Data from FDA - Curated by EPG Health - Last updated 12 April 2018

Indication(s)

1 INDICATIONS AND USAGE XTANDI® is indicated for the treatment of patients with metastatic castration-resistant prostate cancer (CRPC). XTANDI is an androgen receptor inhibitor indicated for the treatment of patients with metastatic castration-resistant prostate cancer. (1)

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Advisory information

contraindications
4 CONTRAINDICATIONS Pregnancy XTANDI can cause fetal harm and potential loss of pregnancy [see Use in Specific Populations (8.1)]. Pregnancy (4, 8.1)
Adverse reactions
6 ADVERSE REACTIONS The following is discussed in more detail in other sections of the labeling: •Seizure [see Warnings and Precautions (5.1)] •Posterior Reversible Encephalopathy Syndrome (PRES) [see Warnings and Precautions (5.2)] The most common adverse reactions (≥ 10%) are 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. (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. 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. Three 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. Two trials were placebo-controlled (Studies 1 and 2), and one trial was bicalutamide-controlled (Study 3). In Studies 1 and 2, patients received XTANDI 160 mg or placebo orally once daily. In Study 3, patients received XTANDI 160 mg or bicalutamide 50 mg orally once daily. 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 placebo-controlled 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: XTANDI versus Placebo in Metastatic CRPC 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: XTANDI versus Placebo in Chemotherapy-naïve Metastatic CRPC 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. Study 3: XTANDI versus Bicalutamide in Chemotherapy-naïve Metastatic CRPC Study 3 enrolled 375 patients with metastatic CRPC who had not received prior cytotoxic chemotherapy, of whom 372 received at least one dose of study drug. The median duration of treatment was 11.6 months with XTANDI and 5.8 months with bicalutamide. Discontinuations with an adverse event as the primary reason were reported for 7.6% of XTANDI-treated patients and 6.3% of bicalutamide-treated patients. The most common adverse reactions leading to treatment discontinuation were back pain and pathological fracture, which occurred in 3.8% of XTANDI-treated patients for each event and in 2.1% and 1.6% of bicalutamide-treated patients, respectively. Table 3 shows overall and common adverse reactions (≥ 10%) in XTANDI-treated patients. Table 3. Adverse Reactions in Study 3 XTANDI (N=183) Bicalutamide (N=189) Grade 1-4 a (%) Grade 3-4 (%) Grade 1-4 a (%) Grade 3-4 (%) Overall 94.0 38.8 94.2 37.6 General Disorders Asthenic Conditionsb 31.7 1.6 22.8 1.1 Musculoskeletal And Connective Tissue Disorders Back Pain 19.1 2.7 18.0 1.6 Musculoskeletal Painc 16.4 1.1 14.3 0.5 Vascular Disorders Hot Flush 14.8 0 11.1 0 Hypertension 14.2 7.1 7.4 4.2 Gastrointestinal Disorders Nausea 14.2 0 17.5 0 Constipation 12.6 1.1 13.2 0.5 Diarrhea 11.5 0 9.0 1.1 Infections And Infestations Upper Respiratory Tract Infectiond 12.0 0 6.3 0.5 Investigational Weight Loss 10.9 0.5 7.9 0.5 a CTCAE v 4 b Including asthenia and fatigue. c Including musculoskeletal pain and pain in extremity d Including nasopharyngitis, upper respiratory tract infection, sinusitis, rhinitis, pharyngitis, and laryngitis Laboratory Abnormalities In the two randomized placebo-controlled 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 placebo-controlled 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 placebo-controlled 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. 6.2 Post-Marketing Experience The following additional adverse reactions have been identified during post approval use of XTANDI. Because these reactions were reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate the frequency or establish a causal relationship to drug exposure. Body as a Whole: hypersensitivity (tongue edema, lip edema, and pharyngeal edema) Gastrointestinal Disorders: vomiting Neurological Disorders: posterior reversible encephalopathy syndrome (PRES) Skin and Subcutaneous Tissue Disorders: rash

Usage information

Dosing and administration
2 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) 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)]. Concomitant Strong CYP3A4 Inducers The concomitant use of strong CYP3A4 inducers should be avoided if possible. If patients must be co-administered a strong CYP3A4 inducer, increase the XTANDI dose from 160 mg to 240 mg once daily. If co-administration of the strong CYP3A4 inducer is discontinued, the XTANDI dose should be returned to the dose used prior to initiation of the strong CYP3A4 inducer [see Drug Interactions (7.2) and Clinical Pharmacology (12.3)].
Use in special populations
8 USE IN SPECIFIC POPULATIONS •Females and Males of Reproductive Potential: Advise males with female partners of reproductive potential to use effective contraception. (8.3) 8.1 Pregnancy Risk Summary XTANDI is contraindicated for use in pregnant women because the drug can cause fetal harm and potential loss of pregnancy. XTANDI is not indicated for use in females. There are no human data on the use of XTANDI in pregnant women. In animal reproduction studies, oral administration of enzalutamide in pregnant mice during organogenesis caused adverse developmental effects at doses lower than the maximum recommended human dose (see Data). Data 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). In a pharmacokinetic study in pregnant rats with a single oral 30 mg/kg enzalutamide administration on gestation day 14, enzalutamide and/or its metabolites were present in the fetus at a Cmax that was approximately 0.3 times the concentration found in maternal plasma and occurred 4 hours after administration. 8.2 Lactation Risk Summary XTANDI is not indicated for use in females. There is no information available on the presence of XTANDI in human milk, the effects of the drug on the breastfed infant, or the effects of the drug on milk production. Enzalutamide and/or its metabolites were present in milk of lactating rats (see Data). Data Following a single oral administration in lactating rats on postnatal day 14, enzalutamide and/or its metabolites were present in milk at a Cmax that was 4 times higher than concentrations in the plasma and occurred 4 hours after administration. 8.3 Females and Males of Reproductive Potential Contraception Males Based on findings in animal reproduction studies, advise male patients with female partners of reproductive potential to use effective contraception during treatment and for 3 months after the final dose of XTANDI [see Use in Specific Populations (8.1)]. Infertility Based on animal studies, XTANDI may impair fertility in males of reproductive potential [see Nonclinical Toxicology (13.1)]. 8.4 Pediatric Use Safety and effectiveness of XTANDI in pediatric patients have not been established. 8.5 Geriatric Use Of 1671 patients who received XTANDI in the two randomized placebo-controlled 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. 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 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)]. 8.7 Patients with Hepatic Impairment Dedicated hepatic impairment trials compared the composite systemic exposure of enzalutamide plus N-desmethyl enzalutamide in volunteers with baseline mild, moderate, or severe hepatic impairment (Child-Pugh Class A, B, or C, respectively) versus healthy controls with normal hepatic function. The composite AUC of enzalutamide plus N-desmethyl enzalutamide was similar in volunteers with mild, moderate, or severe baseline hepatic impairment compared to volunteers with normal hepatic function. No initial dosage adjustment is necessary for patients with baseline mild, moderate, or severe hepatic impairment [see Clinical Pharmacology (12.3)].

Interactions

7 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 CYP3A4 inducers as they can decrease the plasma exposure to XTANDI. If co-administration is necessary, increase the dose of XTANDI. (2.2, 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) 7.1 Drugs that Inhibit 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. 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)]. 7.2 Drugs that Induce CYP3A4 Co-administration of rifampin (strong CYP3A4 inducer and moderate CYP2C8 inducer) decreased the composite AUC of enzalutamide plus N-desmethyl enzalutamide by 37%. Co-administration of strong CYP3A4 inducers (e.g., carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, rifapentine) with XTANDI should be avoided if possible. St John’s wort may decrease enzalutamide exposure and should be avoided. If co-administration of a strong CYP3A4 inducer with XTANDI cannot be avoided, increase the dose of XTANDI [see Dosage and Administration (2.2) and 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)].

More information

Category Value
Authorisation number NDA203415
Agency product number 93T0T9GKNU
Orphan designation No
Product NDC 0469-0125
Date Last Revised 25-07-2017
Type HUMAN PRESCRIPTION DRUG
RXCUI 1307309
Marketing authorisation holder Astellas Pharma US, Inc.