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

Seizure

  • Seizure occurred in 0.5% of patients receiving XTANDI in clinical studies. In the AFFIRM and PREVAIL trials, 8 of 1671 (0.5%) patients treated with XTANDI and 1 of 1243 (0.1%) patients treated with placebo experienced a seizure. In the TERRAIN trial, 3 of 380 (0.8%) patients treated with XTANDI and 1 of 387 (0.3%) patients treated with bicalutamide experienced a seizure1
  • Patients experiencing seizure were permanently discontinued from therapy and all seizure events resolved. There is no clinical trial experience with re-administering XTANDI to patients who experienced seizure1
  • Limited safety data are available in patients with predisposing factors for seizure because these patients were generally excluded from the trials. 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, and brain arteriovenous malformation. AFFIRM excluded the use of concomitant medications that may lower the seizure threshold, whereas PREVAIL permitted the use of these medications1
  • 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. Permanently discontinue XTANDI in patients who develop a seizure during treatment1
Most common adverse reactions1,2
  • In the PREVAIL trial, the most common adverse reaction leading to treatment discontinuation was fatigue/asthenia, which occurred in 1% of patients on each treatment arm. Grade 3-4 adverse reactions were reported in 44% of XTANDI patients and 37% of placebo patients1
  • In the AFFIRM trial, the most common adverse reaction leading to treatment discontinuation was seizure, which occurred in 0.9% of the XTANDI patients compared to none (0%) of the placebo patients. Grade 3 and higher adverse reactions were reported among 47% of XTANDI patients and 53% of placebo patients1
  • In the TERRAIN trial, the most common adverse reactions leading to treatment discontinuation were back pain and pathological fracture, which occurred in 3.8% of XTANDI patients for each event and in 2.1% and 1.6% of bicalutamide patients, respectively. Grade 3 and higher adverse reactions were reported among 38.8% of XTANDI patients and 37.6% of placebo patients1
  • The most common adverse reactions (≥ 10%) that occurred more commonly (≥ 2% over placebo) in the XTANDI patients from the AFFIRM and PREVAIL 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/vertigo1
  • In the AFFIRM, PREVAIL, and TERRAIN trials, all adverse reactions were reported regardless of cause2

Laboratory abnormalities: PREVAIL and AFFIRM1

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
Thrombocytopenia 6 5 0.3 0.5
Elevations in ALT 10 16 0.2 0.2
Elevations in bilirubin 3 2 0.1 0.0

ALT, alanine aminotransferase.

Infections

In the AFFIRM trial, 1% of XTANDI patients compared to 0.3% of placebo patients died from infections or sepsis. In the PREVAIL trial, 1 patient in each treatment group (0.1%) had an infection resulting in death.1

Falls

Falls (including fall-related injuries) occurred in 9% of XTANDI patients and 4% of placebo patients in the AFFIRM and PREVAIL trials. Falls were not associated with loss of consciousness or seizure. Fall-related injuries were more severe in XTANDI patients, and included non-pathologic fractures, joint injuries, and hematomas.1

Hypertension

Hypertension occurred in 11% of XTANDI patients and 4% of placebo patients in the AFFIRM and PREVAIL trials. No patients experienced hypertensive crisis. Medical history of hypertension was balanced between arms. Hypertension led to study discontinuation in < 1% of all patients.1

Postmarketing experience1
  • 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
  • PRES has 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
Xtandi

Indication

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

Important Safety Information

Contraindications
XTANDI is not indicated for women. XTANDI can cause fetal harm and potential loss of pregnancy.

Warnings and Precautions
Seizure occurred in 0.5% of patients receiving XTANDI in clinical studies. In placebo-controlled studies, 8 of 1671 (0.5%) patients treated with XTANDI and 1 of 1243 (0.1%) patients treated with placebo experienced a seizure. In patients who previously received docetaxel, 7 of 800 (0.9%) patients treated with XTANDI experienced a seizure and no patients treated with placebo experienced a seizure. In a placebo-controlled study in chemotherapy-naïve patients, 1 of 871 (0.1%) patients treated with XTANDI and 1 of 844 (0.1%) patients treated with placebo experienced a seizure. In bicalutamide-controlled studies conducted in chemotherapy-naïve patients, 3 of 380 (0.8%) patients treated with XTANDI and 1 of 387 (0.3%) patients treated with bicalutamide experienced a seizure. 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.

Adverse Reactions
The most common adverse reactions (≥ 10%) that occurred more commonly (≥ 2% over placebo) in the XTANDI patients from the two 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. In the bicalutamide-controlled study of chemotherapy-naïve patients, the most common adverse reactions (≥ 10%) reported in XTANDI patients were asthenia/fatigue, back pain, musculoskeletal pain, hot flush, hypertension, nausea, constipation, upper respiratory tract infection, diarrhea, and weight loss.

In the study of 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 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 bicalutamide-controlled study of chemotherapy-naïve patients, Grade 3-4 adverse reactions were reported in 38.8% of XTANDI patients and 37.6% of bicalutamide patients. Discontinuations due to adverse events were reported for 7.6% of XTANDI patients and 6.3% of bicalutamide patients.

Lab Abnormalities: In the two placebo-controlled trials, Grade 1-4 neutropenia occurred in 15% of XTANDI patients (1% Grade 3-4) and 6% of placebo patients (0.5% Grade 3-4). Grade 1-4 thrombocytopenia occurred in 6% of XTANDI patients (0.3% Grade 3-4) and 5% of placebo patients (0.5% Grade 3-4). Grade 1-4 elevations in ALT occurred in 10% of XTANDI patients (0.2% Grade 3-4) and 16% of placebo patients (0.2% Grade 3-4). Grade 1-4 elevations in bilirubin occurred in 3% of XTANDI patients (0.1% Grade 3-4) and 2% of placebo patients (no Grade 3-4).

Infections: In a study of patients taking XTANDI who previously received docetaxel, 1% of XTANDI patients compared to 0.3% of placebo patients died from infections or sepsis. In the placebo-controlled study of chemotherapy-naïve patients, 1 patient in each treatment group (0.1%) had an infection resulting in death.

Falls (including fall-related injuries) occurred in 9% of XTANDI patients and 4% of placebo patients in the two placebo-controlled trials. Falls were not associated with loss of consciousness or seizure. Fall-related injuries were more severe in XTANDI patients, and included non-pathologic fractures, joint injuries, and hematomas.

Hypertension occurred in 11% of XTANDI patients and 4% of placebo patients in the two placebo-controlled trials. 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.

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.

Please see Full Prescribing Information for additional safety information.

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

Indication and Important Safety Information

Indication

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

Important Safety Information

Contraindications
XTANDI is not indicated for women. XTANDI can cause fetal harm and potential loss of pregnancy.