Xtandi Soft

Xtandi Soft^® is indicated for the treatment of patients with metastatic castration-resistant prostate cancer (CRPC).

Dosing Information

The recommended dose of Xtandi Soft is 160 mg (four 40 mg capsules) administered orally once daily. Xtandi Soft can be taken with or without food. Swallow capsules whole. Do not chew, dissolve, or open the capsules.

Dose Modifications

If a patient experiences a ≥Grade 3 toxicity or an intolerable side effect, withhold dosing for one week or until symptoms improve to ≤ Grade 2, then resume at the same or a reduced dose (120 mg or 80 mg), if warranted.

Concomitant Strong CYP2C8 Inhibitors

The concomitant use of strong CYP2C8 inhibitors should be avoided if possible. If patients must be co-administered a strong CYP2C8 inhibitor, reduce the Xtandi Soft dose to 80 mg once daily. If co-administration of the strong inhibitor is discontinued, the Xtandi Soft dose should be returned to the dose used prior to initiation of the strong CYP2C8 inhibitor

.

Concomitant Strong CYP3A4 Inducers

The concomitant use of strong CYP3A4 inducers should be avoided if possible. If patients must be co-administered a strong CYP3A4 inducer, increase the Xtandi Soft dose from 160 mg to 240 mg once daily. If co-administration of the strong CYP3A4 inducer is discontinued, the Xtandi Soft dose should be returned to the dose used prior to initiation of the strong CYP3A4 inducer.

Pregnancy

Xtandi Soft can cause fetal harm and potential loss of pregnancy.

WARNINGS

Included as part of the "PRECAUTIONS" Section

PRECAUTIONS

Seizure

Seizure occurred in 0.5% of patients receiving Xtandi Soft in clinical studies. In these trials patients with predisposing factors for seizure were generally excluded. Seizure occurred from 31 to 603 days after initiation of Xtandi Soft. Patients experiencing seizure were permanently discontinued from therapy and all seizure events resolved.

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 Soft-treated patients experienced a seizure. Three of the 8 patients experienced a second seizure during continued treatment with Xtandi Soft after their first seizure resolved. It is unknown whether anti-epileptic medications will prevent seizures with Xtandi Soft. Patients in the 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 Soft and of engaging in any activity where sudden loss of consciousness could cause serious harm to themselves or others.

Permanently discontinue Xtandi Soft in patients who develop a seizure during treatment.

Posterior Reversible Encephalopathy Syndrome (PRES)

There have been reports of posterior reversible encephalopathy syndrome (PRES) in patients receiving Xtandi Soft. 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 Soft in patients who develop PRES.

Patient Counseling Information

Advise the patient to read the FDA-approved patient labeling (PATIENT INFORMATION).

Seizure

• Inform patients that Xtandi Soft has been associated with an increased risk of seizure. Discuss conditions that may predispose to seizures and medications that may lower the seizure threshold. Advise patients of the risk of engaging in any activity where sudden loss of consciousness could cause serious harm to themselves or others. Inform patients to contact their healthcare provider right away if they have loss of consciousness or seizure.

Posterior Reversible Encephalopathy Syndrome (PRES)

• Inform patients to contact their healthcare provider right away if they experience rapidly worsening symptoms possibly indicative of PRES such as seizure, headache, decreased alertness, confusion, reduced eyesight, or blurred vision.

Falls And Fall-Related Injuries

• Inform patients that Xtandi Soft is associated with an increased incidence of dizziness/vertigo, falls, and fall-related injuries.

Hypertension

• Inform patients that Xtandi Soft is associated with an increased incidence of hypertension.

Infections

• Inform patients that Xtandi Soft may be associated with an increased incidence of infections. Advise patients to immediately contact their healthcare provider if they develop signs and symptoms of infection.

Dosing And Administration

• Inform patients receiving GnRH therapy that they need to maintain this treatment during the course of treatment with Xtandi Soft.
• Instruct patients to take their dose at the same time each day (once daily). Xtandi Soft can be taken with or without food. Each capsule should be swallowed whole. Do not chew, dissolve, or open the capsules.
• Inform patients that they should not interrupt, modify the dose, or stop Xtandi Soft without first consulting their healthcare provider.
• Inform patients that if they miss a dose, then they should take it as soon as they remember. If they forget to take the dose for the whole day, then they should take their normal dose the next day. They should not take more than their prescribed dose per day.

Embryo-Fetal Toxicity

• Inform patients that Xtandi Soft can be harmful to a developing fetus. Advise male patients with female partners of reproductive potential to use effective contraception during treatment and for 3 months after the last dose of Xtandi Soft. Advise male patients to use a condom if having sex with a pregnant woman.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Long-term animal studies have not been conducted to evaluate the carcinogenic potential of enzalutamide.

Enzalutamide did not induce mutations in the bacterial reverse mutation (Ames) assay and was not genotoxic in either the in vitro mouse lymphoma thymidine kinase (Tk) gene mutation assay or the in vivo mouse micronucleus assay.

Based on nonclinical findings in repeat-dose toxicology studies, which were consistent with the pharmacological activity of enzalutamide, male fertility may be impaired by treatment with Xtandi Soft. In a 26-week study in rats, atrophy of the prostate and seminal vesicles was observed at ≥ 30 mg/kg/day (equal to the human exposure based on AUC). In 4-, 13-, and 39-week studies in dogs, hypospermatogenesis and atrophy of the prostate and epididymides were observed at ≥ 4 mg/kg/day (0.3 times the human exposure based on AUC).

Use In Specific Populations

Pregnancy

Risk Summary

Xtandi Soft is contraindicated for use in pregnant women because the drug can cause fetal harm and potential loss of pregnancy. Xtandi Soft is not indicated for use in females. There are no human data on the use of Xtandi Soft in pregnant women. In animal reproduction studies, oral administration of enzalutamide in pregnant mice during organogenesis caused adverse developmental effects at doses lower than the maximum recommended human dose (see Data).

Data

Animal Data

In an embryo-fetal developmental toxicity study in mice, enzalutamide caused developmental toxicity when administered at oral doses of 10 or 30 mg/kg/day throughout the period of organogenesis (gestational days 6-15). Findings included embryo-fetal lethality (increased post-implantation loss and resorptions) and decreased anogenital distance at ≥ 10 mg/kg/day, and cleft palate and absent palatine bone at 30 mg/kg/day. Doses of 30 mg/kg/day caused maternal toxicity. The doses tested in mice (1, 10 and 30 mg/kg/day) resulted in systemic exposures (AUC) approximately 0.04, 0.4 and 1.1 times, respectively, the exposures in patients. Enzalutamide did not cause developmental toxicity in rabbits when administered throughout the period of organogenesis (gestational days 6-18) at dose levels up to 10 mg/kg/day (approximately 0.4 times the exposures in patients based on AUC).

In a pharmacokinetic study in pregnant rats with a single oral 30 mg/kg enzalutamide administration on gestation day 14, enzalutamide and/or its metabolites were present in the fetus at a Cmax that was approximately 0.3 times the concentration found in maternal plasma and occurred 4 hours after administration.

Lactation

Risk Summary

Xtandi Soft is not indicated for use in females. There is no information available on the presence of Xtandi Soft in human milk, the effects of the drug on the breastfed infant, or the effects of the drug on milk production. Enzalutamide and/or its metabolites were present in milk of lactating rats (see Data).

Data

Following a single oral administration in lactating rats on postnatal day 14, enzalutamide and/or its metabolites were present in milk at a Cmax that was 4 times higher than concentrations in the plasma and occurred 4 hours after administration.

Females And Males Of Reproductive Potential

Contraception

Males

Based on findings in animal reproduction studies, advise male patients with female partners of reproductive potential to use effective contraception during treatment and for 3 months after the final dose of Xtandi Soft.

Infertility Based on animal studies, Xtandi Soft may impair fertility in males of reproductive potential.

Pediatric Use

Safety and effectiveness of Xtandi Soft in pediatric patients have not been established.

Geriatric Use

Of 1671 patients who received Xtandi Soft in the two randomized placebo-controlled clinical trials, 75% were 65 and over, while 31% were 75 and over. No overall differences in safety or effectiveness were observed between these patients and younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Patients With Renal Impairment

A dedicated renal impairment trial for Xtandi Soft has not been conducted. Based on the population pharmacokinetic analysis using data from clinical trials in patients with metastatic CRPC and healthy volunteers, no significant difference in enzalutamide clearance was observed in patients with pre-existing mild to moderate renal impairment (30 mL/min ≤ creatinine clearance [CrCL] ≤ 89 mL/min) compared to patients and volunteers with baseline normal renal function (CrCL ≥ 90 mL/min). No initial dosage adjustment is necessary for patients with mild to moderate renal impairment. Severe renal impairment (CrCL < 30 mL/min) and end-stage renal disease have not been assessed.

Patients With Hepatic Impairment

Dedicated hepatic impairment trials compared the composite systemic exposure of enzalutamide plus N-desmethyl enzalutamide in volunteers with baseline mild, moderate, or severe hepatic impairment (Child-Pugh Class A, B, or C, respectively) versus healthy controls with normal hepatic function. The composite AUC of enzalutamide plus N-desmethyl enzalutamide was similar in volunteers with mild, moderate, or severe baseline hepatic impairment compared to volunteers with normal hepatic function. No initial dosage adjustment is necessary for patients with baseline mild, moderate, or severe hepatic impairment.

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

• Seizure
• Posterior Reversible Encephalopathy Syndrome (PRES)

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.

Three 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. Two trials were placebo-controlled (Studies 1 and 2), and one trial was bicalutamide-controlled (Study 3). In Studies 1 and 2, patients received Xtandi Soft 160 mg or placebo orally once daily. In Study 3, patients received Xtandi Soft 160 mg or bicalutamide 50 mg orally once daily. 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 Soft-treated patients from the two randomized 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.

Study 1: Xtandi Soft versus Placebo in Metastatic CRPC 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 Soft and 3.0 months with placebo. During the trial, 48% of patients on the Xtandi Soft arm and 46% of patients on the placebo arm received glucocorticoids.

Grade 3 and higher adverse reactions were reported among 47% of Xtandi Soft-treated patients and 53% of placebo-treated patients. Discontinuations due to adverse events were reported for 16% of Xtandi Soft-treated 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 Soft-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 Soft arm compared to the placebo arm.

Table 1. Adverse Reactions in Study 1

Study 2: Xtandi Soft Versus Placebo In Chemotherapy-Naive Metastatic CRPC

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 Soft and 4.6 months with placebo. Grade 3-4 adverse reactions were reported in 44% of Xtandi Soft-treated patients and 37% of placebo-treated patients. Discontinuations due to adverse events were reported for 6% of Xtandi Soft-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 Soft arm compared to the placebo arm.

Table 2. Adverse Reactions in Study 2

Study 3: Xtandi Soft Versus Bicalutamide In Chemotherapy-Naive Metastatic CRPC

Study 3 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 Soft and 5.8 months with bicalutamide. Discontinuations with an adverse event as the primary reason were reported for 7.6% of Xtandi Soft-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 Soft-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 Soft-treated patients.

Table 3. Adverse Reactions in Study 3

Laboratory Abnormalities

In the two randomized placebo-controlled clinical trials, Grade 1-4 neutropenia occurred in 15% of patients treated with Xtandi Soft (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 Soft (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 Soft (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 Soft (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 Soft 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 placebo-controlled clinical trials, falls including fall-related injuries, occurred in 9% of patients treated with Xtandi Soft 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 Soft and included non-pathologic fractures, joint injuries, and hematomas.

Hypertension

In the two randomized placebo-controlled trials, hypertension was reported in 11% of patients receiving Xtandi Soft 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.

Post-Marketing Experience

The following additional adverse reactions have been identified during post approval use of Xtandi Soft. 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.

Body as a Whole: hypersensitivity (tongue edema, lip edema, and pharyngeal edema)

Gastrointestinal Disorders: vomiting

Neurological Disorders: posterior reversible encephalopathy syndrome (PRES)

Skin and Subcutaneous Tissue Disorders: rash

In the event of an overdose, stop treatment with Xtandi Soft and initiate general supportive measures taking into consideration the half-life of 5.8 days. In a dose escalation study, no seizures were reported at ≤ 240 mg daily, whereas 3 seizures were reported, 1 each at 360 mg, 480 mg, and 600 mg daily. Patients may be at increased risk of seizure following an overdose.

Cardiac Electrophysiology The effect of enzalutamide 160 mg/day at steady state on the QTc interval was evaluated in 796 patients with metastatic CRPC. No large difference (i.e., greater than 20 ms) was observed between the mean QT interval change from baseline in patients treated with Xtandi Soft and that in patients treated with placebo, based on the Fridericia correction method. However, small increases in the mean QTc interval (i.e., less than 10 ms) due to enzalutamide cannot be excluded due to limitations of the study design.

The pharmacokinetics of enzalutamide and its major active metabolite (N-desmethyl enzalutamide) were evaluated in patients with metastatic CRPC and healthy male volunteers. The plasma enzalutamide pharmacokinetics are adequately described by a linear two-compartment model with first-order absorption.

Absorption

Following oral administration (Xtandi Soft 160 mg daily) in patients with metastatic CRPC, the median time to reach maximum plasma enzalutamide concentrations (Cmax) is 1 hour (range 0.5 to 3 hours). At steady state, the plasma mean Cmax values for enzalutamide and N-desmethyl enzalutamide are 16.6 μg/mL (23% CV) and 12.7 μg/mL (30% CV), respectively, and the plasma mean predose trough values are 11.4 μg/mL (26% CV) and 13.0 μg/mL (30% CV), respectively.

With the daily dosing regimen, enzalutamide steady state is achieved by Day 28, and enzalutamide accumulates approximately 8.3-fold relative to a single dose. Daily fluctuations in enzalutamide plasma concentrations are low (mean peak-to-trough ratio of 1.25). At steady state, enzalutamide showed approximately dose proportional pharmacokinetics over the daily dose range of 30 to 360 mg.

A single 160 mg oral dose of Xtandi Soft was administered to healthy volunteers with a high-fat meal or in the fasted condition. A high-fat meal did not alter the AUC to enzalutamide or N-desmethyl enzalutamide. The results are summarized in Figure 1.

Distribution And Protein Binding

The mean apparent volume of distribution (V/F) of enzalutamide in patients after a single oral dose is 110 L (29% CV).

Enzalutamide is 97% to 98% bound to plasma proteins, primarily albumin. N-desmethyl enzalutamide is 95% bound to plasma proteins. In vitro, there was no protein binding displacement between enzalutamide and other highly protein bound drugs (warfarin, ibuprofen, and salicylic acid>) at clinically relevant concentrations.

Metabolism

Following single oral administration of ¹⁴C-enzalutamide 160 mg, plasma samples were analyzed for enzalutamide and its metabolites up to 77 days post dose. Enzalutamide, N-desmethyl enzalutamide, and a major inactive carboxylic acid metabolite accounted for 88% of the ¹⁴C-radioactivity in plasma, representing 30%, 49%, and 10%, respectively, of the total ¹⁴C-AUC0-inf.

In vitro, human CYP2C8 and CYP3A4 are responsible for the metabolism of enzalutamide. Based on in vivo and in vitro data, CYP2C8 is primarily responsible for the formation of the active metabolite (N-desmethyl enzalutamide). In vitro data suggest that carboxylesterase 1 metabolizes N-desmethyl enzalutamide and enzalutamide to the inactive carboxylic acid metabolite.

In vitro, N-desmethyl enzalutamide is not a substrate of human CYP1A1, CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C18, CYP2C19, CYP2D6, CYP2E1 and CYP3A4/5.

Elimination

Enzalutamide is primarily eliminated by hepatic metabolism. Following single oral administration of ¹⁴C-enzalutamide 160 mg, 85% of the radioactivity is recovered by 77 days post dose: 71% is recovered in urine (including only trace amounts of enzalutamide and N-desmethyl enzalutamide), and 14% is recovered in feces (0.4% of dose as unchanged enzalutamide and 1% as N-desmethyl enzalutamide).

The mean apparent clearance (CL/F) of enzalutamide in patients after a single oral dose is 0.56 L/h (range 0.33 to 1.02 L/h).

The mean terminal half-life (t_1/2) for enzalutamide in patients after a single oral dose is 5.8 days (range 2.8 to 10.2 days). Following a single 160 mg oral dose of enzalutamide in healthy volunteers, the mean terminal t_1/2 for N-desmethyl enzalutamide is approximately 7.8 to 8.6 days.