Xtandi Side Effects Center

SIDE EFFECTS

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

• Seizure [see WARNINGS AND PRECAUTIONS]
• Posterior Reversible Encephalopathy Syndrome (PRES) [see WARNINGS AND PRECAUTIONS]
• Hypersensitivity [see WARNINGS AND PRECAUTIONS]
• Ischemic Heart Disease [see WARNINGS AND PRECAUTIONS]
• Falls and Fractures [see WARNINGS AND PRECAUTIONS]

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.

The data in WARNINGS AND PRECAUTIONS reflect seven randomized, controlled trials [AFFIRM, PREVAIL, TERRAIN, PROSPER, ARCHES, Asian PREVAIL (NCT02294461), and STRIVE (NCT01664923)] that were pooled to conduct safety analyses in patients with CRPC (N=3509) or mCSPC (N= 572) treated with XTANDI. Patients received XTANDI 160 mg (N= 4081) or placebo orally once daily (N= 2472) or bicalutamide 50 mg orally once daily (N= 387). All patients continued androgen deprivation therapy (ADT). In these seven trials, the median duration of treatment was 13.8 months (range: <0.1 to 87.6) in the XTANDI group.

In four placebo-controlled trials (AFFIRM, PROSPER, PREVAIL, and ARCHES), the median duration of treatment was 14.3 months (range: <0.1 to 87.6) in the XTANDI group [see Clinical Studies]. In these four trials, the most common adverse reactions (≥ 10%) that occurred more frequently (≥ 2% over placebo) in the XTANDI-treated patients were asthenia/fatigue, back pain, hot flush, constipation, arthralgia, decreased appetite, diarrhea, and hypertension.

AFFIRM: XTANDI Versus Placebo In Metastatic CRPC Following Chemotherapy

AFFIRM 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. Discontinuations due to adverse events were reported for 16% of XTANDI-treated patients. The most common adverse reaction leading to treatment discontinuation was seizure, which occurred in 0.9% of the XTANDI-treated patients compared to none (0%) of the placebo-treated patients. Table 1 shows adverse reactions reported in AFFIRM that occurred at a ≥ 2% higher frequency in the XTANDI arm compared to the placebo arm.

Table 1: Adverse Reactions in AFFIRM

	XTANDI (N = 800)		Placebo (N = 399)
	Grade 1-4 1(%)	Grade 3-4 (%)	Grade 1-4 (%)	Grade 3-4 (%)
General Disorders
Asthenic Conditions2	51	9.0	44	9.3
Peripheral Edema	15	1.0	13	0.8
Musculoskeletal and Connective Tissue Disorders
Back Pain	26	5.3	24	4.0
Arthralgia	21	2.5	17	1.8
Musculoskeletal Pain	15	1.3	12	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	22	1.1	18	0.3
Vascular Disorders
Hot Flush	20	0.0	10	0.0
Hypertension	6.4	2.1	2.8	1.3
Nervous System Disorders
Headache	12	0.9	5.5	0.0
Dizziness3	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 Disorders4	4.3	0.3	1.8	0.0
Hypoesthesia	4.0	0.3	1.8	0.0
Infections and Infestations
Upper Respiratory Tract Infection5	11	0.0	6.5	0.3
Lower Respiratory Tract And Lung Infection6	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
1. CTCAE v4 2. Includes asthenia and fatigue. 3. Includes dizziness and vertigo. 4. Includes amnesia, memory impairment, cognitive disorder, and disturbance in attention. 5. Includes nasopharyngitis, upper respiratory tract infection, sinusitis, rhinitis, pharyngitis, and laryngitis. 6. Includes pneumonia, lower respiratory tract infection, bronchitis, and lung infection.

PREVAIL: XTANDI Versus Placebo In Chemotherapy-naive Metastatic CRPC

PREVAIL 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. 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 PREVAIL that occurred at a ≥ 2% higher frequency in the XTANDI arm compared to the placebo arm.

Table 2: Adverse Reactions in PREVAIL

	XTANDI (N = 871)		Placebo (N = 844)
	Grade 1-41 (%)	Grade 3-4 (%)	Grade 1-4 (%)	Grade 3-4 (%)
General Disorders
Asthenic Conditions2	47	3.4	33	2.8
Peripheral Edema	12	0.2	8.2	0.4
Musculoskeletal and Connective Tissue Disorders
Back Pain	29	2.5	22	3.0
Arthralgia	21	1.6	16	1.1
Gastrointestinal Disorders
Constipation	23	0.7	17	0.4
Diarrhea	17	0.3	14	0.4
Vascular Disorders
Hot Flush	18	0.1	7.8	0.0
Hypertension	14	7.2	4.1	2.3
Nervous System Disorders
Dizziness3	11	0.3	7.1	0.0
Headache	11	0.2	7.0	0.4
Dysgeusia	7.6	0.1	3.7	0.0
Mental Impairment Disorders4	5.7	0.0	1.3	0.1
Restless Legs Syndrome	2.1	0.1	0.4	0.0
Respiratory Disorders
Dyspnea5	11	0.6	8.5	0.6
Infections and Infestations
Upper Respiratory Tract Infection6	16	0.0	11	0.0
Lower Respiratory Tract And Lung Infection7	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	13	1.6	5.3	0.7
Non-Pathological Fracture	8.8	2.1	3.0	1.1
Metabolism and Nutrition Disorders
Decreased Appetite	19	0.3	16	0.7
Investigations
Weight Decreased	12	0.8	8.5	0.2
Reproductive System and Breast Disorders
Gynecomastia	3.4	0.0	1.4	0.0
1. CTCAE v4 2. Includes asthenia and fatigue. 3. Includes dizziness and vertigo. 4. Includes amnesia, memory impairment, cognitive disorder, and disturbance in attention. 5. Includes dyspnea, exertional dyspnea, and dyspnea at rest. 6. Includes nasopharyngitis, upper respiratory tract infection, sinusitis, rhinitis, pharyngitis, and laryngitis. 7. Includes pneumonia, lower respiratory tract infection, bronchitis, and lung infection.

TERRAIN: XTANDI Versus Bicalutamide In Chemotherapy-naive Metastatic CRPC

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

Table 3: Adverse Reactions in TERRAIN XTANDI

	XTANDI (N = 183)		Bicalutamide (N = 189)
	Grade 1-41 (%)	Grade 3-4 (%)	Grade 1-4 (%)	Grade 3-4 (%)
Overall	94	39	94	38
General Disorders
Asthenic Conditions2	32	1.6	23	1.1
Musculoskeletal and Connective Tissue Disorders
Back Pain	19	2.7	18	1.6
Musculoskeletal Pain3	16	1.1	14	0.5
Vascular Disorders
Hot Flush	15	0	11	0
Hypertension	14	7.1	7.4	4.2
Gastrointestinal Disorders
Nausea	14	0	18	0
Constipation	13	1.1	13	0.5
Diarrhea	12	0	9.0	1.1
Infections and Infestations
Upper Respiratory Tract Infection4	12	0	6.3	0.5
Investigational
Weight Loss	11	0.5	7.9	0.5
1. CTCAE v 4 2. Including asthenia and fatigue. 3. Including musculoskeletal pain and pain in extremity. 4. Including nasopharyngitis, upper respiratory tract infection, sinusitis, rhinitis, pharyngitis, and laryngitis.

PROSPER: XTANDI Versus Placebo In Non-metastatic CRPC Patients

PROSPER enrolled 1401 patients with non-metastatic CRPC, of whom 1395 received at least one dose of study drug. Patients were randomized 2:1 and received either XTANDI at a dose of 160 mg once daily (N = 930) or placebo (N = 465). The median duration of treatment at the time of analysis was 18.4 months (range: 0.0 to 42 months) with XTANDI and 11.1 months (range: 0.0 to 43 months) with placebo.

Overall, 32 patients (3.4%) receiving XTANDI died from adverse events. The reasons for death with ≥ 2 patients included coronary artery disorders (n = 7), sudden death (n = 2), cardiac arrhythmias (n = 2), general physical health deterioration (n = 2), stroke (n = 2), and secondary malignancy (n = 5; one each of acute myeloid leukemia, brain neoplasm, mesothelioma, small cell lung cancer, and malignant neoplasm of unknown primary site). Three patients (0.6%) receiving placebo died from adverse events of cardiac arrest (n = 1), left ventricular failure (n = 1), and pancreatic carcinoma (n = 1). Grade 3 or higher adverse reactions were reported among 31% of XTANDI-treated patients and 23% of placebo-treated patients. Discontinuations with an adverse event as the primary reason were reported for 9.4% of XTANDI-treated patients and 6.0% of placebo-treated patients. Of these, the most common adverse event leading to treatment discontinuation was fatigue, which occurred in 1.6% of the XTANDI-treated patients compared to none of the placebo-treated patients. Table 4 shows adverse reactions reported in PROSPER that occurred at a ≥ 2% higher frequency in the XTANDI arm than in the placebo arm.

Table 4: Adverse Reactions in PROSPER

	XTANDI (N = 930)		Placebo (N = 465)
	Grade 1-41 (%)	Grade 3-4 (%)	Grade 1-4 (%)	Grade 3-4 (%)
Metabolism and Nutrition Disorders
Decreased Appetite	9.6	0.2	3.9	0.2
Nervous System Disorders
Dizziness2	12	0.5	5.2	0
Headache	9.1	0.2	4.5	0
Cognitive and Attention Disorders3	4.6	0.1	1.5	0
Vascular Disorders
Hot Flush	13	0.1	7.7	0
Hypertension	12	4.6	5.2	2.2
Gastrointestinal Disorders
Nausea	11	0.3	8.6	0
Constipation	9.1	0.2	6.9	0.4
General Disorders and Administration Site Conditions
Asthenic Conditions4	40	4.0	20	0.9
Investigations
Weight Decreased	5.9	0.2	1.5	0
Injury, Poisoning and Procedural Complications
Fall	11	1.3	4.1	0.6
Fractures5	9.8	2.0	4.9	1.7
Psychiatric Disorders
Anxiety	2.8	0.2	0.4	0
1. CTCAE v 4 2. Includes dizziness and vertigo. 3. Includes amnesia, memory impairment, cognitive disorder, and disturbance in attention. 4. Includes asthenia and fatigue. 5. Includes all osseous fractures from all sites.

ARCHES: XTANDI Versus Placebo In Metastatic CSPC Patients

ARCHES randomized 1150 patients with mCSPC, of whom 1146 received at least one dose of study drug. All patients received either a gonadotropin-releasing hormone (GnRH) analogue concurrently or had bilateral orchiectomy. Patients received either XTANDI at a dose of 160 mg once daily (N=572) or placebo (N=574). The median duration of treatment was 12.8 months (range: 0.2 to 26.6 months) with XTANDI and 11.6 months (range: 0.2 to 24.6 months) with placebo.

Overall, 10 patients (1.7%) receiving XTANDI died from adverse events. The reasons for death in ≥ 2 patients included heart disease (n=3), sepsis (n=2) and pulmonary embolism (n=2). Eight patients (1.4%) receiving placebo died from adverse events. The reasons for death in ≥ 2 patients included heart disease (n=2) and sudden death (n=2). Grade 3 or higher adverse events were reported in 24% of patients treated with XTANDI. Permanent discontinuation due to adverse events as the primary reason was reported in 4.9% of XTANDI-treated patients and 3.7% of placebo-treated patients. The most common adverse events resulting in permanent discontinuation in XTANDI-treated patients were alanine aminotransferase increased, aspartate aminotransferase elevation, and seizure, each in 0.3%. The most common adverse events leading to permanent discontinuation in placebo-treated patients were arthralgia, and fatigue, each in 0.3%.

Dose reductions due to an adverse reaction occurred in 4.4% of patients who received XTANDI. Fatigue/asthenia was the most frequent adverse reaction requiring dose reduction in 2.1% of XTANDI-treated patients and 0.7% of placebo-treated patients.

Table 5 shows adverse reactions reported in ARCHES that occurred at a ≥ 2% higher frequency in the XTANDI arm than in the placebo arm.

Table 5: Adverse Reactions in ARCHES

	XTANDI (N = 572)		Placebo (N = 574)
	Grade 1-41 (%)	Grade 3-4 (%)	Grade 1-4 (%)	Grade 3-4 (%)
Metabolism and Nutrition Disorders
Decreased Appetite	4.9	0.2	2.6	0
Nervous System Disorders
Cognitive and Memory Impairment2	4.5	0.7	2.1	0
Restless Legs Syndrome	2.4	0	0.3	0
Vascular Disorders
Hot Flush	27	0.3	22	0
Hypertension	8.0	3.3	5.6	1.7
General Disorders and Administration Site Conditions
Asthenic conditions3	24	1.7	20	1.6
Musculoskeletal and Connective Tissue Disorders
Musculoskeletal Pain	6.3	0.2	4.0	0.2
Injury, Poisoning and Procedural Complications
Fractures4	6.5	1.0	4.2	1.0
1. CTCAE v 4.03. 2. Includes memory impairment, amnesia, cognitive disorder, dementia, disturbance in attention, transient global amnesia, dementia alzheimer's type, mental impairment, senile dementia and vascular dementia. 3. Includes asthenia and fatigue. 4. Includes Fracture related preferred terms under high level terms: fractures NEC; fractures and dislocations NEC; limb fractures and dislocations; pelvic fractures and dislocations; skull and brain therapeutic procedures; skull fractures, facial bone fractures and dislocations; spinal fractures and dislocations; thoracic cage fractures and dislocations.

Laboratory Abnormalities

Table 6 shows laboratory abnormalities that occurred in ≥ 5% of patients, and more frequently (> 2%) in the XTANDI arm compared to placebo in the pooled, randomized, placebo-controlled studies.

Table 6: Laboratory Abnormalities

	XTANDI (N = 3173)		Placebo (N = 2282)
	Grade 1-4 (%)	Grade 3-4 (%)	Grade 1-4 (%)	Grade 3-4 (%)
Hematology
Neutrophil count decreased	20	0.9	17	0.4
White blood cell decreased	17	0.4	9.8	0.2
Chemistry
Hyperglycemia	83	3.2	75	3.1
Hypermagnesemia	16	0.1	13	0
Hyponatremia	13	1.4	8.6	1.5
Hypercalcemia	6.8	0.1	4.5	0

Hypertension

In the combined data from four randomized placebo-controlled clinical trials, hypertension was reported in 12% of patients receiving XTANDI and 5% of patients receiving placebo. Medical history of hypertension was balanced between arms. Hypertension led to study discontinuation in < 1% of patients in each arm.

Post-Marketing Experience

The following additional adverse reactions have been identified during post-approval use of XTANDI. Because these reactions are 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.

Gastrointestinal Disorders: vomiting

Immune System Disorders: hypersensitivity (edema of the face, tongue, lip, or pharynx)

Neurological Disorders: posterior reversible encephalopathy syndrome (PRES), dysgeusia

Skin and Subcutaneous Tissue Disorders: rash, severe cutaneous adverse reactions (including Stevens-Johnson syndrome (SJS), erythema multiforme, toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS) and acute generalized exanthematous pustulosis (AGEP))

DRUG INTERACTIONS

Effect Of Other Drugs On XTANDI

Strong CYP2C8 Inhibitors

The coadministration of XTANDI with gemfibrozil (a strong CYP2C8 inhibitor) increases plasma concentrations of enzalutamide plus N-desmethyl enzalutamide, which may increase the incidence and severity of adverse reactions of XTANDI. Avoid the coadministration of XTANDI with strong CYP2C8 inhibitors. If the coadministration of XTANDI with a strong CYP2C8 inhibitor cannot be avoided, reduce the dosage of XTANDI [see DOSAGE AND ADMINISTRATION, CLINICAL PHARMACOLOGY].

Strong CYP3A4 Inducers

The coadministration of XTANDI with rifampin (a strong CYP3A4 inducer and a moderate CYP2C8 inducer) decreases plasma concentrations of enzalutamide plus N-desmethyl enzalutamide, which may decrease the efficacy of XTANDI. Avoid the coadministration of XTANDI with strong CYP3A4 inducers. If the coadministration of XTANDI with a strong CYP3A4 inducer cannot be avoided, increase the dosage of XTANDI [see DOSAGE AND ADMINISTRATION, CLINICAL PHARMACOLOGY].

Effect Of XTANDI On Other Drugs

Certain CYP3A4, CYP2C9, Or CYP2C19 Substrates

XTANDI is a strong CYP3A4 inducer and a moderate CYP2C9 and CYP2C19 inducer. The coadministration of XTANDI decreases the concentrations of certain CYP3A4, CYP2C9, or CYP2C19 substrates [see CLINICAL PHARMACOLOGY], which may reduce the efficacy of these substrates. Avoid the coadministration of XTANDI with certain CYP3A4, CYP2C9, or CYP2C19 substrates for which a minimal decrease in concentration may lead to therapeutic failure of the substrate. If the coadministration cannot be avoided, increase the dosage of these substrates in accordance with their Prescribing Information. In cases where active metabolites are formed, there may be increased exposure to the active metabolites.

Read the entire FDA prescribing information for Xtandi (Enzalutamide Capsules)