Safety Profile and Adverse Effects for XTANDI® (enzalutamide) capsules

Warnings and Precautions

Seizure1
  • Seizure occurred in 0.4% of patients receiving XTANDI in clinical studies. In these trials patients with predisposing factors for seizure were generally excluded
  • In a single-arm trial designed to assess the risk of seizure in patients with pre-disposing factors for seizure, 8 of 366 (2.2%) XTANDI-treated patients experienced a seizure. Three of the 8 patients experienced a second seizure during continued treatment with XTANDI after their first seizure resolved. It is unknown whether anti-epileptic medications will prevent seizures with XTANDI
  • Patients in the single-arm study had one or more of the following pre-disposing factors: the use of medications that may lower the seizure threshold (~ 54%), history of traumatic brain or head injury (~ 28%), history of cerebrovascular accident or transient ischemic attack (~ 24%), and Alzheimer’s disease, meningioma, or leptomeningeal disease from prostate cancer, unexplained loss of consciousness within the last 12 months, past history of seizure, presence of a space occupying lesion of the brain, history of arteriovenous malformation, or history of brain infection (all < 5%). Approximately 17% of patients had more than one risk factor
  • Advise patients of the risk of developing a seizure while receiving XTANDI and 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
Posterior Reversible Encephalopathy Syndrome (PRES)1
  • There have been reports of posterior reversible encephalopathy syndrome (PRES) in patients receiving XTANDI. PRES is a neurological disorder which can present with rapidly evolving symptoms including seizure, headache, lethargy, confusion, blindness, and other visual and neurological disturbances, with or without associated hypertension
  • A diagnosis of PRES requires confirmation by brain imaging, preferably magnetic resonance imaging (MRI). Discontinue XTANDI in patients who develop PRES
Hypersensitivity1
  • Hypersensitivity reactions, including edema of the face (0.5%), tongue (0.1%), or lip (0.1%) have been observed with enzalutamide in four randomized clinical trials. Pharyngeal edema has been reported in post-marketing cases
  • Advise patients who experience any symptoms of hypersensitivity to temporarily discontinue XTANDI and promptly seek medical care. Permanently discontinue XTANDI for serious hypersensitivity reactions
Ischemic Heart Disease1
  • In the combined data of three randomized, placebo-controlled clinical studies, ischemic heart disease occurred more commonly in patients on the XTANDI arm compared to patients on the placebo arm (2.7% vs 1.2%). Grade 3-4 ischemic events occurred in 1.2% of patients on the XTANDI arm compared to 0.5% on the placebo arm. Ischemic events led to death in 0.4% of patients on the XTANDI arm compared to 0.1% on the placebo arm
  • Monitor for signs and symptoms of ischemic heart disease. Optimize management of cardiovascular risk factors, such as hypertension, diabetes, or dyslipidemia. Discontinue XTANDI for Grade 3-4 ischemic heart disease
Falls and Fractures1
  • Falls and fractures occurred in patients receiving XTANDI. Evaluate patients for fracture and fall risk. Monitor and manage patients at risk for fractures according to established treatment guidelines and consider use of bone-targeted agents
  • In the combined data of three randomized, placebo-controlled clinical studies, falls occurred in 10% of patients treated with XTANDI compared to 4% of patients treated with placebo. Falls were not associated with loss of consciousness or seizure
  • Fractures occurred in 8% of patients treated with XTANDI and in 3% of patients treated with placebo. Grade 3-4 fractures occurred in 2% of patients treated with XTANDI and in < 1% of patients treated with placebo. The median time to onset of fracture was 337 days (range: 2 to 996 days) for patients treated with XTANDI
  • Routine bone density assessment and treatment of osteoporosis with bone-targeted agents were not performed in the studies
Embryo-Fetal Toxicity1
  • 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. XTANDI should not be handled by females who are or may become pregnant

Adverse Reactions

Most common adverse reactions1,2
  • In the placebo-controlled study of metastatic CRPC (mCRPC) patients taking XTANDI who previously received docetaxel, Grade 3 and higher adverse reactions were reported among 47% of XTANDI patients and 53% of placebo patients. Discontinuations due to adverse events were reported for 16% of XTANDI patients and 18% of placebo patients
  • In the placebo-controlled study of chemotherapy-naïve mCRPC patients, Grade 3-4 adverse reactions were reported in 44% of XTANDI patients and 37% of placebo patients. Discontinuations due to adverse events were reported for 6% of both study groups
  • In the placebo-controlled study of non-metastatic CRPC (nmCRPC) patients, Grade 3-4 adverse reactions were reported in 31% of XTANDI patients and 23% of placebo patients. Discontinuations with an adverse event as the primary reason were reported for 9% of XTANDI patients and 6% of placebo patients
  • In the bicalutamide-controlled study of chemotherapy-naïve mCRPC patients, Grade 3-4 adverse reactions were reported in 39% of XTANDI patients and 38% of bicalutamide patients. Discontinuations with an adverse event as the primary reason were reported for 8% of XTANDI patients and 6% of bicalutamide patients
  • The most common adverse reactions (≥ 10%) that occurred more frequently (≥ 2% over placebo) in the XTANDI-treated patients from the randomized placebo-controlled clinical trials were asthenia/fatigue, decreased appetite, hot flush, arthralgia, dizziness/vertigo, hypertension, headache, and weight decreased
  • In the AFFIRM, PREVAIL, TERRAIN, and PROSPER trials, all adverse reactions were reported regardless of cause

Laboratory abnormalities: PREVAIL, AFFIRM and PROSPER1

LABORATORY ABNORMALITIES PREVAIL and AFFIRM
GRADE 1-4 (%) GRADE 3-4 (%)
XTANDI (n = 1671) Placebo (n = 1243) XTANDI (n = 1671) Placebo (n = 1243)
Neutropenia 15 6 1 0.5
LABORATORY ABNORMALITIES PROSPER
Grade 1-4 (%) Grade 3-4 (%)
XTANDI (n = 930) Placebo (n = 465) XTANDI (n = 930) Placebo (n = 465)
Hematology
Neutropenia 8.2 5.4 0.5 0.2
Chemistry
Hyponatremia 16 8.8 1.3 1.5
Hyperglycemia 78 73 2.9 1.3
Hypermagnesemia 26 21 0 0

Important Safety Information and Indication

Indication

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

Important Safety Information

Warnings and Precautions
Seizure occurred in 0.4% of patients receiving XTANDI in clinical studies. In a study of patients with predisposing factors for seizure, 2.2% of XTANDI-treated patients experienced a seizure. Patients in the study had one or more of the following pre-disposing factors: use of medications that may lower the seizure threshold; history of traumatic brain or head injury, cerebrovascular accident or transient ischemic attack, Alzheimer's disease, meningioma, or leptomeningeal disease from prostate cancer, unexplained loss of consciousness within the last 12 months, history of seizure, presence of a space occupying lesion of the brain, history of arteriovenous malformation, or history of brain infection. It is unknown whether anti-epileptic medications will prevent seizures with XTANDI. Advise patients of the risk of developing a seizure while taking XTANDI and 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.

Posterior Reversible Encephalopathy Syndrome (PRES)   In post approval use, there have been reports of PRES in patients receiving XTANDI. PRES is a neurological disorder which can present with rapidly evolving symptoms including seizure, headache, lethargy, confusion, blindness, and other visual and neurological disturbances, with or without associated hypertension. A diagnosis of PRES requires confirmation by brain imaging, preferably MRI. Discontinue XTANDI in patients who develop PRES.

Hypersensitivity reactions, including edema of the face (0.5%), tongue (0.1%), or lip (0.1%) have been observed with XTANDI in clinical trials. Pharyngeal edema has been reported in post-marketing cases. Advise patients who experience any symptoms of hypersensitivity to temporarily discontinue XTANDI and promptly seek medical care. Permanently discontinue XTANDI for serious hypersensitivity reactions.

Ischemic Heart Disease  In the placebo-controlled clinical studies, ischemic heart disease occurred more commonly in patients on the XTANDI arm compared to patients on the placebo arm (2.7% vs 1.2%). Grade 3-4 ischemic events occurred in 1.2% of patients on XTANDI versus 0.5% on placebo. Ischemic events led to death in 0.4% of patients on XTANDI compared to 0.1% on placebo. Monitor for signs and symptoms of ischemic heart disease. Optimize management of cardiovascular risk factors, such as hypertension, diabetes, or dyslipidemia. Discontinue XTANDI for Grade 3-4 ischemic heart disease.

Falls and Fractures  In the placebo-controlled clinical studies, falls occurred in 10% of patients treated with XTANDI compared to 4% of patients treated with placebo. Fractures occurred in 8% of patients treated with XTANDI and in 3% of patients treated with placebo. Evaluate patients for fracture and fall risk. Monitor and manage patients at risk for fractures according to established treatment guidelines and consider use of bone-targeted agents.

Embryo-Fetal Toxicity  Safety and efficacy of XTANDI have not been established in females. 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. XTANDI should not be handled by females who are or may become pregnant.

Adverse Reactions
The most common adverse reactions (≥ 10%) that occurred more frequently (≥ 2% over placebo) in the XTANDI patients from the randomized placebo-controlled trials were asthenia/fatigue, decreased appetite, hot flush, arthralgia, dizziness/vertigo, hypertension, headache and weight decreased. In the bicalutamide-controlled study, the most common adverse reactions (≥ 10%) reported in XTANDI patients were asthenia/fatigue, back pain, musculoskeletal pain, hot flush, hypertension, nausea, constipation, diarrhea, upper respiratory tract infection, and weight loss.

In the placebo-controlled study of metastatic CRPC (mCRPC) patients taking XTANDI who previously received docetaxel, Grade 3 and higher adverse reactions were reported among 47% of XTANDI patients and 53% of placebo patients. Discontinuations due to adverse events were reported for 16% of XTANDI patients and 18% of placebo patients. In the placebo-controlled study of chemotherapy-naïve mCRPC patients, Grade 3-4 adverse reactions were reported in 44% of XTANDI patients and 37% of placebo patients. Discontinuations due to adverse events were reported for 6% of both study groups. In the placebo-controlled study of non-metastatic CRPC (nmCRPC) patients, Grade 3 or higher adverse reactions were reported in 31% of XTANDI patients and 23% of placebo patients. Discontinuations with an adverse event as the primary reason were reported for 9% of XTANDI patients and 6% of placebo patients. In the bicalutamide-controlled study of chemotherapy-naïve mCRPC patients, Grade 3-4 adverse reactions were reported in 39% of XTANDI patients and 38% of bicalutamide patients. Discontinuations with an AE as the primary reason were reported for 8% of XTANDI patients and 6% of bicalutamide patients.

Lab Abnormalities:  In the two placebo-controlled trials in patients with mCRPC, Grade 1-4 neutropenia occurred in 15% of XTANDI patients (1% Grade 3-4) and 6% of placebo patients (0.5% Grade 3-4). In the placebo-controlled trial in patients with nmCRPC, Grade 1-4 neutropenia occurred in 8% of patients receiving XTANDI (0.5% Grade 3-4) and in 5% of patients receiving placebo (0.2% Grade 3-4).

Hypertension:  In the two placebo-controlled trials in patients with mCRPC, hypertension was reported in 11% of XTANDI patients and 4% of placebo patients. Hypertension led to study discontinuation in < 1% of patients in each arm. In the placebo-controlled trial in patients with nmCRPC, hypertension was reported in 12% of patients receiving XTANDI and 5% of patients receiving placebo.

Drug Interactions
Effect of Other Drugs on XTANDI   Avoid strong CYP2C8 inhibitors, as they can increase the plasma exposure to XTANDI. If co-administration is necessary, reduce the dose of XTANDI.

Avoid strong CYP3A4 inducers as they can decrease the plasma exposure to XTANDI. If co-administration is necessary, increase the dose of XTANDI.

Effect of XTANDI on Other Drugs   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.

Indication

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

Please see Full Prescribing Information for additional safety information.

References: 1. XTANDI [package insert]. Northbrook, IL: Astellas Pharma US, Inc. 2. Pfizer. XTANDI. Data on File.
+

Important Safety Information and Indication

Indication

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

Important Safety Information

Warnings and Precautions
Seizure occurred in 0.4% of patients receiving XTANDI in clinical studies. In a study of patients with predisposing factors for seizure, 2.2% of XTANDI-treated patients experienced a seizure. Patients in the study had one or more of the following pre-disposing factors: use of medications that may lower the seizure threshold; history of traumatic brain or head injury,