Xtandi

Enzalutamide is a white crystalline non-hygroscopic solid. It is practically insoluble in water.

XTANDI is provided as liquid-filled soft gelatin capsules for oral administration. Each capsule contains 40 mg of enzalutamide as a solution in caprylocaproyl polyoxylglycerides. The inactive ingredients are caprylocaproyl polyoxylglycerides, butylated hydroxyanisole, butylated hydroxytoluene, gelatin, sorbitol sorbitan solution, glycerin, purified water, titanium dioxide, and black iron oxide.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Enzalutamide is an androgen receptor inhibitor that acts on different steps in the androgen receptor signaling pathway. Enzalutamide has been shown to competitively inhibit androgen binding to androgen receptors and inhibit androgen receptor nuclear translocation and interaction with DNA. A major metabolite, N-desmethyl enzalutamide, exhibited similar in vitro activity to enzalutamide. Enzalutamide decreased proliferation and induced cell death of prostate cancer cells in vitro, and decreased tumor volume in a mouse prostate cancer xenograft model.

12.3 Pharmacokinetics

The pharmacokinetics of enzalutamide and its major active metabolite (N-desmethyl enzalutamide) were evaluated in patients with metastatic castration-resistant prostate cancer and healthy male volunteers. The plasma enzalutamide pharmacokinetics are adequately described by a linear two-compartment model with first-order absorption.

Absorption

Following oral administration (XTANDI 160 mg daily) in patients with metastatic castration-resistant prostate cancer, the median time to reach maximum plasma enzalutamide concentrations (C_max) is 1 hour (range 0.5 to 3 hours). At steady state, the plasma mean C_max values for enzalutamide and N-desmethyl enzalutamide are 16.6 μg/mL (23% CV) and 12.7 μg/mL (30% CV), respectively, and the plasma mean predose trough values are 11.4 μg/mL (26% CV) and 13.0 μg/mL (30% CV), respectively.

With the daily dosing regimen, enzalutamide steady state is achieved by Day 28, and enzalutamide accumulates approximately 8.3-fold relative to a single dose. Daily fluctuations in enzalutamide plasma concentrations are low (mean peak-to-trough ratio of 1.25). At steady state, enzalutamide showed approximately dose proportional pharmacokinetics over the daily dose range of 30 to 360 mg.

A single 160 mg oral dose of XTANDI was administered to healthy volunteers with a high-fat meal or in the fasted condition. A high-fat meal did not alter the AUC to enzalutamide or N-desmethyl enzalutamide. The results are summarized in Figure 1.

Distribution and Protein Binding

The mean apparent volume of distribution (V/F) of enzalutamide in patients after a single oral dose is 110 L (29% CV).

Enzalutamide is 97% to 98% bound to plasma proteins, primarily albumin. N-desmethyl enzalutamide is 95% bound to plasma proteins.

Metabolism 

Following single oral administration of ¹⁴C-enzalutamide 160 mg, plasma samples were analyzed for enzalutamide and its metabolites up to 77 days post dose. Enzalutamide, N-desmethyl enzalutamide, and a major inactive carboxylic acid metabolite accounted for 88% of the ¹⁴C-radioactivity in plasma, representing 30%, 49%, and 10%, respectively, of the total ¹⁴C-AUC_0-inf.

In vitro, human CYP2C8 and CYP3A4 are responsible for the metabolism of enzalutamide. Based on in vivo and in vitro data, CYP2C8 is primarily responsible for the formation of the active metabolite (N-desmethyl enzalutamide).

Elimination

Enzalutamide is primarily eliminated by hepatic metabolism. Following single oral administration of ¹⁴C-enzalutamide 160 mg, 85% of the radioactivity is recovered by 77 days post dose: 71% is recovered in urine (including only trace amounts of enzalutamide and N-desmethyl enzalutamide), and 14% is recovered in feces (0.4% of dose as unchanged enzalutamide and 1% as N-desmethyl enzalutamide).

The mean apparent clearance (CL/F) of enzalutamide in patients after a single oral dose is 0.56 L/h (range 0.33 to 1.02 L/h).

The mean terminal half-life (t_1/2) for enzalutamide in patients after a single oral dose is 5.8 days (range 2.8 to 10.2 days). Following a single 160 mg oral dose of enzalutamide in healthy volunteers, the mean terminal t_1/2 for N-desmethyl enzalutamide is approximately 7.8 to 8.6 days.

Pharmacokinetics in Special Populations

Renal Impairment:

A population pharmacokinetic analysis (based on pre-existing renal function) was carried out with data from 59 healthy male volunteers and 926 patients with metastatic castration-resistant prostate cancer enrolled in clinical trials, including 512 with normal renal function (CrCL ≥ 90 mL/min), 332 with mild renal impairment (CrCL 60 to < 90 mL/min), 88 with moderate renal impairment (CrCL 30 to < 60 mL/min), and 1 with severe renal impairment (CrCL < 30 mL/min). The apparent clearance of enzalutamide was similar in patients with pre-existing mild and moderate renal impairment (CrCL 30 to < 90 mL/min) compared to patients and volunteers with normal renal function. The potential effect of severe renal impairment or end stage renal disease on enzalutamide pharmacokinetics cannot be determined as clinical and pharmacokinetic data are available from only one patient [see Use in Specific Populations (8.6)].

Hepatic Impairment:

The plasma pharmacokinetics of enzalutamide and N-desmethyl enzalutamide were examined in volunteers with normal hepatic function (N = 16) and with pre-existing mild (N = 8, Child-Pugh Class A) or moderate (N = 8, Child-Pugh B) hepatic impairment. XTANDI was administered as a single 160 mg dose. The composite AUC of enzalutamide plus N-desmethyl enzalutamide was similar in volunteers with mild or moderate baseline hepatic impairment compared to volunteers with normal hepatic function. The results are summarized in Figure 1. Clinical and pharmacokinetic data are not available for patients with severe hepatic impairment (Child-Pugh Class C) [see Use in Specific Populations (8.7)].

Body Weight and Age:

Population pharmacokinetic analyses showed that weight (range: 46 to 163 kg) and age (range: 41 to 92 yr) do not have a clinically meaningful influence on the exposure to enzalutamide.

Gender:

The effect of gender on the pharmacokinetics of enzalutamide has not been evaluated.

Race:

The majority of patients in the randomized clinical trial were Caucasian (> 92%). There are insufficient data to evaluate potential differences in the pharmacokinetics of enzalutamide in other races.

Drug Interactions

Effect of Other Drugs on XTANDI:

In a drug-drug interaction trial in healthy volunteers, a single 160 mg oral dose of XTANDI was administered alone or after multiple oral doses of gemfibrozil (strong CYP2C8 inhibitor). Gemfibrozil increased the AUC_0-inf of enzalutamide plus N-desmethyl enzalutamide by 2.2-fold with minimal effect on C_max. The results are summarized in Figure 1 [see Dosage and Administration (2.2) and Drug Interactions (7.1)].

In a drug-drug interaction trial in healthy volunteers, a single 160 mg oral dose of XTANDI was administered alone or after multiple oral doses of itraconazole (strong CYP3A4 inhibitor). Itraconazole increased the AUC_0-inf of enzalutamide plus N-desmethyl enzalutamide by 1.3-fold with no effect on C_max. The results are summarized in Figure 1 [see Dosage and Administration (2.2) and Drug Interactions (7.2)].

The effects of CYP2C8 and CYP3A4 inducers on the exposure of XTANDI have not been evaluated in vivo.

^#PK parameters (C_max and AUC_0-inf) are for enzalutamide plus N-desmethyl enzalutamide, except in the food-effect trial, where they are for enzalutamide alone. *See Dosage and Administration (2.2).

Effect of XTANDI on Other Drugs:

In an in vivo phenotypic cocktail drug-drug interaction trial in patients with castration-resistant prostate cancer, a single oral dose of the CYP probe substrate cocktail (for CYP2C8, CYP2C9, CYP2C19, and CYP3A4) was administered before and concomitantly with XTANDI (following at least 55 days of dosing at 160 mg daily). The results are summarized in Figure 2. Results showed that in vivo, at steady state, XTANDI is a strong CYP3A4 inducer and a moderate CYP2C9 and CYP2C19 inducer [see Drug Interactions (7.3)]. XTANDI did not cause clinically meaningful changes in exposure to the CYP2C8 substrate.

*See Drug Interactions (7.3).

In vitro, enzalutamide, N-desmethyl enzalutamide, and the major inactive carboxylic acid metabolite caused direct inhibition of multiple CYP enzymes including CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4/5; however, subsequent clinical data showed that XTANDI is an inducer of CYP2C9, CYP2C19, and CYP3A4 and had no clinically meaningful effect on CYP2C8 (see Figure 2). In vitro, enzalutamide caused time-dependent inhibition of CYP1A2.

In vitro studies showed that enzalutamide caused induction of CYP3A4 and that enzalutamide is not expected to induce CYP1A2 at therapeutically relevant concentrations.

In vitro, enzalutamide, N-desmethyl enzalutamide, and the major inactive carboxylic acid metabolite are not substrates for human P-glycoprotein. In vitro, enzalutamide and N-desmethyl enzalutamide are inhibitors of human P-glycoprotein, while the major inactive carboxylic acid metabolite is not.

12.6 Cardiac Electrophysiology

The effect of enzalutamide 160 mg/day at steady state on the QTc interval was evaluated in 796 patients with castration-resistant prostate cancer. No large difference (i.e., greater than 20 ms) was observed between the mean QT interval change from baseline in patients treated with XTANDI and that in patients treated with placebo, based on the Fridericia correction method. However, small increases in the mean QTc interval (i.e., less than 10 ms) due to enzalutamide cannot be excluded due to limitations of the study design.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term animal studies have not been conducted to evaluate the carcinogenic potential of enzalutamide.

Enzalutamide did not induce mutations in the bacterial reverse mutation (Ames) assay and was not genotoxic in either the in vitro mouse lymphoma thymidine kinase (Tk) gene mutation assay or the in vivo mouse micronucleus assay.

Based on nonclinical findings in repeat-dose toxicology studies, which were consistent with the pharmacological activity of enzalutamide, male fertility may be impaired by treatment with XTANDI. In a 26-week study in rats, atrophy of the prostate and seminal vesicles was observed at ≥ 30 mg/kg/day (equal to the human exposure based on AUC). In 4- and 13-week studies in dogs, hypospermatogenesis and atrophy of the prostate and epididymides were observed at ≥ 4 mg/kg/day (0.3 times the human exposure based on AUC).

14 CLINICAL STUDIES

The efficacy and safety of XTANDI in patients with metastatic castration-resistant prostate cancer who had received prior docetaxel-based therapy were assessed in a randomized, placebo-controlled, multicenter phase 3 clinical trial. The primary endpoint was overall survival. A total of 1199 patients were randomized 2:1 to receive either XTANDI orally at a dose of 160 mg once daily (N = 800) or placebo orally once daily (N = 399). All patients continued androgen deprivation therapy. Patients were allowed, but not required to continue or initiate glucocorticoids. Study treatment continued until disease progression (evidence of radiographic progression, a skeletal-related event, or clinical progression), initiation of new systemic antineoplastic treatment, unacceptable toxicity, or withdrawal. Patients with a history of seizure, taking medicines known to decrease the seizure threshold, or with other risk factors for seizure were not eligible [see Warnings and Precautions (5.1)].

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. Ninety-two percent of patients had an ECOG performance status score of 0-1 and 28% had a mean Brief Pain Inventory score of ≥ 4. Ninety-one percent of patients had metastases in bone and 23% had visceral involvement in the lung and/or liver. Fifty-nine percent of patients had radiographic evidence of disease progression and 41% had PSA-only progression on study entry. All patients had received prior docetaxel-based therapy and 24% had received two cytotoxic chemotherapy regimens. During the trial, 48% of patients on the XTANDI arm and 46% of patients on the placebo arm received glucocorticoids.

The pre-specified interim analysis at the time of 520 events showed a statistically significant improvement in overall survival in patients on the XTANDI arm compared to patients on the placebo arm (Table 2 and Figure 3).

16 HOW SUPPLIED/STORAGE AND HANDLING

• •XTANDI (enzalutamide) 40 mg capsules are supplied as white to off-white oblong soft gelatin capsules imprinted in black ink with ENZ. XTANDI capsules are available in the following package sizes:
  • •Bottles of 120 capsules (NDC 0469-0125-99)

Recommended storage: Store XTANDI 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).

17 PATIENT COUNSELING INFORMATION

See FDA-approved patient labeling (PATIENT INFORMATION).

• •Instruct patients to take their dose at the same time each day (once daily). XTANDI can be taken with or without food. Each capsule should be swallowed whole. Do not chew, dissolve, or open the capsules.
• •Inform patients receiving a GnRH analog that they need to maintain this treatment during the course of treatment with XTANDI.
• •Inform patients that XTANDI has been associated with an increased risk of seizure. Discuss conditions that may predispose to seizures and medications that may lower the seizure threshold. Advise patients of the risk of engaging in any activity where sudden loss of consciousness could cause serious harm to themselves or others.
• • Inform patients that XTANDI may cause dizziness, mental impairment, paresthesia, hypoesthesia, and falls.
• •Inform patients that they should not interrupt, modify the dose, or stop XTANDI without first consulting their physician. Inform patients that if they miss a dose, then they should take it as soon as they remember. If they forget to take the dose for the whole day, then they should take their normal dose the next day. They should not take more than their prescribed dose per day.
• •Apprise patients of the common side effects associated with XTANDI: asthenia/fatigue, back pain, diarrhea, arthralgia, hot flush, peripheral edema, musculoskeletal pain, headache, upper respiratory infection, muscular weakness, dizziness, insomnia, lower respiratory infection, spinal cord compression and cauda equina syndrome, hematuria, paresthesia, anxiety, and hypertension. Direct the patient to a complete list of adverse drug reactions in PATIENT INFORMATION.
• •Inform patients that XTANDI may be harmful to a developing fetus. Patients should also be informed that they should use a condom if having sex with a pregnant woman. A condom and another effective method of birth control should be used if the patient is having sex with a woman of child-bearing potential. These measures are required during and for three months after treatment with XTANDI.

Manufactured by: Catalent Pharma Solutions, LLC, St. Petersburg, FL 33716

Manufactured for and Distributed by: Astellas Pharma US, Inc., Northbrook, IL 60062

Marketed by:

Astellas Pharma US, Inc., Northbrook, IL 60062

Medivation, Inc., San Francisco, CA 94105

Revised: March 2013

12J069-XTA-SPL

Rx Only

© 2012 Astellas Pharma US, Inc.

XTANDI^® is a registered trademark of Astellas Pharma Inc.

PATIENT INFORMATION

XTANDI^® (ex TAN dee)

(enzalutamide)

capsules

Read this Patient Information before you start taking XTANDI and each time you get a refill. There may be new information. This information does not take the place of talking with your healthcare provider about your medical condition or your treatment.

What is XTANDI?

XTANDI is a prescription medicine used to treat men with castration-resistant prostate cancer (prostate cancer that is resistant to medical or surgical treatments that lower testosterone) that has spread to other parts of the body and who have received treatment with docetaxel.

It is not known if XTANDI is safe and effective in children.

Who should not take XTANDI?

XTANDI is not for use in women.

Do not take XTANDI if you are pregnant or may become pregnant. XTANDI may harm your unborn baby.

What should I tell my healthcare provider before taking XTANDI?

Before you take XTANDI, tell your healthcare provider if you:

• •have a history of seizures, brain injury, stroke, or brain tumors
• •have any other medical conditions
• •have a partner who is pregnant or plans to become pregnant. Men who are sexually active with a pregnant woman must use a condom during and for 3 months after treatment with XTANDI. If their sexual partner may become pregnant, a condom and another form of birth control must be used during and for 3 months after treatment. Talk with your healthcare provider if you have questions about birth control. See “Who should not take XTANDI?”

Tell your healthcare provider about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. XTANDI can interact with many other medicines.

You should not start or stop any medicine before you talk with the healthcare provider that prescribed XTANDI.

Know the medicines you take. Keep a list of them with you to show your healthcare provider and pharmacist when you get a new medicine.

How should I take XTANDI?

• •Take XTANDI capsules exactly as your healthcare provider tells you.
• •Take your prescribed dose of XTANDI one time a day.
• •Your healthcare provider may change your dose if needed.
• •Do not stop taking your prescribed dose of XTANDI without talking with your healthcare provider first.
• •XTANDI capsules can be taken with or without food.
• •Swallow XTANDI capsules whole. Do not chew, dissolve, or open the capsules.
• •If you miss a dose of XTANDI, take your prescribed dose as soon as you remember that day. If you miss your daily dose, take your prescribed dose at your regular time the next day. Do not take more than your prescribed dose of XTANDI.
• •If you take too much XTANDI, call your healthcare provider or go to the nearest emergency room right away.

What are the possible side effects of XTANDI?

XTANDI may cause serious side effects including:

● Seizure. Some people have had seizures during treatment with XTANDI. If you take XTANDI you may be at risk of having a seizure. You should avoid activities where a sudden loss of consciousness could cause serious harm to yourself or others. Tell your healthcare provider right away if you have loss of consciousness or seizure.

The most common side effects of XTANDI include:

• •weakness or feeling more tired than usual
• •back pain
• •diarrhea
• •pain in your joints
• •hot flashes
• •swelling in your hands, arms, legs or feet
• •muscle or bone pain
• •headache
• •cold like symptoms
• •muscle weakness
• •dizziness
• •trouble falling or staying asleep (insomnia)
• •trouble breathing (pneumonia)
• •back pain with nerve problems in the lower body, including leg numbness or weakness
• •pink or red urine (hematuria)
• •sensation of tingling, burning, pricking, or numbness of skin (paresthesia)
• •anxiety
• •high blood pressure (hypertension)

Tell your healthcare provider if you have any falls or problems thinking clearly.

Tell your healthcare provider if you have any side effect that bothers you or that does not go away.

These are not all the possible side effects of XTANDI. For more information, ask your healthcare provider or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at
1-800-FDA-1088.

How should I store XTANDI?

• •Store XTANDI between 68°F to 77°F (20°C to 25°C).
• •Keep XTANDI capsules dry and in a tightly closed container.

Keep XTANDI and all medicines out of the reach of children.

General information about XTANDI

Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use XTANDI for a condition for which it was not prescribed. Do not give XTANDI to other people, even if they have the same symptoms that you have. It may harm them.

This Patient Information leaflet summarizes the most important information about XTANDI. If you would like more information, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about XTANDI that is written for healthcare professionals.

For more information go to www.AboutXtandi.com or call 1-800-727-7003.

What are the ingredients in XTANDI?

Active ingredient: enzalutamide

Inactive ingredients: caprylocaproyl polyoxylglycerides, butylated hydroxyanisole, butylated hydroxytoluene, gelatin, sorbitol sorbitan solution, glycerin, purified water, titanium dioxide, black iron oxide.

This Patient Information has been approved by the U.S. Food and Drug Administration.

Manufactured by: Catalent Pharma Solutions, LLC, St. Petersburg, FL 33716

Marketed by:

Astellas Pharma US, Inc., Northbrook, IL 60062

Medivation Inc., San Francisco, CA 94105

Revised: March 2013

12J069-XTA-SPL

© 2012 Astellas Pharma US, Inc.

XTANDI^® is a registered trademark of Astellas Pharma Inc.

PACKAGE/LABEL PRINCIPAL DISPLAY PANEL