Recommended Topic Related To:

Xtandi

"The U.S. Food and Drug Administration today approved Xofigo (radium Ra 223 dichloride) to treat men with symptomatic late-stage (metastatic) castration-resistant prostate cancer that has spread to bones but not to other organs. It is intended for"...

Xtandi

Side Effects
Interactions

SIDE EFFECTS

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

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.

Two 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. In both studies, patients received XTANDI 160 mg orally once daily in the active treatment arm or placebo in the control arm. 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 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: Metastatic Castration-Resistant Prostate Cancer 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 XTANDItreated 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: Chemotherapy-naive Metastatic Castration-Resistant Prostate Cancer

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.

Laboratory Abnormalities

In the two randomized 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 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 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.

Read the Xtandi (enzalutamide capsules) Side Effects Center for a complete guide to possible side effects

DRUG INTERACTIONS

Drugs That Inhibit Or Induce 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 in healthy volunteers. 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 and CLINICAL PHARMACOLOGY].

The effects of CYP2C8 inducers on the pharmacokinetics of enzalutamide have not been evaluated in vivo. Co-administration of XTANDI with strong or moderate CYP2C8 inducers (e.g., rifampin) may alter the plasma exposure of XTANDI and should be avoided if possible. Selection of a concomitant medication with no or minimal CYP2C8 induction potential is recommended [see CLINICAL PHARMACOLOGY].

Drugs That Inhibit Or Induce CYP3A4

Co-administration of a strong CYP3A4 inhibitor (itraconazole) increased the composite AUC of enzalutamide plus N-desmethyl enzalutamide by 1.3-fold in healthy volunteers [see CLINICAL PHARMACOLOGY].

The effects of CYP3A4 inducers on the pharmacokinetics of enzalutamide have not been evaluated in vivo. Co-administration of XTANDI with strong CYP3A4 inducers (e.g., carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, rifapentine) may decrease the plasma exposure of XTANDI and should be avoided if possible. Selection of a concomitant medication with no or minimal CYP3A4 induction potential is recommended. Moderate CYP3A4 inducers (e.g., bosentan, efavirenz, etravirine, modafinil, nafcillin) and St. John's Wort may also reduce the plasma exposure of XTANDI and should be avoided if possible [see CLINICAL PHARMACOLOGY].

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].

Read the Xtandi Drug Interactions Center for a complete guide to possible interactions

Last reviewed on RxList: 9/17/2014
This monograph has been modified to include the generic and brand name in many instances.

Side Effects
Interactions
A A A

Report Problems to the Food and Drug Administration

 

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit the FDA MedWatch website or call 1-800-FDA-1088.


Cancer

Get the latest treatment options.


NIH talks about Ebola on WebMD