------------------------------ADVERSE REACTIONS------------------------------­
`The most common adverse reactions (≥ 5%) are 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. (6.1)
`
`
`To report SUSPECTED ADVERSE REACTIONS, contact Astellas
`
`Pharma US, Inc. at 1-800-727-7003 or FDA at 1-800-FDA-1088 or
`
`
`www.fda.gov/medwatch.
`
`-----------------------------DRUG INTERACTIONS-------------------------------­
`
`
` Avoid strong CYP2C8 inhibitors, as they can increase the plasma exposure
`to XTANDI. If co-administration is necessary, reduce the dose of
`XTANDI. (2.2, 7.1)
`
`
` Avoid strong or moderate CYP3A4 or CYP2C8 inducers as they can alter
`
`
`
`the plasma exposure to XTANDI. (7.1, 7.2)
`
`
` Avoid CYP3A4, CYP2C9 and CYP2C19 substrates with a narrow
`therapeutic index, as XTANDI may decrease the plasma exposures of these
`
`drugs. If XTANDI is co-administered with warfarin (CYP2C9 substrate),
`
`conduct additional INR monitoring. (7.3)
`
`
`
`
`
`
`
`See 17 for PATIENT COUNSELING INFORMATION and FDA-
`approved patient labeling.
`
`Revised: 08/2012
`
` 
`8.3 Nursing Mothers
`8.4 Pediatric Use
`8.5 Geriatric Use
` 
`8.6 Patients with Renal Impairment
` 
`8.7 Patients with Hepatic Impairment
` 
`10 OVERDOSAGE
`
` 
`11 DESCRIPTION
`
` 
`12 CLINICAL PHARMACOLOGY
`
` 
`12.1 Mechanism of Action
` 
`12.3 Pharmacokinetics
` 
`12.6 Cardiac Electrophysiology
` 
`13 NONCLINICAL TOXICOLOGY
` 
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
` 
`14 CLINICAL STUDIES
`
` 
`16 HOW SUPPLIED/STORAGE AND HANDLING
`
` 
`17 PATIENT COUNSELING INFORMATION
`
`*Sections or subsections omitted from the Full Prescribing Information are not listed.
`
`
`  
`
` HIGHLIGHTS OF PRESCRIBING INFORMATION
`
`These highlights do not include all the information needed to use
`XTANDI® safely and effectively. See full prescribing information for
`XTANDI.
`
`
`XTANDI® (enzalutamide) capsules for oral use
`
`Initial U.S. Approval: 2012
`
`
`---------------------------INDICATIONS AND USAGE---------------------------
`XTANDI is an androgen receptor inhibitor indicated for the treatment of
`
`patients with metastatic castration-resistant prostate cancer who have
`
`previously received docetaxel. (1)
`
`-----------------------DOSAGE AND ADMINISTRATION----------------------­
`
`XTANDI 160 mg (four 40 mg capsules) administered orally once daily.
`
`
`
`Swallow capsules whole. XTANDI can be taken with or without food. (2.1)
`
`---------------------DOSAGE FORMS AND STRENGTHS---------------------­
`
`Capsule 40 mg (3)
`
`--------------------------CONTRAINDICATIONS-------------------------------­
`Pregnancy (4, 8.1)
`
`-------------------------WARNINGS AND PRECAUTIONS---------------------­
`Seizure occurred in 0.9% of patients receiving XTANDI. There is no clinical
`trial experience with XTANDI in patients who have had a seizure, in patients
`with predisposing factors for seizure, or in patients using concomitant
`medications that may lower the seizure threshold. (5.1)
`
`
`
`
`
`
`
`
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
` 
`1 INDICATIONS AND USAGE
` 
`2 DOSAGE AND ADMINISTRATION
`2.1 Dosing Information
`2.2 Dose Modifications
` 
`3 DOSAGE FORMS AND STRENGTHS
` 
`4 CONTRAINDICATIONS
` 
`5 WARNINGS AND PRECAUTIONS
` 
`5.1 Seizure
` 
`6 ADVERSE REACTIONS
` 
`6.1 Clinical Trial Experience
` 
`7 DRUG INTERACTIONS
`7.1 Drugs that Inhibit or Induce CYP2C8
`7.2 Drugs that Inhibit or Induce CYP3A4
` 
`7.3 Effect of XTANDI on Drug Metabolizing Enzymes
` 
`8 USE IN SPECIFIC POPULATIONS
` 
`8.1 Pregnancy
`
`  
`
`  
`
`Reference ID: 3183415
`
`AVENTIS EXHIBIT 2173
`Mylan v. Aventis IPR2016-00712
`
`1
`
`

`
`FULL PRESCRIBING INFORMATION
`
` 1 INDICATIONS AND USAGE
`
`XTANDI is indicated for the treatment of patients with metastatic castration-resistant prostate cancer who have previously
`received docetaxel.
`
`2 DOSAGE AND ADMINISTRATION
`2.1 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.
`
`
`2.2 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)].
`
`3 DOSAGE FORMS AND STRENGTHS
`
`XTANDI 40 mg capsules are white to off-white oblong soft gelatin capsules imprinted in black ink with MDV.
`
`4 CONTRAINDICATIONS
`Pregnancy
`XTANDI can cause fetal harm when administered to a pregnant woman based on its mechanism of action. 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)].
`
`5 WARNINGS AND PRECAUTIONS
`5.1 Seizure
`In the randomized clinical trial, 7 of 800 (0.9%) patients treated with XTANDI 160 mg once daily experienced a seizure.
`No seizures occurred in patients treated with placebo. Seizures occurred from 31 to 603 days after initiation of XTANDI.
`
`Patients experiencing seizure were permanently discontinued from therapy and all seizures resolved. There is no clinical
`
`trial experience re-administering XTANDI to patients who experienced seizures.
`
`The safety of XTANDI in patients with predisposing factors for seizure is not known because these patients were
`excluded from the trial. These exclusion criteria included a history of seizure, underlying brain injury with loss of
`consciousness, transient ischemic attack within the past 12 months, cerebral vascular accident, brain metastases, brain
`
`arteriovenous malformation or the use of concomitant medications that may lower the seizure threshold.
`
`
`
`
`
`Because of the risk of seizure associated with 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.
`
`Reference ID: 3183415
`
`2
`
`

`
`6 ADVERSE REACTIONS
`
`The following is discussed in more detail in other sections of the labeling:
`
` Seizure [see Warnings and Precautions (5.1)]
`
`
`6.1 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.
`
`In the randomized clinical trial in patients with metastatic castration-resistant prostate cancer who had previously received
`docetaxel, patients received XTANDI 160 mg orally once daily (N = 800) or placebo (N = 399). The median duration of
`treatment was 8.3 months with XTANDI and 3.0 months with placebo. All patients continued androgen deprivation
`therapy. Patients were allowed, but not required, to take glucocorticoids. During the trial, 48% of patients on the
`XTANDI arm and 46% of patients on the placebo arm received glucocorticoids. All adverse events and laboratory
`
`
`abnormalities were graded using NCI CTCAE version 4.
`
`
`The most common adverse drug reactions (≥ 5%) reported in patients receiving XTANDI in the randomized clinical trial
`were 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. 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 the
`randomized clinical trial that occurred at a ≥ 2% absolute increase in frequency in the XTANDI arm compared to the
`placebo arm.
`
`
`
`
`Table 1. Adverse Reactions in the Randomized Trial
`
`XTANDI
`
`
`N = 800
`Grade 1-4
`Grade 3-4
`(%)
`(%)
`
`Placebo
`N = 399
`Grade 1-4
`Grade 3-4
`(%)
`(%)
`
`44.4
`13.3
`
`24.3
`17.3
`11.5
`6.8
`0.3
`
`17.5
`
`10.3
`2.8
`
`5.5
`7.5
`4.5
`
`4.5
`1.8
`
`9.3
`0.8
`
`4.0
`1.8
`0.3
`1.8
`0.0
`
`0.3
`
`0.0
`1.3
`
`0.0
`0.5
`3.8
`
`0.0
`0.0
`
`9.0
`1.0
`
`5.3
`2.5
`1.3
`1.5
`0.3
`
`1.1
`
`0.0
`2.1
`
`0.9
`0.5
`6.6
`
`0.0
`0.3
`
`
`General Disorders
`Asthenic Conditionsa
`50.6
`
`15.4
`Peripheral Edema
`Musculoskeletal And Connective Tissue Disorders
`Back Pain
`26.4
`Arthralgia
`20.5
`
`Musculoskeletal Pain
`15.0
`
`Muscular Weakness
`9.8
`Musculoskeletal Stiffness
`2.6
`Gastrointestinal Disorders
`
`Diarrhea
`
`Vascular Disorders
`
`Hot Flush
`
`Hypertension
`
`Nervous System Disorders
`
`Headache
`
`Dizzinessb
`Spinal Cord Compression and
`
`
`Cauda Equina Syndrome
`
`
`Paresthesia
`
`Mental Impairment Disordersc
`
`21.8
`
`20.3
`6.4
`
`12.1
`9.5
`7.4
`
`6.6
`4.3
`
`
`
`
`
`Reference ID: 3183415
`
`3
`
`

`
`
`
` XTANDI
`
`N = 800
`Grade 1-4
`Grade 3-4
`(%)
`(%)
`4.0
`0.3
`
`Placebo
`N = 399
`Grade 1-4
`Grade 3-4
`(%)
`(%)
`1.8
`0.0
`
`10.9
`
`8.5
`
`3.3
`
`0.0
`
`2.4
`
`0.0
`0.3
`
`1.8
`0.0
`
`0.3
`1.4
`
`0.0
`0.0
`
`0.1
`
`6.5
`
`4.8
`
`6.0
`4.0
`
`4.5
`2.5
`
`1.3
`0.8
`
`1.3
`1.3
`
`1.3
`
`0.3
`
`1.3
`
`0.5
`0.0
`
`1.0
`0.0
`
`0.0
`0.3
`
`0.0
`0.0
`
`0.3
`
`
`8.8
`6.5
`
`
`Hypoesthesia
`
`Infections And Infestations
`Upper Respiratory Tract
`
`Infectiond
`Lower Respiratory Tract And
`
`Lung Infectione
`
`Psychiatric Disorders
`
`Insomnia
`
`Anxiety
`
`Renal And Urinary Disorders
`
`6.9
`Hematuria
`
`4.8
`Pollakiuria
`Injury, Poisoning And Procedural Complications
`
`
`Fall
`4.6
`
`Non-pathologic Fractures
`4.0
`Skin And Subcutaneous Tissue Disorders
`
`Pruritus
`3.8
`
`Dry Skin
`3.5
`Respiratory Disorders
`
`Epistaxis
`
`a
`Includes asthenia and fatigue.
`b
`Includes dizziness and vertigo.
`
`
`c
`Includes amnesia, memory impairment, cognitive disorder, and disturbance in attention.
`
`Includes nasopharyngitis, upper respiratory tract infection, sinusitis, rhinitis, pharyngitis, and laryngitis.
`d
`
`
`e
`Includes pneumonia, lower respiratory tract infection, bronchitis, and lung infection.
`
`
`Laboratory Abnormalities
`
`In the randomized clinical trial, Grade 1-4 neutropenia occurred in 15% of patients on XTANDI (1% Grade 3-4) and in
`6% of patients on placebo (no Grade 3-4). The incidence of Grade 1-4 thrombocytopenia was similar in both arms; 0.5%
`of patients on XTANDI and 1% on placebo experienced Grade 3-4 thrombocytopenia. Grade 1-4 elevations in ALT
`occurred in 10% of patients on XTANDI (0.3% Grade 3-4) and 18% of patients on placebo (0.5% Grade 3-4). Grade 1-4
`elevations in bilirubin occurred in 3% of patients on XTANDI and 2% of patients on placebo.
`
`
`Infections
`
`
`In the randomized clinical trial, 1.0% of patients treated with XTANDI compared to 0.3% of patients on placebo died
`from infections or sepsis. Infection-related serious adverse events were reported in approximately 6% of the patients on
`
`both treatment arms.
`
`
`Falls and Fall-related Injuries
`
`
`In the randomized clinical trial, falls or injuries related to falls occurred in 4.6% of patients treated with XTANDI
`compared to 1.3% of patients on 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.
`
`
`
`
`
`
`
`
`Hallucinations
`
`In the randomized clinical 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. Of the patients with hallucinations, the majority were on opioid-containing
`medications at the time of the event. Hallucinations were visual, tactile, or undefined.
`
`
`Reference ID: 3183415
`
`4
`
`

`
`7 DRUG INTERACTIONS
`
`7.1 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 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)].
`
`
` 7.2 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)].
`
` 7.3 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)].
`
`8 USE IN SPECIFIC POPULATIONS
`
`8.1 Pregnancy
`Pregnancy Category X [see Contraindications (4)].
`
`
`XTANDI can cause fetal harm when administered to a pregnant woman based on its mechanism of action. While there are
`no human or animal 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. 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.
`
`8.3 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.
`
`Reference ID: 3183415
`
`5
`
`

`
`8.4 Pediatric Use
`Safety and effectiveness of XTANDI in pediatric patients have not been established.
`
`8.5 Geriatric Use
`Of 800 patients who received XTANDI in the randomized clinical trial, 71 percent were 65 and over, while 25 percent
`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.
`
`
`8.6 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 castration-resistant prostate cancer 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)].
`
`8.7 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)].
`
`
`10 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 seizures
`following an overdose.
`
`11 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:
`
`
`
`CF3
`
`NC
`
`S
`
`N
`
`N
`
`O
`
`F
`
`O
`
`NHMe
`
`
`
`
`Enzalutamide is a white crystalline non-hygroscopic solid. It is practically insoluble in water.
`
`
`Reference ID: 3183415
`
`6
`
`

`
`
`
`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 (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.
`
`
`
`
`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).
`
`
`Reference ID: 3183415
`
`7
`
`

`
`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 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 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)].
`
`
`
`Reference ID: 3183415
`
`8
`
`

`
`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
`Population Description PK#
`
`
`
`Fold Change and 90% CI
`
`Recommendation
`
`
`
`
`Reduce XTANDI dose*
`
`
`
`
`No initial dose adjustment
`
`
`
`
`No initial dose adjustment
`
`
`
`
`No initial dose adjustment
`
`
`
`
`Take with or without food
`
`
` Ratio Relative to Reference
`
`
`# 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).
`
`
`Reference ID: 3183415
`
`9
`
`

`
` 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.
`
`
`Figure 2. Effect of XTANDI on Other Drugs
`
` Fold Change and 90% CI
`Population Description PK
`
`Recommendation
`
`Avoid concomitant use of
`substrates with a narrow
`therapeutic index*
`
`Avoid concomitant use of
`substrates with a narrow
`therapeutic index*
`
`Avoid concomitant use of
`substrates with a narrow
`therapeutic index*
`
`
`
`No dose adjustment
`
`
`*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.
`
`
`Reference ID: 3183415
`
`10
`
`

`
`
`
`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