Generic Name: enzalutamide
Dosage Form: capsule

Indications and Usage for Xtandi

Xtandi is indicated for the treatment of patients with metastatic castration-resistant prostate cancer (CRPC).

Xtandi Dosage and Administration

Dosing Information

The recommended dose of Xtandi is 160 mg (four 40 mg capsules) administered orally once daily. Xtandi can be taken with or without food [see Clinical Pharmacology (12.3)]. Swallow capsules whole. Do not chew, dissolve, or open the capsules.

Slideshow: Flashback: FDA Drug Approvals 2013

Dose Modifications

If a patient experiences a ≥ Grade 3 toxicity or an intolerable side effect, 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.

Concomitant 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 Xtandi dose to 80 mg once daily. If co-administration of the strong inhibitor is discontinued, the Xtandi dose should be returned to the dose used prior to initiation of the strong CYP2C8 inhibitor [see Drug Interactions (7.1) and Clinical Pharmacology (12.3)].

Dosage Forms and Strengths

Xtandi 40 mg capsules are white to off-white oblong soft gelatin capsules imprinted in black ink with ENZ.

Contraindications

Pregnancy
Xtandi can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings in animals. Xtandi is not indicated for use in women. Xtandi is contraindicated in women who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus and the potential risk for pregnancy loss [see Use in Specific Populations (8.1)].

Warnings and Precautions

Seizure

In Study 1, which enrolled patients who previously received docetaxel, 7 of 800 (0.9%) patients treated with Xtandi experienced a seizure and no patients treated with placebo experienced a seizure. Seizure occurred from 31 to 603 days after initiation of Xtandi. In Study 2, 1 of 871 (0.1%) chemotherapy-naive patients treated with Xtandi 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. There is no clinical trial experience re-administering Xtandi to patients who experienced seizure.

Limited safety data are available in patients with predisposing factors for seizure because these patients were generally excluded from the trials. These exclusion criteria included a history of seizure, underlying brain injury with loss of consciousness, transient ischemic attack within the past 12 months, cerebral vascular accident, brain metastases, and brain arteriovenous malformation. Study 1 excluded the use of concomitant medications that may lower the seizure threshold, whereas Study 2 permitted the use of these medications.

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. Permanently discontinue Xtandi in patients who develop a seizure during treatment.

Adverse Reactions

The following is discussed in more detail in other sections of the labeling:

Seizure [see Warnings and Precautions (5.1)]

Clinical Trial Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Two randomized clinical trials enrolled patients with metastatic prostate cancer that has progressed on androgen deprivation therapy (GnRH therapy or bilateral orchiectomy), a disease setting that is also defined as metastatic CRPC. In both studies, patients received Xtandi 160 mg orally once daily in the active treatment arm or placebo in the control arm. All patients continued androgen deprivation therapy. Patients were allowed, but not required, to take glucocorticoids.

The most common adverse reactions (≥ 10%) that occurred more commonly (≥ 2% over placebo) in the Xtandi-treated patients from the two randomized clinical trials were asthenia/fatigue, back pain, decreased appetite, constipation, arthralgia, diarrhea, hot flush, upper respiratory tract infection, peripheral edema, dyspnea, musculoskeletal pain, weight decreased, headache, hypertension, and dizziness/vertigo.

Study 1: Metastatic Castration-Resistant Prostate Cancer Following Chemotherapy

Study 1 enrolled 1199 patients with metastatic 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 Study 1 that occurred at a ≥ 2% higher frequency in the Xtandi arm compared to the placebo arm.

Table 1. Adverse Reactions in Study 1

Xtandi

N = 800

Placebo

N = 399

Grade 1-4a

(%)

Grade 3-4

(%)

Grade 1-4

(%)

Grade 3-4

(%)

General Disorders

    Asthenic Conditionsb

50.6

9.0

44.4

9.3

    Peripheral Edema

15.4

1.0

13.3

0.8

Musculoskeletal And Connective Tissue Disorders

    Back Pain

26.4

5.3

24.3

4.0

    Arthralgia

20.5

2.5

17.3

1.8

    Musculoskeletal Pain

15.0

1.3

11.5

0.3

    Muscular Weakness

9.8

1.5

6.8

1.8

    Musculoskeletal Stiffness

2.6

0.3

0.3

0.0

Gastrointestinal Disorders

    Diarrhea

21.8

1.1

17.5

0.3

Vascular Disorders

    Hot Flush

20.3

0.0

10.3

0.0

    Hypertension

6.4

2.1

2.8

1.3

Nervous System Disorders

    Headache

12.1

0.9

5.5

0.0

    Dizzinessc

9.5

0.5

7.5

0.5

    Spinal Cord Compression
    and Cauda Equina Syndrome

7.4

6.6

4.5

3.8

    Paresthesia

6.6

0.0

4.5

0.0

    Mental Impairment Disordersd

4.3

0.3

1.8

0.0

    Hypoesthesia

4.0

0.3

1.8

0.0

Infections And Infestations

    Upper Respiratory Tract
    Infectione

10.9

0.0

6.5

0.3

    Lower Respiratory Tract And
    Lung Infectionf

8.5

2.4

4.8

1.3

Psychiatric Disorders

    Insomnia

8.8

0.0

6.0

0.5

    Anxiety

6.5

0.3

4.0

0.0

Renal And Urinary Disorders

    Hematuria

6.9

1.8

4.5

1.0

    Pollakiuria

4.8

0.0

2.5

0.0

Injury, Poisoning And Procedural Complications

    Fall

4.6

0.3

1.3

0.0

    Non-pathologic Fractures

4.0

1.4

0.8

0.3

Skin And Subcutaneous Tissue Disorders

    Pruritus

3.8

0.0

1.3

0.0

    Dry Skin

3.5

0.0

1.3

0.0

Respiratory Disorders

    Epistaxis

3.3

0.1

1.3

0.3

a    CTCAE v4

b    Includes asthenia and fatigue.

c    Includes dizziness and vertigo.

d    Includes amnesia, memory impairment, cognitive disorder, and disturbance in attention.

e    Includes nasopharyngitis, upper respiratory tract infection, sinusitis, rhinitis, pharyngitis, and laryngitis.

f    Includes pneumonia, lower respiratory tract infection, bronchitis, and lung infection.

Study 2: Chemotherapy-naive Metastatic Castration-Resistant Prostate Cancer

Study 2 enrolled 1717 patients with metastatic CRPC who had not received prior cytotoxic chemotherapy, of whom 1715 received at least one dose of study drug. The median duration of treatment was 17.5 months with Xtandi and 4.6 months with placebo. Grade 3-4 adverse reactions were reported in 44% of Xtandi-treated patients and 37% of placebo-treated patients. Discontinuations due to adverse events were reported for 6% of Xtandi-treated patients and 6% of placebo-treated patients. The most common adverse reaction leading to treatment discontinuation was fatigue/asthenia, which occurred in 1% of patients on each treatment arm. Table 2 includes adverse reactions reported in Study 2 that occurred at a ≥ 2% higher frequency in the Xtandi arm compared to the placebo arm.

Table 2. Adverse Reactions in Study 2
Xtandi
N = 871
Placebo
N = 844
Grade 1-4a
(%)
Grade 3-4
(%)
Grade 1-4
(%)
Grade 3-4
(%)

General Disorders

    Asthenic Conditionsb

46.9

3.4

33.0

2.8

    Peripheral Edema

11.5

0.2

8.2

0.4

Musculoskeletal And Connective Tissue Disorders

    Back Pain

28.6

2.5

22.4

3.0

    Arthralgia

21.4

1.6

16.1

1.1

Gastrointestinal Disorders

    Constipation

23.2

0.7

17.3

0.4

    Diarrhea

16.8

0.3

14.3

0.4

Vascular Disorders

    Hot Flush

18.0

0.1

7.8

0.0

    Hypertension

14.2

7.2

4.1

2.3

Nervous System Disorders

    Dizzinessc

11.3

0.3

7.1

0.0

    Headache

11.0

0.2

7.0

0.4

    Dysgeusia

7.6

0.1

3.7

0.0

    Mental Impairment Disordersd

5.7

0.0

1.3

0.1

    Restless Legs Syndrome

2.1

0.1

0.4

0.0

Respiratory Disorders

    Dyspneae

11.0

0.6

8.5

0.6

Infections And Infestations

    Upper Respiratory Tract
    Infectionf

16.4

0.0

10.5

0.0

    Lower Respiratory Tract And
    Lung Infectiong

7.9

1.5

4.7

1.1

Psychiatric Disorders

    Insomnia

8.2

0.1

5.7

0.0

Renal And Urinary Disorders

    Hematuria

8.8

1.3

5.8

1.3

Injury, Poisoning And Procedural Complications

    Fall

12.7

1.6

5.3

0.7

    Non-Pathological Fracture

8.8

2.1

3.0

1.1

Metabolism and Nutrition Disorders

    Decreased Appetite

18.9

0.3

16.4

0.7

Investigations

    Weight Decreased

12.4

0.8

8.5

0.2

Reproductive System and Breast disorders

    Gynecomastia

3.4

0.0

1.4

0.0

a    CTCAE v4

b    Includes asthenia and fatigue.

c    Includes dizziness and vertigo.

d    Includes amnesia, memory impairment, cognitive disorder, and disturbance in attention.

e    Includes dyspnea, exertional dyspnea, and dyspnea at rest.

f    Includes nasopharyngitis, upper respiratory tract infection, sinusitis, rhinitis, pharyngitis, and laryngitis.

g    Includes pneumonia, lower respiratory tract infection, bronchitis, and lung infection.

Laboratory Abnormalities
In the two randomized clinical trials, Grade 1-4 neutropenia occurred in 15% 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 treated with 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 (no Grade 3-4).

Infections
In Study 1, 1% of patients treated with Xtandi compared to 0.3% of patients treated with placebo died from infections or sepsis. In Study 2, 1 patient in each treatment group (0.1%) had an infection resulting in death.

Falls and Fall-related Injuries
In the two randomized clinical trials, falls including fall-related injuries, occurred in 9% 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 hematomas.

Hypertension
In the two randomized trials, hypertension was reported in 11% of patients receiving Xtandi and 4% of patients receiving 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.

Drug Interactions

Drugs that Inhibit or Induce CYP2C8

Co-administration of a strong CYP2C8 inhibitor (gemfibrozil) increased the composite area under the plasma concentration-time curve (AUC) of enzalutamide plus N-desmethyl enzalutamide by 2.2-fold in healthy volunteers. Co‑administration of Xtandi with strong CYP2C8 inhibitors should be avoided if possible. If co-administration of Xtandi with a strong CYP2C8 inhibitor cannot be avoided, reduce the dose of Xtandi [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3)].

The effects of CYP2C8 inducers on the pharmacokinetics of enzalutamide have not been evaluated in vivo. Co-administration of Xtandi with strong or moderate CYP2C8 inducers (e.g., rifampin) may alter the plasma exposure of Xtandi and should be avoided if possible. Selection of a concomitant medication with no or minimal CYP2C8 induction potential is recommended [see Clinical Pharmacology (12.3)].

Drugs that Inhibit or Induce CYP3A4

Co-administration of a strong CYP3A4 inhibitor (itraconazole) increased the composite AUC of enzalutamide plus N-desmethyl enzalutamide by 1.3-fold in healthy volunteers [see Clinical Pharmacology (12.3)].

The effects of CYP3A4 inducers on the pharmacokinetics of enzalutamide have not been evaluated in vivo. Co-administration of Xtandi with strong CYP3A4 inducers (e.g., carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, rifapentine) may decrease the plasma exposure of Xtandi and should be avoided if possible. Selection of a concomitant medication with no or minimal CYP3A4 induction potential is recommended. Moderate CYP3A4 inducers (e.g., bosentan, efavirenz, etravirine, modafinil, nafcillin) and St. John’s Wort may also reduce the plasma exposure of Xtandi and should be avoided if possible [see Clinical Pharmacology (12.3)].

Effect of Xtandi on Drug Metabolizing Enzymes

Enzalutamide is a strong CYP3A4 inducer and a moderate CYP2C9 and CYP2C19 inducer in humans. At steady state, Xtandi reduced the plasma exposure to midazolam (CYP3A4 substrate), warfarin (CYP2C9 substrate), and omeprazole (CYP2C19 substrate). Concomitant use of Xtandi with narrow therapeutic index drugs that are metabolized by CYP3A4 (e.g., alfentanil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus and tacrolimus), CYP2C9 (e.g., phenytoin, warfarin) and CYP2C19 (e.g., S-mephenytoin) should be avoided, as enzalutamide may decrease their exposure. If co-administration with warfarin cannot be avoided, conduct additional INR monitoring [see Clinical Pharmacology (12.3)].

USE IN SPECIFIC POPULATIONS

Pregnancy

Pregnancy Category X [see Contraindications (4)].

Risk Summary
Xtandi can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings in animals. While there are no human data on the use of Xtandi in pregnancy and Xtandi is not indicated for use in women, it is important to know that maternal use of an androgen receptor inhibitor could affect development of the fetus. Enzalutamide caused embryo-fetal toxicity in mice at exposures that were lower than in patients receiving the recommended dose. Xtandi is contraindicated in women who are or may become pregnant while receiving the drug. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus and the potential risk for pregnancy loss. Advise females of reproductive potential to avoid becoming pregnant during treatment with Xtandi.

Animal Data
In an embryo-fetal developmental toxicity study in mice, enzalutamide caused developmental toxicity when administered at oral doses of 10 or 30 mg/kg/day throughout the period of organogenesis (gestational days 6-15). Findings included embryo-fetal lethality (increased post-implantation loss and resorptions) and decreased anogenital distance at ≥ 10 mg/kg/day, and cleft palate and absent palatine bone at 30 mg/kg/day. Doses of 30 mg/kg/day caused maternal toxicity. The doses tested in mice (1, 10 and 30 mg/kg/day) resulted in systemic exposures (AUC) approximately 0.04, 0.4 and 1.1 times, respectively, the exposures in patients. Enzalutamide did not cause developmental toxicity in rabbits when administered throughout the period of organogenesis (gestational days 6-18) at dose levels up to 10 mg/kg/day (approximately 0.4 times the exposures in patients based on AUC).

Nursing Mothers

Xtandi is not indicated for use in women. It is not known if enzalutamide is excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from Xtandi, a decision should be made to either discontinue nursing, or discontinue the drug taking into account the importance of the drug to the mother.

Pediatric Use

Safety and effectiveness of Xtandi in pediatric patients have not been established.

Geriatric Use

Of 1671 patients who received Xtandi in the two randomized clinical trials, 75% were 65 and over, while 31% were 75 and over. No overall differences in safety or effectiveness were observed between these patients and younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Patients with Renal Impairment

A dedicated renal impairment trial for Xtandi has not been conducted. Based on the population pharmacokinetic analysis using data from clinical trials in patients with metastatic CRPC and healthy volunteers, no significant difference in enzalutamide clearance was observed in patients with pre-existing mild to moderate renal impairment (30 mL/min ≤ creatinine clearance [CrCL] ≤ 89 mL/min) compared to patients and volunteers with baseline normal renal function (CrCL ≥ 90 mL/min). No initial dosage adjustment is necessary for patients with mild to moderate renal impairment. Severe renal impairment (CrCL < 30 mL/min) and end-stage renal disease have not been assessed [see Clinical Pharmacology (12.3)].

Patients with Hepatic Impairment

A dedicated hepatic impairment trial compared the composite systemic exposure of enzalutamide plus N-desmethyl enzalutamide in volunteers with baseline mild or moderate hepatic impairment (Child-Pugh Class A and B, respectively) versus healthy controls with normal hepatic function. 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. No initial dosage adjustment is necessary for patients with baseline mild or moderate hepatic impairment. Baseline severe hepatic impairment (Child-Pugh Class C) has not been assessed [see Clinical Pharmacology (12.3)].

Overdosage

In the event of an overdose, stop treatment with Xtandi and initiate general supportive measures taking into consideration the half-life of 5.8 days. In a dose escalation study, no seizures were reported at < 240 mg daily, whereas 3 seizures were reported, 1 each at 360 mg, 480 mg, and 600 mg daily. Patients may be at increased risk of seizure following an overdose.

Xtandi Description

Enzalutamide is an androgen receptor inhibitor. The chemical name is 4 - {3 - [4 - cyano - 3 - (trifluoromethyl)phenyl] - 5,5 - dimethyl - 4 - oxo - 2 - sulfanylideneimidazolidin - 1 - yl} - 2 - fluoro - N-methylbenzamide.

The molecular weight is 464.44 and molecular formula is C21H16F4N4O2S. The structural formula is:

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.

Xtandi - Clinical Pharmacology

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.

Pharmacokinetics

The pharmacokinetics of enzalutamide and its major active metabolite (N-desmethyl enzalutamide) were evaluated in patients with metastatic CRPC 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 CRPC, the median time to reach maximum plasma enzalutamide concentrations (Cmax) is 1 hour (range 0.5 to 3 hours). At steady state, the plasma mean Cmax 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. In vitro, there was no protein binding displacement between enzalutamide and other highly protein bound drugs (warfarin, ibuprofen, and salicylic acid) at clinically relevant concentrations.

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-AUC0-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).

In vitro, N-desmethyl enzalutamide is not a substrate of human CYP1A1, CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C18, CYP2C19, CYP2D6, CYP2E1 and CYP3A4/5.

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 (t1/2) 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 t1/2 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 CRPC 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 Xtandi-treated patients in the randomized clinical trials were Caucasian (85%). Based on pharmacokinetic data from a study in Japanese patients with prostate cancer, there were no clinically relevant differences in exposure between Japanese and Caucasians. 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 AUC0-inf of enzalutamide plus N-desmethyl enzalutamide by 2.2-fold with minimal effect on Cmax. 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 AUC0-inf of enzalutamide plus N-desmethyl enzalutamide by 1.3-fold with no effect on Cmax. 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

Figure 1. Effects of Other Drugs and Intrinsic/Extrinsic Factors on Xtandi

#PK parameters (Cmax and AUC0-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 metastatic CRPC, 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.


Figure 2. Effect of Xtandi on Other Drugs

*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 induces CYP2B6 and CYP3A4 and does not 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.

In vitro, enzalutamide and N-desmethyl enzalutamide do not appear to be substrates of human breast cancer resistance protein (BCRP); however, enzalutamide and N-desmethyl enzalutamide are inhibitors of human BCRP at clinically relevant concentrations.

Cardiac Electrophysiology

The effect of enzalutamide 160 mg/day at steady state on the QTc interval was evaluated in 796 patients with metastatic CRPC. 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.

Nonclinical Toxicology

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-, 13-, and 39-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).

Clinical Studies

The efficacy and safety of Xtandi in patients with metastatic CRPC were demonstrated in two randomized, placebo-controlled, multicenter phase 3 clinical trials. All patients continued on GnRH therapy or had prior bilateral orchiectomy. Patients were allowed, but not required, to continue or initiate glucocorticoids.

Study 1: Metastatic Castration-Resistant Prostate Cancer Following Chemotherapy
A total of 1199 patients who had received prior docetaxel-based chemotherapy 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). 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 previous 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.

A statistically significant improvement in overall survival was demonstrated at the pre-specified interim analysis at the time of 520 deaths in patients on the Xtandi arm compared to patients on the placebo arm (Table 3 and Figure 3).

Table 3. Overall Survival of Patients Treated with Either Xtandi or Placebo in Study 1

Xtandi

N = 800

Placebo

N = 399

Number of Deaths (%)

308 (38.5%)

212 (53.1%)

Median Survival (months) (95% CI)

18.4 (17.3, NR)

13.6 (11.3, 15.8)

P-valuea

< 0.0001

Hazard Ratio (95% CI)b

0.63 (0.53, 0.75)

a) P-value is derived from a log-rank test stratified by baseline ECOG performance status score (0-1 vs. 2) and mean baseline pain score (BPI-SF score < 4 vs. ≥ 4)
b) Hazard Ratio is derived from a stratified proportional hazards model. Hazard ratio <1 favors Xtandi
NR denotes “not reached”.

Figure 3. Kaplan-Meier Overall Survival Curves in Study 1

Study 2: Chemotherapy-naive Metastatic Castration-Resistant Prostate Cancer
In Study 2, 1717 chemotherapy-naive patients were randomized 1:1 to receive either Xtandi orally at a dose of 160 mg once daily (N=872) or placebo orally once daily (N=845). Patients with visceral metastases, patients with a history of mild to moderate heart failure (NYHA class I or II), 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 a cytotoxic chemotherapy or an investigational agent, unacceptable toxicity, or withdrawal. Overall survival and radiographic progression-free survival (rPFS) were assessed. Radiographic progression was assessed with the use of sequential imaging and was defined by bone scan identification of 2 or more new bone lesions with confirmation (Prostate Cancer Clinical Trials Working Group 2 criteria) and/or Response Evaluation Criteria in Solid Tumors (RECIST v 1.1) criteria for progression of soft tissue lesions. The primary analysis of rPFS utilized centrally reviewed radiographic assessment of progression.

Patient demographics and baseline disease characteristics were balanced between the treatment arms at entry. The median age was 71 years (range 42-93) and the racial distribution was 77% Caucasian, 10% Asian, 2% Black and 11% Other. The ECOG performance status score was 0 for 68% of patients, and 1 for 32% of patients. Baseline pain assessment was 0-1 (asymptomatic) in 67% of patients, and 2-3 (mildly symptomatic) in 32% of patients as defined by the Brief Pain Inventory Short Form (worst pain over past 24 hours at study entry). Fifty-four percent of patients had radiographic evidence of disease progression and 43% had PSA-only progression. Twelve percent of patients had visceral (lung and/or liver) disease involvement. During the study, 27% of patients on the Xtandi arm and 30% of patients on the placebo arm received glucocorticoids for varying reasons.

A statistically significant improvement in overall survival was demonstrated at the pre-specified interim analysis, conducted after 540 deaths in patients treated with Xtandi compared to those treated with placebo (Table 4, Figure 4). Forty percent of Xtandi-treated and 70% of placebo-treated patients received subsequent therapies for metastatic CRPC that may prolong overall survival.

Table 4. Overall Survival of Patients Treated with Either Xtandi or Placebo in Study 2

Xtandi

N = 872

Placebo

N = 845

Pre-specified Interim Analysis

    Number of Deaths (%)

241 (28%)

299 (35%)

    Median Survival (months) (95% CI)

32.4 (30.1, NR)

30.2 (28.0, NR)

    P-valuea

< 0.0001

    Hazard Ratio (95% CI)b

0.71 (0.60, 0.84)

a) P-value is derived from an unstratified log-rank test
b) Hazard Ratio is derived from an unstratified proportional hazards model. Hazard ratio <1 favors Xtandi
NR denotes “not reached”.


Figure 4. Kaplan-Meier Overall Survival Curves in Study 2

A statistically significant improvement in rPFS was demonstrated in patients treated with Xtandi compared to patients treated with placebo (Table 5, Figure 5).

Table 5. Radiographic Progression-free Survival of Patients Treated with Either Xtandi or Placebo in Study 2

Xtandi

N = 832

Placebo

N = 801

Number of Progression or Deaths (%)

118 (14%)

320 (40%)

Median rPFS (months) (95% CI)

NR (13.8, NR)

3.7 (3.6, 4.6)

P-valuea

< 0.0001

Hazard Ratio (95% CI)b

0.17 (0.14, 0.21)

a) P-value is derived from an unstratified log-rank test
b) Hazard Ratio is derived from an unstratified proportional hazards model. Hazard ratio <1 favors Xtandi
NR denotes “not reached”.
Note: As of the cutoff date for the rPFS analysis, 1633 patients had been randomized.

Figure 5. Kaplan-Meier Curves for Duration of Radiographic Progression-free Survival in Study 2

Time to initiation of cytotoxic chemotherapy was prolonged after Xtandi treatment, with a median of 28.0 months for patients on the Xtandi arm versus a median of 10.8 months for patients on the placebo arm [HR=0.35 (95% CI: 0.30, 0.40), p < 0.0001)].

The median time to first skeletal‑related event was 31.1 months for patients on the Xtandi arm versus 31.3 months for patients on the placebo arm [HR = 0.72 (95% CI: 0.61, 0.84), p < 0.0001]. 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.

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).

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 GnRH therapy 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 to contact their physician right away if they have loss of consciousness or seizure.
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 most common side effects associated with Xtandi: asthenia/fatigue, back pain, decreased appetite, constipation, arthralgia, diarrhea, hot flush, upper respiratory tract infection, peripheral edema, dyspnea, musculoskeletal pain, weight decreased, headache, hypertension, and dizziness/vertigo. Direct the patient to a complete list of adverse drug reactions in PATIENT INFORMATION.
Inform patients that Xtandi may cause infections, falls and fall-related injuries, and hypertension.
Inform patients that Xtandi can 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

14B006-XTA-SPL

Rx Only
© 2014 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 prostate cancer that no longer responds to a medical or surgical treatment that lowers testosterone and that has spread to other parts of the body.

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 can 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 may 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 your 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 over-the-counter medicines, vitamins, and herbal supplements. Xtandi may affect the way other medicines work, and other medicines may affect how Xtandi works.

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 exactly as your healthcare provider tells you.
Take your prescribed dose of Xtandi one time a day, at the same time each day.
Your healthcare provider may change your dose if needed.
Do not change or stop taking your prescribed dose of Xtandi without talking with your healthcare provider first.
Xtandi 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 in one day.
If you take too much Xtandi, call your healthcare provider or go to the nearest emergency room right away. You may have an increased risk of seizure if you take too much Xtandi.



What are the possible side effects of Xtandi?

Xtandi may cause serious side effects including:

Seizure. 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. Your healthcare provider will stop Xtandi if you have a seizure during treatment.

The most common side effects of Xtandi include:

weakness or feeling more tired                   •     shortness of breath
than usual                                                    •     muscle and bone pain
back pain                                                     •     weight loss
decreased appetite                                       •     headache
constipation                                                 •     high blood pressure
joint pain                                                     •     dizziness
diarrhea                                                       •     a feeling that you or things
hot flashes                                                          around you are moving or spinning (vertigo)
upper respiratory tract infection
swelling in your hands, arms,
legs, or feet

Xtandi may cause infections, falls and injuries from falls. Tell your healthcare provider if you have signs or symptoms of an infection or if you fall.

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 health professionals.

For more information go to www.Xtandi.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: September 2014
14B006-XTA-SPL 


© 2014 Astellas Pharma US, Inc.

Xtandi® is a registered trademark of Astellas Pharma Inc.

PACKAGE/LABEL PRINCIPAL DISPLAY PANEL

Xtandi 
enzalutamide capsule
Product Information
Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:0469-0125
Route of Administration ORAL DEA Schedule     
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
ENZALUTAMIDE (ENZALUTAMIDE) ENZALUTAMIDE 40 mg
Product Characteristics
Color WHITE Score no score
Shape CAPSULE Size 12mm
Flavor Imprint Code ENZ
Contains         
Packaging
# Item Code Package Description
1 NDC:0469-0125-99 1 BOTTLE in 1 CARTON
1 120 CAPSULE in 1 BOTTLE
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
NDA NDA203415 08/31/2012
Labeler - Astellas Pharma US, Inc. (605764828)
Revised: 09/2014
 
Astellas Pharma US, Inc.
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