Enzalutamide (Xtandi) is a non-steroidal anti-androgen that acts by blocking the effects of testosterone. It is used in patients with castration-resistant prostatic carcinoma who have previously received docetaxel.

Enzalutamide (Xtandi) Uses:

• Prostate cancer:

  • It is used for castration in Prostatic carcinoma.

Enzalutamide (Xtandi) Dose in Adults

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

Enzalutamide (Xtandi) Dose in the treatment of Prostate cancer, castration-resistant:

• Oral: 160 mg once daily.

• Dosage adjustment for concomitant strong CYP2C8 inhibitors:

  • Avoid concomitant use if possible.
  • If co-administration is necessary, reduce Enzalutamide dose to 80 mg once daily.
  • If the strong CYP2C8 inhibitor is discontinued, adjust the Enzalutamide dose back up to the dose used prior to the initiation of the strong CYP2C8 inhibitor.

• Dosage adjustment for concomitant strong CYP3A4 inducers:

  • Avoid concomitant use if possible.
  • If co-administration is necessary, increase the Enzalutamide dose to 240 mg once daily.
  • If the strong CYP3A4 inducer is discontinued, adjust the Enzalutamide dose back to the dose used prior to the initiation of the strong CYP3A4 inducer.

Use in Children:

Not indicated.

Pregnancy Risk Category: X

• Females are not recommended to use Enzalutamide. 
• Based on animal reproduction research and the mechanism of action, it is possible for fetal harm or loss to occur.
• Effective contraception should be used by male patients who have female partners with reproductive potential during treatment, and for three months following the last Enzalutamide dosage.
• Enzalutamide should not be used by pregnant women.
• It can lead to decreased sperm production, which may result in permanent male fertility impairment.

Use of Enzalutamide while breastfeeding

• It is unknown if Enzalutamide may be present in breast milk.
• Females should not use Enzalutamide.

Enzalutamide (Xtandi) Dose in Kidney disease:

• CrCl 30 to 89 mL/minute at baseline:

  • No initial dosage adjustment is necessary.

• CrCl <30 mL/minute at baseline:

  • There are no dosage adjustments provided in the manufacturer's labeling (it has not been studied).

• ESRD at baseline:

  • There are no dosage adjustments provided in the manufacturer's labeling (it has not been studied).

Dose in Liver disease:

• Preexisting mild, moderate, or severe impairment (Child-Pugh class A, B, or C):

  • No initial dosage adjustment is necessary.

Common Side Effects of Enzalutamide (Xtandi):

• Cardiovascular:

  • Peripheral Edema
  • Hypertension

• Central Nervous System:

  • Fatigue
  • Falling
  • Dizziness
  • Headache

• Endocrine & Metabolic:

  • Hypoglycemia
  • Hypomagnesemia
  • Hot Flash
  • Hyponatremia
  • Weight Loss

• Gastrointestinal:

  • Constipation
  • Diarrhea
  • Decreased Appetite
  • Nausea

• Hematologic & Oncologic:

  • Neutropenia

• Neuromuscular & Skeletal:

  • Asthenia
  • Back Pain
  • Arthralgia
  • Musculoskeletal Pain

• Respiratory:

  • Upper Respiratory Tract Infection
  • Dyspnea

Less Common Side Effects Of Enzalutamide (Xtandi):

• Cardiovascular:

  • Ischemic Heart Disease

• Central Nervous System:

  • Myasthenia
  • Insomnia
  • Paresthesia
  • Cauda Equina Syndrome
  • Spinal Cord Compression
  • Anxiety
  • Altered Mental Status
  • Cognitive Dysfunction
  • Hypoesthesia
  • Restless Leg Syndrome

• Dermatologic:

  • Pruritus
  • Xeroderma

• Endocrine & Metabolic:

  • Gynecomastia

• Gastrointestinal:

  • Dysgeusia

• Genitourinary:

  • Hematuria
  • Pollakiuria

• Neuromuscular & Skeletal:

  • Bone Fracture
  • Stiffness

• Respiratory:

  • Lower Respiratory Tract Infection
  • Epistaxis

Contraindication to Enzalutamide (Xtandi):

• The US labeling of the manufacturer does not list any contraindications.
• Canadian labeling
  • Patients with hypersensitivity to Enzalutamide and any of its components are advised not to use it.
  • It is not recommended for women who are pregnant or breastfeeding.

Warnings and precautions

• Cardiovascular effects

  • Patients who received enzalutamide were more likely to develop ischemic heart disease, including grades 3 and 4 ischemic events (as opposed to patients who were given placebo). In some cases, the events proved fatal.
  • Also, it was observed that androgen deprivation therapy could increase the risk of developing cardiovascular disease.
  • A rise in blood pressures systolic (and diastolic) has been also observed. This could lead to hypertension.
  • During treatment, be aware of signs and symptoms that could indicate ischemic heart disease.
  • The physician should optimize management of cardiovascular risk factors, including hypertension, diabetes and/or dyslipidemia.
  • Stop using Enzalutamide if you have ischemic heart disease, grade 3 or 4.

• Fractures

  • Patients who received enzalutamide have been known to suffer from falls and fractures. 
  • Patients who were given Enzalutamide (versus placebo) had a higher incidence of falling and fractures in clinical trials. Most fractures that occurred were graded 3-4.
  • The average time it took to fracture onset was 337 Days, with a range of 2 days up to 3 Years.
  • Studies on bone density and osteoporosis treatment effectiveness were not conducted.
  • Patients receiving treatment should be evaluated for fall and fracture risk
  • Guidelines should be followed for managing fractures risk. Protective and bone modifying agents should be used.

• Hypersensitivity

  • Hypersensitivity reactions to Enzalutamide have been reported. These include pharyngeal swelling, facial swelling, tongue swelling, and lip swelling.
  • If you notice signs or symptoms of hypersensitivity, discontinue use immediately and consult a doctor.
  • If the treating physician deems it appropriate, the treatment can be stopped permanently.

• The posterior reversible syndrome of encephalopathy:

  • Some studies have shown that patients who use the drug may develop Posterior Reversible Ecencephalopathy Syndrome.
  • This condition is characterised by headaches, seizures, confusion and lethargy. This could be due to an increase in blood pressure.
  • Diagnostic MRIs are available
  • In such cases, discontinue use of the drug.

• Seizures

  • In enzalutamide clinical trial, seizures were recorded. Patients with predisposing risk factors were generally excluded.
  • Seizures could occur anywhere from 13 days to as long as 20 months after the treatment was initiated.
  • Patients with seizures were advised to stop taking Enzalutamide. Seizures are resolved by stopping therapy.
  • A study to evaluate seizure risk among patients with predisposing conditions found that 2.2% of patients receiving the drug had a seizure.
  • Some patients also experienced a second seizure after continuing treatment.
  • It is unknown if antiepileptic medication can prevent seizures related to enzalutamide.
  • The study found that patients had at least one of the following predisposing factors:
    • Concomitant medication that could lower seizure threshold
    • History of head or traumatic brain injury
    • History of cerebrovascular accident/transient Ischemia, Alzheimer disease, meningioma or leptomeningeal cancer from prostate cancer
    • Unexplained loss in consciousness during the past 12 months
    • Prior seizure history, presence a space-occupying cerebral lesion
    • History of arteriovenous malformations, or
    • History of brain infection
    • Some patients were exposed to more than one risk factor.
  • Inform patients about the possibility of seizures and the danger of engaging in activities that could lead to sudden loss of consciousness.
  • If seizures occur, stop the treatment immediately.

Enzalutamide: Drug Interaction

Note: Drug Interaction Categories:

• Risk Factor C: Monitor When Using Combination
• Risk Factor D: Consider Treatment Modification
• Risk Factor X: Avoid Concomitant Use

Monitoring parameters:

• Complete blood picture with a differential count.
• LFTs at the start of treatment and then at regular intervals.
• PT/INR monitoring if on warfarin.
• Blood pressure at the start and then at regular intervals.
• Monitor for signs and symptoms of worsening cardiac disease and markers of disease relating to PRES.
• The patient should be evaluated for fall and Fracture risk.
• Adherence to treatment should be monitored.

How to administer Enzalutamide (Xtandi)?

It is given orally once a day regardless of the food intake. The capsule should be swallowed as a whole.

Mechanism of action of Enzalutamide (Xtandi):

It is different from other anti-androgen therapy because it does not act as a partial antagonist and has no antagonistic properties.

• Its MOA includes
  • Nuclear translocation through the receptor.
  • DNA binding
  • Mobilization of co-factors

This ultimately leads to cell death and a decrease in prostate tumor size.

Absorption:

• Rapid

Protein binding:

• Parent drug: 97% to 98% is bound primarily to albumin;
• Active metabolite: 95% to plasma proteins

Metabolism:

• It is metabolized primarily in the liver via CYP2C8 (responsible for the formation of active metabolite N-desmethyl enzalutamide) and CYP3A4; carboxylesterase 1 metabolizes N-desmethyl enzalutamide and enzalutamide to the inactive carboxylic acid metabolite.

Half-life elimination:

• Parent drug: 5.8 days (range: 2.8 to 10.2 days); N-desmethyl enzalutamide: 7.8 to 8.6 days

Time to peak:

• 1 hour (range: 0.5 to 3 hours)

Excretion: It is excreted primarily as inactive metabolites.

• Urine (71%);
• feces (14%);

International Brand Names of Enzalutamide:

• Xtandi
• Xtandi SC

Enzalutamide Brand Names in Pakistan:

No Brands Available in Pakistan.