Medicine > All about Enzalu (Enzalutamide) tablet

All about Enzalu (Enzalutamide) tablet

Name of Medicine:- Enzalu

Composition:- Enzalutamide 40mg

Chemical Formula:- C21H16F4N4O2S

What is Enzalu?

Enzalu is an anti-cancer formulation comprising Enzalutamide. It is a prescription medication used for the treatment of men suffering from metastatic castration-resistant prostate cancer who have previously been administered Docetaxel. It works to block the effect of androgen, which is a male reproductive hormone responsible for the growth and multiplication of cancer cells in the body. 

Clinical Relevance

The clinical relevance of medicine tells about its significance in the healthcare segment. Enzalu is an effective regimen available as capsules in the strength of 40mg, indicated for oral administration. It is used to treat a certain type of Prostate Cancer:

  • Metastatic Castration-Resistant Prostate Cancer: It is a type of Prostate Cancer that keeps on growing and spreading even when the amount of testosterone is decreased in the body to a very low level. 

Clinical Pharmacology 

Pharmacodynamics 

Enzalutamide’s effect at steady-state on the QTc interval was calculated in 796 patients with metastatic CRPC with a dose of 160 mg/day. No large difference was noted between the mean QT interval change from baseline in patients treated with Enzalu which in patients treated with placebo, supported the Fridericia correction method. However, small increases within the mean QTc interval because of Enzalutamide can't be excluded thanks to limitations of the study design. 

Mechanism of Action 

Enzalutamide is termed as a competitive androgen receptor inhibitor that affects multiple stages of the signaling pathway. It's ready to inhibit androgen binding to its receptor, androgen receptor nuclear translocation, and subsequent interaction with DNA. As a result, the proliferation of prostatic adenocarcinoma cells decreases which ultimately results in apoptosis and decreased tumor volume. 

Distribution and Protein Binding

Enzalutamide’s average apparent volume of distribution in patients after a single oral dose is 110 L (29% CV). This compound is 97% to 98% bound to plasma proteins, primarily Albumin. N-desmethyl enzalutamide is 95% bound to plasma proteins. 

Metabolism

Enzalutamide is a compound that is metabolized primarily by CYP2C8 and CYP3A4 hepatically. The enzyme which is responsible for the conversion of Enzalutamide to its active metabolite, N-desmethyl enzalutamide, is CYP2C8. The activity of N-desmethyl-enzalutamide analogous thereto of the parent compound.

Route of Elimination 

Enzalutamide is primarily eliminated by hepatic metabolism. After the oral administration of 14C-Enzalutamide single dose 160 mg, 85% of the radioactivity is recovered by 77 days post-dose: 71% is recovered in urine, and 14% is recovered in feces. The average apparent clearance of the compound in patients after the administration of one oral dose is 0.56 L/h (range 0.33 to 1.02 L/h). The average terminal half-life (t1/2) for enzalutamide in patients after a single oral dose is 5.8 days (range 2.8 to 10.2 days). After the administration of one 160 mg oral dose of enzalutamide in healthy volunteers, the average of terminal t1/2 for N-desmethyl enzalutamide is about 7.8 to 8.6 days.

Toxicity 

The most common adverse reactions (greater than about  5%) of Enzalu are lack of energy or fatigue, back pain, diarrhea, arthralgia, hot flush, peripheral edema, musculoskeletal pain, headache, upper respiratory infection, muscular weakness, dizziness, insomnia, lower respiratory infection, spinal cord compression, and cauda equina syndrome, blood in urine, paresthesia, anxiety, and high blood pressure.

Clinical Trials

Enzalu is an oral androgen receptor inhibitor. It targets a number of steps in the pathway of 

androgen receptor signaling. In the randomized phase III AFFIRM study, major improvements in survival versus placebo were noted when this compound was used for the treatment of patients suffering from metastatic castration-resistant prostate cancer (mCRPC) after the administration of Docetaxel. Other benefits involved a notable delay in time to the first skeletal-related event and improvement in certain measures of pain and health-related quality of life. Treatment effects were consistent across all prespecified subgroups. Phase III PREVAIL study calculated Enzalutamide versus placebo in patients suffering from mCRPC who had not been treated using chemotherapy. 

Enzalutamide, most importantly, decreased the risk of radiographic progression and death. There were also improvements in all secondary and prespecified exploratory endpoints, including: 

  • delayed initiation of chemotherapy

  • reduction in risk of the first skeletal-related event

  • a high percentage of patients with the objective response as compared to placebo. 

The compound was studied as monotherapy also in a small, open-label phase II study in patients suffering from prostate cancer who were eligible for androgen deprivation therapy. A prostate-specific antigen (PSA) response, defined as >80% decline in PSA level from baseline at week 25, was reached in 92.5% of patients. Long-term follow-up is ongoing. Despite differences between the trials and studies, Enzalutamide showed a favorable safety profile in the three populations of patients. Relatable rates of adverse effects between the two groups were seen in AFFIRM and PREVAIL, with effects being more common with enzalutamide than with placebo such as:

  • Fatigue   

  • Diarrhea  

  • Back pain 

  • Hot flashes

  • Hypertension

Hypertension was observed at a greater rate in the enzalutamide patients group than in the placebo group in PREVAIL. Few seizures were reported in the trials. 

Drug Category

  • Antiandrogens:- These medicines belong to a group of drugs, known as Testosterone Blockers, that have many uses. Antiandrogens are used in the treatment of Prostate Cancer in men. They are used to reduce masculine features in patients.  

  • Antineoplastic Agents:- Alkylating Antineoplastic Agents are also known as chemotherapeutic drugs or cytotoxic drugs. Such medications are available in different forms including tablets, capsules, and injections. 

  • P-Glycoprotein Inhibitors:- These drugs use the energy of ATP hydrolysis to pump toxic xenobiotics out of cells in the body. P-Glycoprotein Inhibitors play a significant role in chemotherapy of cancer patients, intestinal absorption, and brain uptake. 

Interactions 

Drug-Drug Interactions 

  • CYP2C8 Inhibitors: In a study, when a CYP2C8 Inhibitor was administered to the individuals while co-administering Enzalutamide, the AUC of Enzalutamide increased. Therefore, co-administration of Enzalu with a CYP2C8 Inhibitor should be avoided if possible. However, if this can not be avoided, dose adjustments (reduction) can be preferred for Enzalu. 

  • CYP2C8 Inducers: The effects of CYP2C8 inducers on the Cmax and AUC of Enzalutamide have not been evaluated. Administration of CYP2C8 inducers with Enzalu may reduce the AUC of Enzalutamide. Therefore, concomitant medication with less or no CYP2C8 induction potential should be preferred during the course of Enzalu. 

  • CYP3A4 Inhibitors: In a study, administration of CYP3A4 Inhibitor with Enzalu increased the AUC of Enzalutamide by 1.3 fold in healthy individuals. Therefore, co-administration of Enzalu with a CYP3A4 Inhibitor should be avoided if possible. However, if this can not be avoided, dose adjustments (reduction) can be preferred for Enzalu.

  • CYP3A4 Inducers: The effects of CYP3A4 inducers on the Cmax and AUC of Enzalutamide have not been evaluated. Administration of CYP2C8 inducers with Enzalu may reduce the AUC of Enzalutamide. Therefore, concomitant medication with less or no CYP3A4 induction potential should be preferred during the course of Enzalu. 

Drug-Disease Interactions

  • Seizures: In patients suffering from seizures, Enzalutamide can cause severe reactions. In a study, people administering Enzalu developed symptoms of seizures. Therefore, if a patient develops seizures during the course of Enzalu, this medication should be discontinued immediately. 

  • Severe Hepatic Impairment: Based on clinical trials in patients suffering from metastatic castrate-resistant Prostate Cancer (CRPC) and healthy volunteers, it was evident that no significant differences in the safety and efficacy of Enzalutamide were observed in patients with mild to moderate hepatic impairment and in patients with normal hepatic function. No initial dose adjustment is needed for patients suffering from mild to moderate renal impairment. However, this factor has not yet been established in the case of patients with severe hepatic impairment. 

  • Severe Renal Impairment: Based on clinical trials in patients suffering from metastatic castrate-resistant Prostate Cancer (CRPC) and healthy volunteers, it was evident that no significant differences in the safety and efficacy of Enzalutamide were observed in patients with mild to moderate renal impairment and in patients with normal renal function. No initial dose adjustment is needed for patients suffering from mild to moderate renal impairment. However, this factor has not yet been established in the case of patients with severe renal impairment. 

Dosage and Administration 

Recommended Dosage:- The recommended dosage of Enzalu is 160 mg (4 capsules of strength 40mg each) for oral administration once a day. The capsules can be administered with or without food. Swallow the capsule as a whole with water. Do not crush, chew or break the capsules. 

Overdosage:- In case of overdose, it is recommended to stop the treatment with Enzalu capsules. Patients may experience seizures. Reach out to a medical professional or call an emergency helpline to get supportive care. 

Dose Adjustments:- Based on clinical trials in patients suffering from metastatic castrate-resistant Prostate Cancer (CRPC) and healthy volunteers, it was evident that no significant differences in the safety and efficacy of Enzalutamide were observed in patients with mild to moderate hepatic/renal impairment and in patients with normal hepatic/renal function. No initial dose adjustment is needed for patients suffering from mild to moderate hepatic/renal impairment. However, this factor has not yet been established in the case of patients with severe hepatic/renal impairment. Therefore, it is necessary to know the need for dose adjustment in severe conditions of any disease. 

Adverse Reactions

The most common adverse reactions observed and noted in clinical studies include fatigue, joint pain, swelling, discomfort, nocturia (frequent urination at night), low blood potassium, edema (swelling or inflammation), hot flush, diarrhea, cough, vomiting, hypertension, dyspnea (shortness of breath), UTI (urinary tract infection), upper respiratory tract infection, arrhythmia (irregular heartbeat), and bruising. 

Some gastrointestinal effects such as constipation, diarrhea (pain or discomfort in the upper abdomen), dyspepsia, and stomach ache are also common in patients administering Enzalu capsules. 

Allergic reactions namely skin rash, swelling, pain, itching, and irritation may occur in some patients who are allergic to Enzalutamide or any other ingredient of this medicament. Hence, it is absolutely important to know the ingredients of the medicine beforehand to avoid adverse events. 

A number of patients also suffer from problems including insomnia and depression during the course of Enzalutamide. A healthcare professional should be contacted to know the appropriate ways of managing the side effects. 

Other common side effects of Enzalu capsules like hypertriglyceridemia (high level of fats in the blood), lymphopenia (reduced levels of certain types of blood cells), elevated alkaline phosphatase, anemia, elevated ALT and hypokalemia, and hypercholesterolemia (high levels of cholesterol in the blood) may occur. 

DRUG DISCONTINUATION REACTIONS:- Sudden discontinuation of Enzalu may lead to an increase in aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT). It may also lead to the signs of heart failure and urosepsis (a urinary tract infection). 

Warnings and Precautions 

  • Pregnant Women
    Enzalu can cause fetal harm when administered to a pregnant female as per its mechanism of action. This medication is, therefore, contraindicated for use in patients who are pregnant or plan to become pregnant. However, if Enzalu is consumed during pregnancy, the patient should be made aware of the potential risks and adverse events. 

  • Nursing Mothers
    Enzalu is not recommended for use in females. It is not known whether Enzalutamide is excreted in human milk. However, most of the drugs are excreted in human milk, which is why breastfeeding should be avoided during the course of Enzalu. 

  • Pediatric Use
    The safety and efficacy of Enzalu are not yet established in pediatric patients. 

  • Geriatric Use
    In clinical trials, 78% of individuals were of age 65 and above. No notable differences in the safety and efficacy of Enzalu were observed in older and younger patients. 

  • Renal Impairment
    Based on clinical trials in patients suffering from metastatic castrate-resistant Prostate Cancer (CRPC) and healthy volunteers, it was evident that no significant differences in the safety and efficacy of Enzalutamide were observed in patients with mild to moderate renal impairment and in patients with normal renal function. No initial dose adjustment is needed for patients suffering from mild to moderate renal impairment. However, this factor has not yet been established in the case of patients with severe renal impairment. 

  • Hepatic Impairment
    Based on clinical trials in patients suffering from metastatic castrate-resistant Prostate Cancer (CRPC) and healthy volunteers, it was evident that no significant differences in the safety and efficacy of Enzalutamide were observed in patients with mild to moderate hepatic impairment and in patients with normal hepatic function. No initial dose adjustment is needed for patients suffering from mild to moderate renal impairment. However, this factor has not yet been established in the case of patients with severe hepatic impairment.