone lesions) and/or Response Evaluation Criteria in Solid Tumours (RECIST v 1.1) criteria (for soft tissue lesions). Analysis of rPFS utilised centrally reviewed radiographic assessment of progression.
At the pre-specified interim analysis for overall survival, when 540 deaths were observed, treatment with enzalutamide demonstrated a statistically significant improvement in overall survival compared to treatment with placebo with a 29% reduction in risk of death [HR = 0.706 (95% CI: 0.60; 0.84), p < 0.0001] (Table 7). Of note, 40.4% of enzalutamide-treated patients and 70.5% of placebo-treated patients received subsequent therapies with a demonstrated survival benefit.
An updated overall survival analysis was conducted when 784 deaths were observed. Results from this analysis were consistent with those from the pre-specified interim analysis (see Table 7, Figures 5 and 6). At the updated analysis, 52% of enzalutamide-treated and 81% of placebo-treated patients had received subsequent therapies for metastatic castration resistant prostate cancer which may prolong overall survival.
At the pre-specified rPFS analysis, a statistically significant improvement was demonstrated between the treatment groups with an 81.4% reduction in risk of radiographic progression or death [HR = 0.19 (95% CI: 0.15, 0.23), p < 0.0001]. One hundred and eighteen (14%) enzalutamide-treated patients and 321 (40%) of placebo-treated patients had an event. The median rPFS was not reached (95% CI: 13.8, not reached) in the enzalutamide-treated group and was 3.9 months (95% CI: 3.7, 5.4) in the placebo-treated group (see Figure 7). Consistent rPFS benefit was observed across all pre-specified patient subgroups (e.g. age, baseline ECOG performance, baseline PSA and LDH, Gleason score at diagnosis, and visceral disease at screening). A pre-specified follow-up rPFS analysis based on the investigator assessment of radiographic progression demonstrated a statistically significant improvement between the treatment groups with a 69.3% reduction in risk of radiographic progression or death [HR = 0.31 (95% CI: 0.27, 0.35), p < 0.0001]. The median rPFS was 19.7 months in the enzalutamide group and 5.4 months in the placebo group.
At the time of the primary analysis there were 1633 patients randomised.
In addition to the co-primary efficacy endpoints, statistically significant improvements were also demonstrated in the following prospectively defined endpoints.
The median time to initiation of cytotoxic chemotherapy was 28.0 months for patients receiving enzalutamide and 10.8 months for patients receiving placebo (HR = 0.35, 95% CI: [0.30, 0.40], p < 0.0001).
The proportion of enzalutamide-treated patients with measurable disease at baseline who had an objective soft tissue response was 58.8% (95% CI: 53.8, 63.7) compared with 5.0% (95% CI: 3.0, 7.7) of patients receiving placebo. The absolute difference in objective soft tissue response between enzalutamide and placebo arms was 53.9% (95% CI: 48.5, 59.1, p < 0.0001). Complete responses were reported in 19.7% of enzalutamide-treated patients compared with 1.0% of placebo-treated patients, and partial responses were reported in 39.1% of enzalutamide-treated patients versus 3.9% of placebo-treated patients.
Enzalutamide significantly decreased the risk of the first skeletal-related event by 27% [HR = 0.526, (95% CI: 0.421, 0.656), p < 0.0001], 21.6% of enzalutamide-treated patients reported a skeletal-related event versus 18.5% of placebo-treated patients, an absolute difference of 3.1% events. A skeletal-related event was defined as radiation therapy or surgery to bone for prostate cancer, pathologic bone fracture, spinal cord compression, or change of antineoplastic therapy to treat bone pain.
The median time to PSA progression per PCWG2 criteria was 11.2 months for patients treated with enzalutamide and 2.8 months for patients who received placebo [HR = 0.17, (95% CI: 0.15, 0.20), p < 0.0001].
Treatment with enzalutamide decreased the risk of FACT-P degradation by 37.5% compared with placebo (p < 0.0001). The median time to degradation in FACT-P was 11.3 months in the enzalutamide group and 5.6 months in the placebo group.

AFFIRM study (patients with metastatic CRPC who previously received chemotherapy).

The efficacy and safety of Xtandi in patients with metastatic castration resistant prostate cancer who had received docetaxel and were using a LHRH analogue or had undergone orchiectomy were assessed in a randomised, placebo controlled, multicentre phase 3 clinical trial (AFFIRM). A total of 1199 patients were randomised 2:1 to receive either Xtandi orally at a dose of 160 mg once daily (N = 800) or placebo once daily (N = 399). Patients were allowed but not required to take prednisone (maximum daily dose allowed was 10 mg prednisone or equivalent). Patients randomised to either arm were to continue treatment until disease progression (defined as confirmed radiographic progression or the occurrence of a skeletal-related event) and initiation of new systemic antineoplastic treatment, unacceptable toxicity, or withdrawal. Following progression, 41% of study drug arm and 61.7% of placebo arm received ≥ 1 further systemic treatment; therefore, the observed survival data and Kaplan-Meier curve reflect a median duration of treatment of 8 months of enzalutamide vs. 3 months of placebo followed by additional treatments.
The following patient demographics and baseline disease characteristics were balanced between the treatment arms. The median age was 69 years (range 41 - 92) and the racial distribution was 92.7% Caucasian, 3.9% Black, 1.1% Asian, and 2.1% Other. The ECOG performance score was 0 - 1 in 91.5% of patients and 2 in 8.5% of patients; 28.4% had a mean Brief Pain Inventory score of ≥ 4 (mean of patient's reported worst pain over the previous 24 hours calculated for seven days prior to randomisation). Most (91.2%) patients had metastases in bone and 23.2% had visceral lung and/or liver involvement. At study entry, 41% of randomised patients had PSA progression only, whereas 59% of patients had radiographic progression. Fifty-one percent (51%) of patients were on bisphosphonates at baseline.
The AFFIRM study excluded patients with medical conditions that may predispose them to seizures and medications known to decrease the seizure threshold, as well as clinically significant cardiovascular disease such as uncontrolled hypertension, recent history of myocardial infarction or unstable angina, New York Heart Association class III or IV heart failure (unless ejection fraction was ≥ 45%), clinically significant ventricular arrhythmias or AV block (without permanent pacemaker).
The protocol pre-specified interim analysis after 520 deaths showed a statistically significant superiority in overall survival in patients treated with Xtandi compared to placebo (see Table 8 and Figures 8 and 9).
In addition to the observed improvement in overall survival, key secondary endpoints (radiographic progression-free survival, and time to first skeletal-related event) favoured Xtandi and were statistically significant after adjusting for multiple testing.
Radiographic progression-free survival as assessed by the investigator using RECIST v1.1 for soft tissue and appearance of 2 or more bone lesions in bone scan was 8.3 months for patients treated with Xtandi and 2.9 months for patients who received placebo [HR = 0.40, (95% CI: 0.35, 0.47)]; p < 0.0001). The analysis involved 216 deaths without documented progression and 645 documented progression events, of which 303 (47%) were due to soft tissue progression, 268 (42%) were due to bone lesion progression and 74 (11%) were due to both soft tissue and bone lesions.
The median time to first skeletal-related event was 16.7 months for patients treated with Xtandi and 13.3 months for patients who received placebo [HR = 0.69, (95% CI: 0.57, 0.84); p < 0.0001]. A skeletal-related event was defined as radiation therapy or surgery to bone, pathologic bone fracture, spinal cord compression, or change of antineoplastic therapy to treat bone pain. The analysis involved 448 skeletal-related events, of which 277 events (62%) were radiation to bone, 95 events (21%) were spinal cord compression, 47 events (10%) were pathologic bone fracture, 36 events (8%) were change in antineoplastic therapy to treat bone pain and 7 events (2%) were surgery to bone.

9785-CL-0410 study (enzalutamide post abiraterone in patients with metastatic CRPC).

The study was a single-arm study in 214 patients with progressing metastatic CRPC who received enzalutamide (160 mg once daily) after at least 24 weeks of treatment with abiraterone acetate plus prednisone. Median rPFS (radiologic progression free survival, the study's primary endpoint) was 8.1 months (95% CI: 6.1, 8.3). Median OS was not reached. PSA Response (defined as ≥ 50% decrease from baseline) was 22.4% (95% CI: 17.0, 28.6).
For the 69 patients who previously received chemotherapy, median rPFS was 7.9 months (95% CI: 5.5, 10.8). PSA Response was 23.2% (95% CI: 13.9, 34.9).
For the 145 patients who had no previous chemotherapy, median rPFS was 8.1 months (95% CI: 5.7, 8.3). PSA Response was 22.1% (95% CI: 15.6, 29.7).
Although there was a limited response in some patients from treatment with enzalutamide after abiraterone, the reason for this finding is currently unknown. The study design could neither identify the patients who are likely to benefit, nor the order in which enzalutamide and abiraterone should be optimally sequenced.

Elderly.

Of the 3179 patients in the controlled clinical trials who received enzalutamide, 2518 patients (79%) were 65 years and over and 1162 patients (37%) were 75 years and over. No overall differences in safety or effectiveness were observed between these older patients and younger patients. The incidence of serious adverse events, fatal adverse events and adverse events leading to discontinuation was higher in older patients (≥ 75 years). For patients ≥ 75 years, one of these adverse events was reported in 50.5% of patients in the enzalutamide arm and 50.0% in the placebo arm. For patients < 75 years, one of these adverse events was reported in 37.0% of patients in the enzalutamide arm and 29.5% of patients in the placebo arm.

5.2 Pharmacokinetic Properties

The pharmacokinetics of enzalutamide have been evaluated in prostate cancer patients and in healthy male subjects. The mean terminal half-life (t1/2) for enzalutamide in patients after a single oral dose is 5.8 days (range 2.8 to 10.2 days), and steady state is achieved in approximately one month. With daily oral administration, enzalutamide accumulates approximately 8.3-fold relative to a single dose. Daily fluctuations in plasma concentrations are low (peak-to-trough ratio of 1.25). Clearance of enzalutamide is primarily via hepatic metabolism, producing an active metabolite that circulates at approximately the same plasma concentration as enzalutamide.

Absorption.

Maximum plasma concentrations (Cmax) of enzalutamide in patients are observed 1 to 2 hours after administration. Based on a mass balance study in humans, oral absorption of enzalutamide is estimated to be at least 84.2%. Enzalutamide is not a substrate of the efflux transporters P-gp or BCRP. At steady state, the mean Cmax values for enzalutamide and its active metabolite are 16.6 microgram/mL (23% coefficient of variation [CV]) and 12.7 microgram/mL (30% CV), respectively.
Food has no clinically significant effect on the extent of absorption. In clinical trials, Xtandi was administered without regard to food.

Distribution.

The mean apparent volume of distribution (V/F) of enzalutamide in patients after a single oral dose is 110 L (29% CV). The volume of distribution of enzalutamide is greater than the volume of total body water, indicative of extensive extravascular distribution. Studies in rodents indicate that enzalutamide and its active metabolite can cross the blood brain barrier.
Enzalutamide is 97% to 98% bound to plasma proteins, primarily albumin. The active metabolite is 95% bound to plasma proteins. There was no protein binding displacement between enzalutamide and other highly bound medicinal products (warfarin, ibuprofen and salicylic acid) in vitro.

Metabolism.

Enzalutamide is extensively metabolised. There are two major metabolites in human plasma: N-desmethyl enzalutamide (active) and a carboxylic acid derivative (inactive). Enzalutamide is metabolised by CYP2C8 and to a lesser extent by CYP3A4/5 (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions), both of which play a role in the formation of the active metabolite. N-desmethyl enzalutamide was not metabolised by CYPs in vitro.
Under conditions of clinical use, enzalutamide is a strong inducer of CYP3A4, a moderate inducer of CYP2C9 and CYP2C19, and has no clinically relevant effect on CYP2C8 (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
In vitro, small amounts of N-desmethyl enzalutamide are metabolised to the carboxylic acid metabolite by carboxylesterase 1 which also plays a minor role in the metabolism of enzalutamide to the inactive carboxylic acid metabolite. Carboxylesterase 2 does not appear to play a role in the metabolism of either enzalutamide or N-desmethyl enzalutamide.

Excretion.

The mean apparent clearance (CL/F) of enzalutamide in patients ranges from 0.520 and 0.564 L/h.
Following oral administration of 14C-enzalutamide, 84.6% of the radioactivity is recovered by 77 days post dose: 71.0% is recovered in urine (primarily as the inactive metabolite, with trace amounts of enzalutamide and the active metabolite), and 13.6% is recovered in faeces (0.39% of dose as unchanged enzalutamide).

Linearity.

No major deviations from dose proportionality are observed over the dose range 40 to 160 mg. The steady-state Cmin values of enzalutamide and the active metabolite in individual patients remained constant during more than one year of chronic therapy, demonstrating time linear pharmacokinetics once steady state is achieved.

Pharmacokinetic characteristics in special populations.

Patients with hepatic impairment.

The pharmacokinetics of enzalutamide were examined in subjects with baseline mild (N = 6), moderate (N = 8) or severe (N = 8) hepatic impairment (Child-Pugh Class A, B and C respectively) and in 22 matched control subjects with normal hepatic function.
Following a single oral 160 mg dose of enzalutamide, the AUC and Cmax for enzalutamide in subjects with mild impairment increased by 5% and 24%, respectively, the AUC and Cmax of enzalutamide in subjects with moderate impairment increased by 29% and decreased by 11%, respectively and the AUC and Cmax of enzalutamide in subjects with severe impairment increased by 5% and decreased by 41%, respectively, compared to healthy control subjects.
For the sum of unbound enzalutamide plus the unbound active metabolite, the AUC and Cmax in subjects with mild impairment increased by 14% and 19%, respectively, the AUC and Cmax in subjects with moderate impairment increased by 14% and decreased by 17%, respectively, and the AUC and Cmax of enzalutamide in subjects with severe hepatic impairment increased by 34% and decreased by 27%, respectively, compared to healthy control subjects.

Patients with renal impairment.

No formal renal impairment study for enzalutamide has been completed. Patients with serum creatinine > 177 micromol/L (2 mg/dL) were excluded from clinical trials. Based on a population pharmacokinetic analysis, no dose adjustment is necessary for patients with calculated creatinine clearance (CrCL) values ≥ 30 mL/min (estimated by the Cockcroft and Gault formula). Enzalutamide has not been evaluated in patients with severe renal impairment (CrCL < 30 mL/min) or end-stage renal disease, and caution is advised when treating these patients. It is unlikely that enzalutamide will be significantly removed by intermittent haemodialysis or continuous ambulatory peritoneal dialysis.

Elderly.

Of the 3179 patients in the controlled clinical trials who received enzalutamide, 2518 patients (79%) were 65 years and over and 1162 patients (37%) were 75 years and over. No overall differences in safety or effectiveness were observed between these elderly patients and younger patients.

Paediatric use.

Safety and efficacy of enzalutamide in paediatric patients have not been established.

Gender and race.

The effect of gender on the pharmacokinetics of enzalutamide has not been evaluated. Most patients in the randomised clinical trials (> 74%) were Caucasian. Based on pharmacokinetic data from studies in Japanese and Chinese patients with prostate cancer, there were no clinically relevant differences in exposure among the populations. There are insufficient data to evaluate potential differences in the pharmacokinetics of enzalutamide in other races.

5.3 Preclinical Safety Data

Genotoxicity.

Enzalutamide did not induce mutations in the microbial mutagenesis (Ames) assay and was not clastogenic in either the in vitro cytogenetic assay with mouse lymphoma cells or the in vivo mouse micronucleus assay.

Carcinogenicity.

In a 6-month study in transgenic rasH2 mice, enzalutamide did not show carcinogenic potential (absence of neoplastic findings) at doses up to 20 mg/kg/day, which resulted in combined exposure levels (based on AUC), for enzalutamide plus its active metabolite M2, approximately half the clinical exposure in metastatic CRPC patients receiving 160 mg daily.
Daily dosing of rats for two years with enzalutamide at 10-100 mg/kg/day produced an increased incidence of several, mostly benign, tumour types. The most prominent of these were benign Leydig cell tumours and urothelium papilloma and carcinoma of urinary bladder, whose induction is not considered relevant to humans. Other tumours included fibroadenoma of mammary glands and benign thymoma of thymus in males, benign granulosa cell tumours of ovaries in females and adenoma of pituitary pars distalis in both sexes. The combined exposure levels (based on AUC) achieved in this study, for enzalutamide plus its active metabolite M2, were less than or similar to those in prostate cancer patients receiving 160 mg daily.

4 Clinical Particulars

4.1 Therapeutic Indications

Xtandi is indicated for:
the treatment of patients with non-metastatic castration-resistant prostate cancer (see Section 5.1, Clinical trials, PROSPER study (patients with non-metastatic CRPC));
the treatment of patients with metastatic castration resistant prostate cancer following failure of androgen deprivation therapy in whom chemotherapy is not yet indicated;
the treatment of patients with metastatic castration-resistant prostate cancer who have previously received docetaxel.

4.3 Contraindications

Xtandi is contraindicated in patients with known hypersensitivity to enzalutamide or to any of the excipients in the formulation (see Section 6.1 List of Excipients).
Xtandi is not indicated for use in women. Xtandi is contraindicated in women who are, or may become, pregnant. (See Section 4.2 Dose and Method of Administration; Section 4.6 Fertility, Pregnancy and Lactation, Use in pregnancy.)

4.4 Special Warnings and Precautions for Use

Xtandi capsules should only be prescribed by a medical practitioner who is experienced with the treatment of prostate cancer and the use of antineoplastic endocrine therapies.
The following are clinically significant: seizures (see Risk of seizure below and see Section 4.8), Posterior reversible encephalopathy syndrome (PRES) (see Posterior reversible encephalopathy syndrome below and see Section 4.8) and drug interactions (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Risk of seizure.

Use of enzalutamide has been associated with seizure. Caution should be used in administering Xtandi to patients with a history of seizures or other predisposing factors including, but not limited to, underlying brain injury, stroke, primary brain tumours or brain metastases, or alcoholism. In addition, the risk of seizure may be increased in patients receiving concomitant medicines that lower the seizure threshold. Permanently discontinue Xtandi in patients who develop a seizure during treatment.
Because of the risk of seizure associated with Xtandi 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.

Posterior reversible encephalopathy syndrome (PRES).

There have been rare reports of PRES in patients receiving Xtandi. 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 Xtandi in patients who develop PRES is recommended.

Falls and fall-related injuries.

In the combined data of three randomised clinical trials (AFFIRM, PREVAIL and PROSPER), falls or injuries related to falls occurred in 10% of patients treated with Xtandi compared to 4% of patients treated with placebo. Falls were not associated with loss of consciousness or seizure. Fall-related injuries were more severe in patients treated with Xtandi and included non-pathologic fractures, joint injuries, and haematomas. Androgen deprivation therapy has been known to cause bone loss. For patients who fall or have a concomitant recognised risk of falling, it is recommended that the physicians consider additional supportive therapy when appropriate.

Hypersensitivity reactions.

Hypersensitivity reactions manifested by symptoms including, but not limited to, face oedema, tongue oedema, lip oedema, pharyngeal oedema, and rash have been observed with enzalutamide (see Section 4.8 Adverse Effects (Undesirable Effects)). Advise patients who experience any symptoms of hypersensitivity to discontinue enzalutamide and promptly seek medical care.

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 Xtandi.

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 (NYHA) Class III or IV heart failure except if Left Ventricular Ejection Fraction (LVEF) ≥ 45%, bradycardia or uncontrolled hypertension. This should be taken into account if Xtandi is prescribed in these patients.

Hypertension.

In the two randomised trials (AFFIRM and PREVAIL), hypertension was reported in 11% of patients receiving Xtandi and 4% of patients receiving placebo. The difference in frequency of hypertensive events between the enzalutamide and placebo-treated groups was larger in the PREVAIL trial (13.9% enzalutamide; 4.7% placebo) than in the AFFIRM trial (7% enzalutamide; 3.2% placebo). No patients experienced hypertensive crisis. Medical history of hypertension was balanced between arms. Hypertension led to study discontinuation in < 1% of patients in each arm.

Risk of second malignancy.

In the PREVAIL study, the event rate of second malignancy was higher in the enzalutamide arm (1.9 events per 100 patient-years; median follow-up time was 17.1 months) than the placebo arm (0.7 events per 100 patient-years; median follow-up time was 5.4 months). Median time to onset of second malignancy, excluding non-melanoma skin cancer, was 267 days (range 8 to 856 days) in the enzalutamide group and 229 days (range 15 to 454 days) in the placebo group.

Use with chemotherapy.

The safety and efficacy of concomitant use of Xtandi with cytotoxic chemotherapy has not been established.

Contraception in males and females.

As it is not known whether Xtandi or its metabolites are present in semen, and there were severe teratogenic effects observed in the animal studies, a condom is required during and for 3 months after treatment with Xtandi if the patient is engaged in sexual activity with a pregnant woman. If the patient engages in sexual intercourse with a woman of childbearing potential, a condom and another form of birth control must be used during and for 3 months after treatment. Studies in animals have shown reproductive toxicity (see Section 4.6 Fertility, Pregnancy and Lactation).

Use in renal impairment.

Caution is required in patients with severe renal impairment as Xtandi has not been studied in this patient population.

Use in the elderly.

No clinically relevant effect of age on Xtandi pharmacokinetics was seen in the population pharmacokinetic analysis. No dose adjustment is required for the elderly.

Paediatric use.

The safety of Xtandi has not been studied in children, and therefore it is not recommended for use in those < 18 years of age.

Effects on laboratory tests.

See Section 4.8 Adverse Effects (Undesirable Effects), Laboratory abnormalities.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Effects of other medicines on Xtandi.

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 daily) to healthy male subjects, the AUC of the sum of enzalutamide plus the active metabolite increased by 2.17-fold while Cmax decreased by 16%. Strong inhibitors (e.g. gemfibrozil) of CYP2C8 are to be avoided or used with caution during enzalutamide treatment. If patients must be coadministered a strong CYP2C8 inhibitor, the dose of enzalutamide should be reduced to 80 mg once daily (see Section 4.2 Dose and Method of Administration).

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 enzalutamide is coadministered with inhibitors of CYP3A4.

CYP2C8 and CYP3A4 inducers.

In a drug-drug interaction trial in healthy volunteers, a single 160 mg oral dose of enzalutamide was administered alone or after multiple oral doses of rifampicin (moderate CYP2C8 and strong CYP3A4 inducer). Rifampicin decreased the AUC of enzalutamide plus N-desmethyl enzalutamide by 37% with no effect on Cmax. No dose adjustment is necessary when enzalutamide is co-administered with inducers of CYP2C8 or CYP3A4.

Effects of Xtandi on other medicines.

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).
In vivo studies have shown that enzalutamide is a strong inducer of CYP3A4 and a moderate inducer of CYP2C9 and CYP2C19. Coadministration of enzalutamide (160 mg once daily) with single oral doses of sensitive CYP substrates in prostate cancer patients resulted in an 86% decrease in the AUC of midazolam (CYP3A4 substrate), a 56% decrease in the AUC of S-warfarin (CYP2C9 substrate), and a 70% decrease in the AUC of omeprazole (CYP2C19 substrate). UGT1A1 may have been induced as well.
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. warfarin, clopidogrel);
beta-blockers (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);
immunosuppressants (e.g. cyclosporin, tacrolimus);
proton pump inhibitors (e.g. omeprazole);
statins metabolised 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 drugs 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 Xtandi treatment, and dose adjustment should be considered as appropriate. In consideration of the long half-life of enzalutamide (5.8 days, see Section 5.2 Pharmacokinetic Properties), effects on enzymes may persist for one month or longer after stopping Xtandi. A gradual dose reduction of the concomitant medicinal product may be necessary when stopping Xtandi treatment.

Warfarin and coumarin-like anticoagulants.

Co-administration with warfarin and coumarin-like anticoagulants should be avoided. If Xtandi is coadministered with an anticoagulant metabolised by CYP2C9 (such as warfarin), additional INR monitoring should be conducted.

CYP1A2, CYP2C8 and CYP2D6 substrates.

Enzalutamide (160 mg once daily) did not cause a clinically relevant change in the AUC or Cmax of caffeine (CYP1A2 substrate), pioglitazone (CYP2C8 substrate) or dextromethorphan (CYP2D6 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, CYP2C8 or CYP2D6 substrate is coadministered with Xtandi.

P-gp substrates.

In vitro data indicate that enzalutamide is not a substrate for, but 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 Xtandi and may require dose adjustment to maintain optimal plasma concentrations.

BCRP, MRP2, OAT1, OAT3, OATP1B1, OATP1B3, OCT1 and OCT2 substrates.

Based on in vitro data, inhibition of BCRP and MRP2 (in the intestine), as well as organic anion transporter 3 (OAT3), OATP1B1, and OCT1 (systemically) cannot be excluded. Theoretically, induction of OAT3, OATP1B1, OCT1, BCRP and MRP2 is also possible, and the net effect is presently unknown. The effects of enzalutamide on these transporters have not been evaluated in vivo. In vitro data indicate that enzalutamide and its major metabolites do not inhibit the following transporters at clinically relevant concentrations: OAT1, OATP1B3, or OCT2.

Effect of food on Xtandi exposure.

Food has no clinically significant effect on the extent of exposure to Xtandi. In clinical trials, Xtandi was administered without regard to food.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Based on its pharmacology and findings in animal studies, male fertility may be impaired by treatment with enzalutamide. Findings in the male reproductive tract of rats and/or dogs treated with enzalutamide included atrophy of the prostate gland and seminal vesicles, testicular hypospermia and seminiferous tubule degeneration. These effects were observed at all dose levels (below the clinical exposure based on AUC) and reversed or partially resolved after an 8-week recovery period. (See Section 4.4 Special Warnings and Precautions for Use, Contraception in males and females).
(Category X)
Category X - Drugs which have such a high risk of causing permanent damage to the foetus that they should not be used in pregnancy or when there is a possibility of pregnancy.
Xtandi is not indicated for use in women. Xtandi has not been shown to be safe for use in women. Xtandi is contraindicated in women who are or may become pregnant (see Section 4.3 Contraindications). There are no human data on the use of Xtandi in pregnancy.
Teratogenicity (cleft palate, cervical rib and decreased anogenital distance) and embryofetal lethality were seen in mouse embryofetal development studies at greater than or equal to 10 mg/kg/day (below the clinical exposure based on AUC). This medicine may cause harm to the unborn child or potential loss of pregnancy if taken by women who are pregnant.
Studies in pregnant rats have shown that enzalutamide and/or its metabolites are transferred to fetuses. After oral administration of radiolabelled 14C-enzalutamide to rats on Day 14 of pregnancy at a dose of 30 mg/kg, the maximum radioactivity in the fetus was reached 4 hours after administration and was lower than that in the maternal plasma with tissue/plasma ratio of 0.27. Radioactivity in the fetus decreased to 0.08 times the maximum concentration at 72 hours after administration.
Xtandi is not indicated for use in women and has not been shown to be safe in children. It is not known whether Xtandi is secreted in human milk.
Xtandi and/or its metabolites are secreted in rat milk. After oral administration of radiolabelled 14C-enzalutamide to lactating rats at a dose of 30 mg/kg, the maximum radioactivity in the milk was reached 4 hours after administration and was up to 3.54-fold higher than that in the maternal plasma. Study results have also shown that enzalutamide and/or its metabolites are transferred to infant rat tissues via milk and subsequently eliminated.

4.8 Adverse Effects (Undesirable Effects)

Clinical trial experience.

Six randomized, controlled clinical trials enrolled patients with castration-resistant prostate cancer that had progressed on androgen deprivation therapy (GnRH therapy or bilateral orchiectomy). Four trials were placebo-controlled and two trials were bicalutamide-controlled. In the AFFIRM, PREVAIL, Asian PREVAIL, and PROSPER studies, patients received enzalutamide 160 mg or placebo orally once daily. In the TERRAIN and STRIVE studies, patients received enzalutamide 160 mg or bicalutamide 50 mg orally once daily. All patients continued androgen deprivation therapy.
The most common adverse reactions seen in clinical trials with a difference of ≥ 10%, in decreasing order of frequency, are fatigue, nausea, hot flush, diarrhea, asthenia, hypertension, and fracture. Other important adverse reactions include seizure, cognitive disorder, neutropenia, and falls.

AFFIRM study: metastatic castration resistant prostate cancer following chemotherapy.

AFFIRM enrolled 1199 patients with metastatic castration-resistant prostate cancer (CRPC) who had previously received docetaxel. The median duration of treatment was 8.3 months with Xtandi and 3.0 months with placebo. During the trial, 48% of patients on the Xtandi arm and 46% of patients on the placebo arm received glucocorticoids.
Grade 3 and higher adverse reactions were reported among 47% of Xtandi-treated patients and 53% of placebo-treated patients. Discontinuations due to adverse events were reported for 16% of Xtandi-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 Xtandi-treated patients compared to none (0%) of the placebo-treated patients. Table 1 shows adverse reactions reported in AFFIRM that occurred at a ≥ 2% absolute increase in frequency in the Xtandi arm compared to the placebo arm.

PREVAIL: chemotherapy-naïve metastatic prostate cancer that progressed on androgen deprivation therapy.

PREVAIL enrolled 1717 patients with metastatic prostate cancer that progressed on an LHRH analogue or after bilateral orchiectomy and had not received prior cytotoxic chemotherapy, of whom 1715 received at least one dose of study drug. The median duration of treatment was 16.6 months with Xtandi and 4.6 months with placebo. The most common adverse reaction leading to treatment discontinuation was fatigue, which occurred in 0.2% of the Xtandi-treated patients compared to 0.9% of placebo-treated patients.
Table 2 includes adverse reactions reported in Study 2 that occurred at a ≥ 2% absolute increase in frequency in the Xtandi arm compared to the placebo arm.

TERRAIN study: Xtandi versus bicalutamide in chemotherapy-naïve metastatic CRPC.

TERRAIN enrolled 375 patients with metastatic CRPC who had not received prior cytotoxic chemotherapy, of whom 372 received at least one dose of study drug. The median duration of treatment was 11.6 months with Xtandi and 5.8 months with bicalutamide. Discontinuations with an adverse event as the primary reason were reported for 7.6% of Xtandi-treated patients and 6.3% of bicalutamide-treated patients. The most common adverse reactions leading to treatment discontinuation were back pain and pathological fracture, which occurred in 3.8% of Xtandi-treated patients for each event and in 2.1% and 1.6% of bicalutamide-treated patients, respectively. Table 3 shows overall and common adverse reactions (≥ 10%) in Xtandi-treated patients.

PROSPER study: Xtandi versus placebo in non-metastatic CRPC patients.

PROSPER enrolled 1401 patients with non-metastatic CRPC, of whom 1395 received at least one dose of study drug. Patients were randomized 2:1 and received either Xtandi at a dose of 160 mg once daily (N = 930) or placebo (N = 465). The median duration of treatment at the time of analysis was 18.4 months (range: 0.0 to 42 months) with Xtandi and 11.1 months (range: 0.0 to 43 months) with placebo.
Overall, 32 patients (3.4%) receiving Xtandi died from adverse events. The reasons for death with ≥ 2 patients included coronary artery disorders (n = 7), sudden death (n = 2), cardiac arrhythmias (n = 2), general physical health deterioration (n = 2), stroke (n = 2), and secondary malignancy (n = 5; one each of acute myeloid leukemia, brain neoplasm, mesothelioma, small cell lung cancer, and malignant neoplasm of unknown primary site). Three patients (0.6%) receiving placebo died from adverse events of cardiac arrest (n = 1), left ventricular failure (n = 1), and pancreatic carcinoma (n = 1). Grade 3 or higher adverse reactions were reported among 31% of Xtandi-treated patients and 23% of placebo-treated patients. Discontinuations with an adverse event as the primary reason were reported for 9.4% of Xtandi-treated patients and 6.0% of placebo-treated patients. Of these, the most common adverse event leading to treatment discontinuation was fatigue, which occurred in 1.6% of the Xtandi-treated patients compared to none of the placebo-treated patients. Table 4 shows adverse reactions reported in PROSPER that occurred at a ≥ 2% higher frequency in the Xtandi arm than in the placebo arm.

Summary of adverse reactions.

Adverse reactions observed during clinical studies are listed in Table 5 by frequency category in each system organ class. Frequency categories are defined as follows: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000); and not known (cannot be estimated from the available data).

Post marketing experience.

The following adverse events, which are not listed in Table 5, have been reported in association with enzalutamide use during worldwide post-marketing experience:

Musculoskeletal and connective tissue disorders.

Myalgia, muscle spasms, muscular weakness, back pain.

Description of selected adverse reactions.

Seizures.

In controlled clinical studies, 13 patients (0.4%) experienced a seizure out of 3179 patients treated with a daily dose of 160 mg enzalutamide, whereas one patient (0.1%) receiving placebo and one patient (0.3%) receiving bicalutamide experienced a seizure. In the patients who experienced seizure when treated with enzalutamide, there was one case of seizure where the patient experienced complications resulting in death. In the controlled clinical studies, patients with prior seizures or other risk factors for seizures were excluded. (See Section 4.4 Special Warnings and Precautions for Use, Risk of seizure).
Patients who are taking concomitant medicines (strong CYP2C8 inhibitors) that increase the blood levels of enzalutamide may be at increased risk of seizure (see Section 4.2 Dose and Method of Administration; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
In the AFFIRM trial, 7 of 800 (0.9%) post-chemotherapy patients treated with Xtandi 160 mg once daily experienced a seizure. Seizures occurred from 31 to 603 days after initiation of Xtandi. No seizures occurred in patients treated with placebo.
In the PREVAIL trial, 1 of 871 (0.1%) chemotherapy naive patients treated with Xtandi 160 mg once daily, and 1 of 844 (0.1%) patients treated with placebo experienced a seizure. Patients experiencing seizure were permanently discontinued from therapy and all seizure events resolved. Seizure reactions identified during the post-marketing experience based on spontaneous reports with Xtandi demonstrate a frequency of ≥ 0.1% and < 1% (Uncommon).
In bicalutamide-controlled trials, 3 patients (0.8%) out of 380 chemotherapy-naïve patients treated with enzalutamide and 1 patient (0.3%) out of 387 chemotherapy-native patients treated with bicalutamide experienced a seizure.
In the single-arm UPWARD study to assess incidence of seizure in patients with predisposing factors for seizure (whereof 1.7% had a history of seizures), 8 of 366 (2.2%) patients treated with Xtandi experienced a seizure. The median duration of treatment was 9.3 months.

Laboratory abnormalities.

In the two randomised clinical trials (AFFIRM and PREVAIL), Grade 1-4 neutropenia occurred in 14% of patients treated with Xtandi (1% Grade 3-4) and in 6% of patients treated with placebo (0.5% Grade 3-4). The incidence of Grade 1-4 thrombocytopenia was 6% of patients treated with Xtandi (0.3% Grade 3-4) and 5% of patients on placebo (0.5% Grade 3-4). Grade 1-4 elevations in ALT occurred in 10% of patients treated with Xtandi (0.2% Grade 3-4) and 16% of patients treated with placebo (0.2% Grade 3-4). Grade 1-4 elevations in bilirubin occurred in 3% of patients treated with Xtandi (0.1% Grade 3-4) and 2% of patients treated with placebo.
In the PROSPER, Grade 1-4 neutropenia occurred in 8% of patients receiving Xtandi (0.5% Grade 3- 4) and in 5% of patients receiving placebo (0.2% Grade 3-4).

Infections.

In the AFFIRM trial, 1% of patients treated with Xtandi compared to 0.3% of patients on placebo died from infections or sepsis. In the PREVAIL trial, 1 patient in each treatment group (0.1%) had an infection resulting in death.

Hallucinations.

In the AFFIRM trial, 1.6% of patients treated with Xtandi were reported to have Grade 1 or 2 hallucinations compared to 0.3% of patients on placebo. In the PREVAIL trial, 1 patient in each treatment group (0.1%) reported an event of Grade 1 hallucination. Of the patients with hallucinations, the majority were on opioid-containing medications at the time of the event. Hallucinations were visual, tactile, or undefined.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-problems.

4.2 Dose and Method of Administration

Dosage.

The recommended dose of Xtandi is 160 mg (four 40 mg capsules) as a single oral daily dose. Xtandi can be taken with or without food. Xtandi should be taken at the same time each day.

Method of administration.

Swallow capsules whole with water. Do not chew, dissolve, or open the capsules.
If a patient misses taking Xtandi 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 daily dose.
If a patient experiences a ≥ Grade 3 toxicity or an intolerable adverse reaction, withhold dosing for one week or until symptoms improve to ≤ Grade 2, then resume at the same or a reduced dose (120 mg or 80 mg) if warranted.
Xtandi should not be handled by persons other than the patient and his caregivers, and especially not by women who are or may become pregnant.

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, reduce the dose of Xtandi to 80 mg once daily. If co-administration of the strong CYP2C8 inhibitor is discontinued, the Xtandi dose should be returned to the dose used prior to initiation of the strong CYP2C8 inhibitor (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Patients with hepatic impairment.

No dose adjustment is required for patients with mild, moderate or severe hepatic impairment (Child-Pugh Class A, B or C, respectively).

Patients with renal impairment.

No dose adjustment is necessary for patients with mild or moderate renal impairment (see Section 5.2 Pharmacokinetic Properties, Pharmacokinetic characteristics in special populations). Caution is advised in patients with severe renal impairment or end-stage renal disease (see Section 4.4 Special Warnings and Precautions for Use, Use in renal impairment).

4.7 Effects on Ability to Drive and Use Machines

No formal studies of the effects of Xtandi on the ability to drive or use machines have been conducted. Neurological and psychiatric events (such as seizure, amnesia, fatigue, memory impairment, cognitive disorder, and disturbance in attention) associated with Xtandi may affect some patients' ability to drive or operate machinery. (See Section 4.8 Adverse Effects (Undesirable Effects)). Patients with a history of seizures or other predisposing factors should be advised of the risk of driving or operating machines (see Section 4.4 Special Warnings and Precautions for Use, Risk of seizure).

4.9 Overdose

There is no antidote for Xtandi. In the event of an overdose, treatment with Xtandi 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.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

7 Medicine Schedule (Poisons Standard)

S4.

6 Pharmaceutical Particulars

6.1 List of Excipients

Xtandi contains the following inactive ingredients: caprylocaproyl macrogolglycerides, butylated hydroxyanisole, butylated hydroxytoluene, gelatin, sorbitol sorbitan solution, glycerol, purified water, titanium dioxide. The soft capsules also contain Opacode WB monogramming ink NSP-78-17827 Black.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.
See Section 4.5 Interactions with Other Medicines and Other Forms of Interactions.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store below 25°C.

6.5 Nature and Contents of Container

Xtandi 40 mg capsules are supplied in a cardboard wallet incorporating a PVC/PCTFE/aluminium blister of 28 soft capsules. Each carton contains 4 wallets (112 soft capsules).

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

Summary Table of Changes