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Enzalutamide
Indications, Uses, Dosage, Drugs Interactions, Side effects
Enzalutamide
Medicine Type :
Allopathy
Allopathy
Prescription Type:
Prescription Required
Prescription Required
Approval :
DCGI (Drugs Controller General of India)
DCGI (Drugs Controller General of India)
Schedule
Schedule H
Schedule H
Pharmacological Class:
Non-steroidal androgen receptor inhibitors, Antineoplastics, Therapy Class:
Antiandrogenic agent, Approved Countries
India, the United States, the United Kingdom, Australia, Canada, Germany, France and Japan.
Enzalutamide is an Anti-androgenic agent belonging to the pharmacological class of third-generation, oral nonsteroidal antiandrogen and antineoplastics.
The FDA approves Enzalutamide for treating castration-resistant prostate cancer and for metastatic, high-risk castration-sensitive prostate cancer.
Enzalutamide is quickly absorbed, reaching peak plasma levels within an hour. It has a high protein binding percentage, undergoes extensive liver metabolism, and primarily exits the body through urine and faeces.
The most common side effects of Enzalutamide include headache, weakness, hot flashes, and high blood pressure.
Enzalutamide is available in the form of oral tablets or capsules.
The molecule is available in India, the United States, the United Kingdom, Australia, Canada, Germany, France and Japan.
Enzalutamide is an Anti-androgenic agent belonging to the pharmacological class of third-generation, oral nonsteroidal antiandrogen and antineoplastics.
Enzalutamide is a competitive inhibitor of androgen receptors (AR) that exhibits a threefold inhibition on the androgen signalling pathway while exhibiting negligible AR agonist activity. It prevents androgen from attaching to its receptor, moving its nuclear position, and interacting with chromosomal DNA to activate oncogenes. Enzalutamide has a 5–8 times higher affinity for the AR than first-generation antiandrogens like bicalutamide, and it has a 2-3-fold lower affinity than the AR's natural ligand, dihydrotestosterone. According to molecular docking analysis, enzalutamide interacts significantly with the AR's ligand binding domain from bicalutamide.
The data duration of Enzalutamide action typically occurs around five to seven days.
The onset of Enzalutamide action typically occurs within a few days to a few days after its initial administration.
The Data of Cmax and Tmax of Enzalutamide has yet to be established.
Enzalutamide is available in the form of oral tablets and capsules.
Tablets/capsules: To be swallowed whole with water/liquid. Do not chew, crush, break, dissolve or open the capsules or tablets.
As the physician recommends, take the medication orally once daily; it can be taken with or without food as directed.
Enzalutamide can be used for the following health conditions:
- To treat prostate cancer in men who have undergone hormone therapy or surgery to reduce their testosterone levels.
- Used occasionally if the cancer has not progressed to other areas of the body but is no longer responding to treatment.
- It is also used in cases of metastatic cancer, which is cancer that has spread to other places of the body despite treatment.
In Prostate cancer
Enzalutamide decreases testosterone, reducing cancer cell growth and easing urinary problems. It inhibits the growth of prostate cancer cells by preventing testosterone from getting to them, which may cause the cancer to shrink. By blocking testosterone, this drug reduces the symptoms of prostate cancer, shrinks tumours, and enhances the quality of life and treatment outcomes.
It is indicated for the treatment of the following conditions:
- Castration-resistant prostate cancer (CRPC).
- Metastatic castration-sensitive prostate cancer (mCSPC) with biochemical recurrence at high risk for metastasis (high-risk BCR). It is also used in combination with talazoparib for the treatment of adult patients with HRR gene-mutated mCRPC.
- Non-metastatic castration-sensitive prostate cancer (nmCSPC) with biochemical recurrence at high risk for metastasis (high-risk BCR).
Orally: Enzalutamide is typically taken orally as four 40 mg capsules once daily, either with or without food. To improve absorption, it is recommended to take this drug after meals. Following the recommended dosage and administration schedule is crucial. If a dose is missed, it should be taken promptly. It is remembered unless the next planned dose is almost here, in which case it should be skipped. It's important to avoid taking two doses to make up for a missing one.
The dosage and duration of treatment should be as per the treating physician's clinical judgment.
Tablets: 40mg, 80mg.
Capsule: 40 mg.
Enzalutamide is available in the form of oral tablets and capsules.
Dose Adjustment in Adult Patients:
Dosage: 160 mg PO every day for CRPC or mCSPC.
In addition, patients should have undergone bilateral orchiectomy nmCSPC with high-risk BCR or concurrent administration of a gonadotropic-releasing hormone (GnRH) analog.
It may be administered as a GnRH analog or enzalutamide.
After 36 weeks of therapy, if PSA is undetectable (<0.2 ng/mL), treatment can be stopped.
When PSA rises to ≥2 ng/mL in patients who have had a prior radical prostatectomy or ≥ five ng/mL in patients who have undergone past primary radiation therapy, patients should resume treatment.
Considerations
- If a patient experiences a ≥ Grade 3 or an intolerable adverse reaction, stop taking enzalutamide for a week or until symptoms improve. One can continue at the same dose (120 mg or 80 mg) if necessary.
- Gonadotropin-releasing hormone (GnRH) analogs should be administered concurrently to patients taking enzalutamide, or they should have undergone bilateral orchiectomy.
- Patient taking potent CYP2C8 inhibitors: Avoid use. If coadministration is unavoidable, reduce the enzalutamide dose to 80 mg qDay.
- Patient taking strong CYP3A4 inducers: Avoid strong CYP3A4 inducers with enzalutamide. Increase the enzalutamide dose from 160 mg to 240 mg daily.
Enzalutamide should be used in treating prostate cancer, along with appropriate dietary restrictions.
A healthy lifestyle involves maintaining a balanced diet and exercising regularly to manage weight effectively. Incorporate leafy greens, citrus fruits, fatty fish, berries, yoghurt, apples, peaches, cauliflower, cabbage, broccoli, beans, and herbs into your meals for a nutrient-rich diet. Ensure adequate sleep to rest well and avoid smoking and alcohol consumption for overall well-being. Steer clear of fast, fried, processed meats, refined carbs, and added sugars to promote a healthier body. These choices actively contribute to a better quality of life and improved health.
The dietary restriction should be individualized as per patient requirements.
None.
- Patients receiving enzalutamide experienced seizures in randomized clinical trials; patients should be cautioned about the possibility of losing consciousness suddenly while participating in activities that could seriously injure them or others; patients who experience seizures during treatment should have their therapy permanently stopped.
- When used, individuals may experience posterior reversible encephalopathy syndrome (PRES); if this occurs, stop treatment.
- Caution patients who suffer from hypersensitivity to stop therapy and seek medical attention immediately temporarily; hypersensitivity reactions, including face, tongue, or lip, have been seen; postmarketing cases have reported pharyngeal oedema. In the event of severe hypersensitivity responses, stop taking the medicine permanently.
- Ischemic heart disease was observed in clinical trials; ischemic heart disease symptoms and signs should be monitored; cardiovascular risk factors (such as diabetes, hypertension, or dyslipidemia) should be optimally managed. Stop treating patients with ischemic heart disease in grades 3–4.
- There were falls and fractures; patients were assessed for fracture and fall risk; patients at fracture risk were monitored and managed in accordance with established treatment guidelines, with consideration for the use of bone-targeted agents; routine bone density assessment and treatment of osteoporosis with bone-targeted agents were not carried out in the studies.
Alcohol Warning
It is unsafe to consume Enzalutamide with alcohol.
Breast Feeding Warning
It is not recommended for use during breastfeeding.
Pregnancy Warning
It is not recommended for use during pregnancy.
Food Warning
Avoid fast food and smoking.
The adverse reactions related to Enzalutamide can be categorized as
- Common Adverse Effects: Asthenic conditions, back pain, constipation, diarrhoea, arthralgia, hot flushes, decreased appetite, upper respiratory tract infections, peripheral oedema, musculoskeletal pain, hypertension, falls, headaches, reduced weight, dyspnea, and dizziness.
- Less Common Adverse Effects: Muscular weakness, insomnia, hematuria, nonpathological fractures, lower respiratory tract and lung infections, dysgeusia, spinal cord compression and cauda equina syndrome, anxiety, pollakiuria, pruritus, dry skin, epistaxis, asthenic conditions, hypertension, paresthesia, back pain, mental impairment disorders, hypoesthesia, gynecomastia, arthralgia, restless leg syndrome, falls, musculoskeletal pain, diarrhoea, and peripheral oedema.
- Rare Adverse Effects: (Grade 3-4) Headache, decreased weight, constipation, dyspnea, dizziness, mental impairment disorders, hypoesthesia, anxiety, reduced appetite, epistaxis, hot flush, dysgeusia, restless leg syndrome, and insomnia.
Reports on post-marketing:
- Hypersensitivity of the entire body, including oedema of the lips, tongue, cheeks, and throat.
- Gastrointestinal issues: vomiting.
- Neurological disorders include seizures and posterior reversible encephalopathy syndrome (PRES).
- Skin and subcutaneous tissue disorders: erythema multiforme, drug reaction with eosinophilia and systemic symptoms (DRESS), rash, toxic epidermal necrolysis (TEN), and acute generalized exanthematous pustulosis (AGEP) are among the conditions that affect the skin and subcutaneous tissue.
- Ischemic heart disease
The clinically relevant drug interactions of Enzalutamide are briefly summarized here.
Drug-Drug Interaction
Drugs that Inhibit CYP2C8: The combined area under the plasma concentration-time curve (AUC) of enzalutamide with N-desmethyl enzalutamide increased by 2.2 times when gemfibrozil, a potent CYP2C8 inhibitor, was administered concurrently with the medication. If possible, avoid coadministration of enzalutamide with potent CYP2C8 inhibitors. Lower the dosage of enzalutamide if it is impossible to avoid coadministration of enzalutamide with a potent CYP2C8 inhibitor.
Drugs that Induce CYP3A4: The composite AUC of enzalutamide with N-desmethyl enzalutamide was reduced by 37% upon coadministration of rifampin, a potent CYP3A4 inducer and a moderate CYP2C8 inducer. Strong CYP3A4 inducers such as carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, and rifapentine should not be administered with enzalutamide. St John's wort should be avoided since it may lessen exposure to enzalutamide. Increase the dosage of enzalutamide if coadministration of a potent CYP3A4 inducer is unavoidable.
Other drugs: This drug decreases the quantities of several of these enzymes' substrates, which may impact their efficacy. It contains a high CYP3A4 inducer and a moderate inducer of CYP2C9 and CYP2C19. Refrain from mixing with these substrates or modify their dosage in accordance with prescription guidelines to avoid therapeutic failure or elevated exposure to active metabolites. Use caution when combining medications processed by specific CYP isoenzymes with narrow therapeutic indications.
Drug-Food Interaction: No interactions found/established.
Drug-Disease Interaction: If one experiences seizures, severe renal or hepatic failure, or infections (bacterial, fungal, protozoal, or viral), inform the physician immediately. These conditions require careful monitoring.
The most common side effects of Enzalutamide include nausea, vomiting, fatigue, back pain, diarrhoea, cold-like symptoms, joint pain, hot flushes, oedema, muscular or musculoskeletal pain, headaches, respiratory infections, weakness, dizziness, insomnia, urinary issues like blood in urine, tingling sensations, anxiety, and hypertension.
- Pregnancy
Pregnancy Category X (FDA): The risks outweigh the potential benefits. Safer alternatives exist.
As per the FDA, safety and effectiveness have not been established.
It is not indicated for women who are pregnant or may become pregnant.
Animal data
Studies on enzalutamide in animals and its mechanism of action demonstrate possible harm to fetuses and miscarriages. There is currently no human data on its use in expectant mothers. When pregnant mice were administered oral enzalutamide during organ development, the amount that resulted in adverse effects in the offspring was lower than the suggested human maximum.
Contraception
Male patients who have female partners who may become pregnant should be advised to use effective contraception during treatment and for three months following the last dose, according to research on animal reproduction.
Infertility
According to research on animals, it may reduce fertility in males who can procreate.
- Nursing Mothers
Enzalutamide is not indicated for use in females; whether it is distributed in breast milk is unknown.
- Pediatric Use
As per the FDA, safety and effectiveness in the pediatric population have not been established.
- Geriatric Use
The safety and efficacy of Enzalutamide in geriatric patients have yet to be thoroughly established.
In four randomized controlled clinical studies, 2784 individuals got enzalutamide; of these, 79% were 65 or older, and 36% were 75 or older. There were no discernible overall variations in safety or efficacy between these patients and younger patients. Although differences in responses between older and younger patients have not been noted in other published clinical experiences, some older patients may be more sensitive than others.
Dose Adjustment in Kidney Impairment Patients:
Moderate to mild (CrCl 30-89 mL/min): No dosage modification is required.
Severe end-stage renal disease (CrCl <30 mL/min): Not recommended.
Dose Adjustment in Hepatic Impairment Patients:
Moderate to severe (Child Pugh A to C): No dosage modification is required.
Signs and Symptoms
The physician should be vigilant about the knowledge pertaining to identifying and treating overdosage of Enzalutamide.
Overconsumption of Enzalutamide could lead to fatigue, weakness, nausea, vomiting, and potential complications such as hypertension and heart-related issues.
Management
There is no specific antidote or treatment for excessive Enzalutamide intake, so treatment typically involves symptomatic and supportive measures. Close monitoring of vital signs and symptomatic treatment are essential. Measures include maintaining hydration, electrolyte balance, and cardiovascular stability. If recently ingested, gastric decontamination may be considered, such as induced vomiting, gastric lavage, and activated charcoal administration. Close monitoring of cardiac function, liver enzymes, renal function, and vital signs is necessary. Additionally, symptomatic treatment to manage complications like hypertension, cardiac arrhythmias, or other systemic effects should be promptly initiated as per standard medical practices.
Pharmacodynamics:
The normal physiology of prostate cells is intimately associated with AR activity, which explains the relationship and justifies androgen deprivation therapy (ADT). But after ADT starts in two to three years, resistance will eventually develop due to a build-up of mutations, such as constitutively active mutations, overexpression of AR, and modifications to AR splicing variants. Therefore, enzalutamide was created to take advantage of these alterations. Enzalutamide has been shown in vitro research using the human prostate cancer cell line VCaP to reduce cell growth and cause apoptosis, a feature that other antiandrogens like bicalutamide did not exhibit.
Electrophysiology of the Heart
In 796 patients with metastatic CRPC, the impact of enzalutamide 160 mg/day at steady state on the QTc interval was assessed. Based on the Fridericia correction approach, no significant difference (i.e., greater than 20 ms) was found between the mean QT interval change from baseline in patients treated with enzalutamide and that in patients treated with placebo.
However, because of the limitations of the study design, minor increases in the mean QTc interval (i.e., less than 10 ms) caused by enzalutamide cannot be ruled out.
Pharmacokinetics:
Absorption
Enzalutamide is rapidly absorbed, reaching peak plasma concentration within approximately 1 hour, with a range of 0.5 to 3 hours.
Distribution
It has a volume of distribution of approximately 110 litres. Plasma protein binding occurs at a high rate of 97-98%, primarily to albumin for enzalutamide and 95% to N-desmethyl enzalutamide.
Metabolism
Extensive liver metabolism is facilitated mainly by the CYP2C8 isoenzyme, transforming enzalutamide into its active metabolite, N-desmethyl enzalutamide. Additionally, the CYP3A4 isoenzyme contributes to a lesser extent. Carboxylesterase 1 further metabolizes it into an inactive carboxylic acid metabolite.
Elimination
The predominant route of excretion is via urine, accounting for 71% as inactive metabolites, while approximately 14% is eliminated through faeces as inactive metabolites. The elimination half-life of enzalutamide is about 6 days, ranging from 2.8 to 10.2 days. For N-desmethyl enzalutamide, the half-life ranges from 7.8 to 8.6 days.
- Payne H, Robinson A, Rappe B, Hilman S, De Giorgi U, Joniau S, Bordonaro R, Mallick S, Dourthe LM, Flores MM, Gumà J, Baron B, Duran A, Pranzo A, Serikoff A, Mott D, Herdman M, Pavesi M, De Santis M. A European, prospective, observational study of enzalutamide in patients with metastatic castration-resistant prostate cancer: PREMISE. Int J Cancer. 2022 Mar 1;150(5):837-846. doi: 10.1002/ijc.33845. Epub 2021 Nov 8. PMID: 34648657; PMCID: PMC9298797.
- Davis ID, Martin AJ, et al; ENZAMET Trial Investigators and the Australian and New Zealand Urogenital and Prostate Cancer Trials Group. Enzalutamide with Standard First-Line Therapy in Metastatic Prostate Cancer. N Engl J Med. 2019 Jul 11;381(2):121-131. doi: 10.1056/NEJMoa1903835. Epub 2019 Jun 2. PMID: 31157964.
- Shore ND, Renzulli J, Fleshner NE, Hollowell CMP, Vourganti S, Silberstein J, Siddiqui R, Hairston J, Elsouda D, Russell D, Cooperberg MR, Tomlins SA. Enzalutamide Monotherapy vs Active Surveillance in Patients With Low-risk or Intermediate-risk Localized Prostate Cancer: The ENACT Randomized Clinical Trial. JAMA Oncol. 2022 Aug 1;8(8):1128-1136. doi: 10.1001/jamaoncol.2022.1641. Erratum in: JAMA Oncol. 2022 Aug 1;8(8):1225. PMID: 35708696; PMCID: PMC9204619.
- Morris MJ, Heller G, Hillman DW, Bobek O, Ryan C, Antonarakis ES, Bryce AH, Hahn O, Beltran H, Armstrong AJ, Schwartz L, Lewis LD, Beumer JH, Langevin B, McGary EC, Mehan PT, Goldkorn A, Roth BJ, Xiao H, Watt C, Taplin ME, Halabi S, Small EJ. Randomized Phase III Study of Enzalutamide Compared With Enzalutamide Plus Abiraterone for Metastatic Castration-Resistant Prostate Cancer (Alliance A031201 Trial). J Clin Oncol. 2023 Jun 20;41(18):3352-3362. doi: 10.1200/JCO.22.02394. Epub 2023 Mar 30. PMID: 36996380; PMCID: PMC10414728.
- https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm
- https://www.accessdata.fda.gov/drugsatfda
- April Hazard Vallerand, Cynthia A. Sanoski. [link]. Sixteenth Edition. Philadelphia, China: F. A. Davis Company; 2019: Page No 500-502
- https://www.ncbi.nlm.nih.gov/books/NBK548070/
Dr. Chumbeni E Lotha has completed her Bachelor of Pharmacy from RIPANS, Mizoram and Doctor of Pharmacy from SGRRU,Dehradun. She can be reached at editorial@medicaldialogues.in
Dr JUHI SINGLA has completed her MBBS from Era’s Lucknow Medical college and done MD pharmacology from SGT UNIVERSITY Gurgaon. She can be contacted at editorial@medicaldialogues.in. Contact no. 011-43720751
Published on: 25 Nov 2023 11:09 AM GMT