Xtandi (Page 2 of 7)

5.6 Embryo-Fetal Toxicity

The safety and efficacy of XTANDI have not been established in females. Based on animal reproductive studies and mechanism of action, XTANDI can cause fetal harm and loss of pregnancy when administered to a pregnant female. Advise males with female partners of reproductive potential to use effective contraception during treatment with XTANDI and for 3 months after the last dose of XTANDI [see Use in Specific Populations (8.1, 8.3)].

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)]
Hypersensitivity [see Warnings and Precautions (5.3)]
Ischemic Heart Disease [see Warnings and Precautions (5.4)]
Falls and Fractures [see Warnings and Precautions (5.5)]

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.

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 (14)]. 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 (NCT00974311): 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 * (%) Grade 3-4 (%) Grade 1-4 (%) Grade 3-4 (%)
*
CTCAE v4
Includes asthenia and fatigue.
Includes dizziness and vertigo.
§
Includes amnesia, memory impairment, cognitive disorder, and disturbance in attention.
Includes nasopharyngitis, upper respiratory tract infection, sinusitis, rhinitis, pharyngitis, and laryngitis.
#
Includes pneumonia, lower respiratory tract infection, bronchitis, and lung infection.

General Disorders

Asthenic Conditions

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

Dizziness

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 Disorders §

4.3

0.3

1.8

0.0

Hypoesthesia

4.0

0.3

1.8

0.0

Infections and Infestations

Upper Respiratory Tract Infection

11

0.0

6.5

0.3

Lower Respiratory Tract And Lung Infection #

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

PREVAIL (NCT01212991): XTANDI versus Placebo in Chemotherapy-naïve 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 1-4 * (%) Grade 3-4 (%) Grade 1-4 (%) Grade 3-4 (%)
*
CTCAE v4
Includes asthenia and fatigue.
Includes dizziness and vertigo.
§
Includes amnesia, memory impairment, cognitive disorder, and disturbance in attention.
Includes dyspnea, exertional dyspnea, and dyspnea at rest.
#
Includes nasopharyngitis, upper respiratory tract infection, sinusitis, rhinitis, pharyngitis, and laryngitis.
Þ
Includes pneumonia, lower respiratory tract infection, bronchitis, and lung infection.

General Disorders

Asthenic Conditions

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

Dizziness

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 Disorders §

5.7

0.0

1.3

0.1

Restless Legs Syndrome

2.1

0.1

0.4

0.0

Respiratory Disorders

Dyspnea

11

0.6

8.5

0.6

Infections and Infestations

Upper Respiratory Tract Infection #

16

0.0

11

0.0

Lower Respiratory Tract And Lung Infection Þ

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

TERRAIN (NCT01288911): XTANDI versus Bicalutamide in Chemotherapy-naïve 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 (N = 183) Bicalutamide (N = 189)
Grade 1-4 * (%) Grade 3-4 (%) Grade 1-4 (%) Grade 3-4 (%)
*
CTCAE v 4
Including asthenia and fatigue.
Including musculoskeletal pain and pain in extremity.
§
Including nasopharyngitis, upper respiratory tract infection, sinusitis, rhinitis, pharyngitis, and laryngitis.

Overall

94

39

94

38

General Disorders

Asthenic Conditions

32

1.6

23

1.1

Musculoskeletal and Connective Tissue Disorders

Back Pain

19

2.7

18

1.6

Musculoskeletal Pain

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 Infection §

12

0

6.3

0.5

Investigational

Weight Loss

11

0.5

7.9

0.5

PROSPER (NCT02003924): 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 1-4 * (%) Grade 3-4 (%) Grade 1-4 (%) Grade 3-4 (%)
*
CTCAE v 4
Includes dizziness and vertigo.
Includes amnesia, memory impairment, cognitive disorder, and disturbance in attention.
§
Includes asthenia and fatigue.
Includes all osseous fractures from all sites.

Metabolism and Nutrition Disorders

Decreased Appetite

9.6

0.2

3.9

0.2

Nervous System Disorders

Dizziness

12

0.5

5.2

0

Headache

9.1

0.2

4.5

0

Cognitive and Attention Disorders

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 Conditions §

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

Fractures

9.8

2.0

4.9

1.7

Psychiatric Disorders

Anxiety

2.8

0.2

0.4

0

ARCHES (NCT02677896): 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 1-4 * (%) Grade 3-4 (%) Grade 1-4 (%) Grade 3-4 (%)
*
CTCAE v 4.03.
Includes memory impairment, amnesia, cognitive disorder, dementia, disturbance in attention, transient global amnesia, dementia alzheimer’s type, mental impairment, senile dementia and vascular dementia.
Includes asthenia and fatigue.
§
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.

Metabolism and Nutrition Disorders

Decreased Appetite

4.9

0.2

2.6

0

Nervous System Disorders

Cognitive and Memory Impairment

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 conditions

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

Fractures §

6.5

1.0

4.2

1.0

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.

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