Xtandi

XTANDI- enzalutamide tablet
Astellas Pharma US, Inc.

1 INDICATIONS AND USAGE

XTANDI® is indicated for the treatment of patients with:

castration-resistant prostate cancer (CRPC)
metastatic castration-sensitive prostate cancer (mCSPC) .

2 DOSAGE AND ADMINISTRATION

2.1 Dosing Information

The recommended dose of XTANDI is 160 mg (two 80 mg tablets or four 40 mg tablets or four 40 mg capsules) administered orally once daily. XTANDI can be taken with or without food [see Clinical Pharmacology (12.3)]. Swallow capsules or tablets whole. Do not chew, dissolve, or open the capsules. Do not cut, crush, or chew the tablets [see How Supplied/Storage and Handling (16)].

2.2 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 [see Warnings and Precautions (5.1), (5.2)].

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 dose to 80 mg once daily. If co-administration of the strong inhibitor is discontinued, the XTANDI dose should be returned to the dose used prior to initiation of the strong CYP2C8 inhibitor [see Drug Interactions (7.1) and Clinical Pharmacology (12.3)].

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 dose from 160 mg to 240 mg once daily. If co-administration of the strong CYP3A4 inducer is discontinued, the XTANDI dose should be returned to the dose used prior to initiation of the strong CYP3A4 inducer [see Drug Interactions (7.2) and Clinical Pharmacology (12.3)].

2.3 Important Administration Instructions

Patients receiving XTANDI should also receive a gonadotropin-releasing hormone (GnRH) analog concurrently or should have had bilateral orchiectomy.

3 DOSAGE FORMS AND STRENGTHS

XTANDI 40 mg capsules are white to off-white oblong soft gelatin capsules imprinted in black ink with ENZ.

XTANDI 40 mg tablets are yellow, round, film-coated and debossed with E 40.

XTANDI 80 mg tablets are yellow, oval, film-coated and debossed with E 80.

4 CONTRAINDICATIONS

None.

5 WARNINGS AND PRECAUTIONS

5.1 Seizure

Seizure occurred in 0.5% of patients receiving XTANDI in seven randomized clinical trials. In these trials, patients with predisposing factors for seizure were generally excluded. Seizure occurred from 13 to 1776 days after initiation of XTANDI. 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-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 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.

5.2 Posterior Reversible Encephalopathy Syndrome (PRES)

There have been reports of posterior reversible encephalopathy syndrome (PRES) in patients receiving XTANDI [see Adverse Reactions (6.2)]. 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.

5.3 Hypersensitivity

Hypersensitivity reactions, including edema of the face (0.5%), tongue (0.1%), or lip (0.1%) have been observed with enzalutamide in seven 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.

5.4 Ischemic Heart Disease

In the combined data of four randomized, placebo-controlled clinical studies, ischemic heart disease occurred more commonly in patients on the XTANDI arm compared to patients on the placebo arm (2.9% vs 1.3%). Grade 3-4 ischemic events occurred in 1.4% of patients on the XTANDI arm compared to 0.7% 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.

5.5 Falls and Fractures

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 four randomized, placebo-controlled clinical studies, falls occurred in 11% 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 10% of patients treated with XTANDI and in 4% of patients treated with placebo. Grade 3-4 fractures occurred in 3% of patients treated with XTANDI and in 2% of patients treated with placebo. The median time to onset of fracture was 336 days (range: 2 to 1914 days) for patients treated with XTANDI. Routine bone density assessment and treatment of osteoporosis with bone-targeted agents were not performed in the studies.

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