Apalutamide - A brief overview.

Overview:

In February 2018, Apalutamide, a non-steroidal anti-androgen (NSAA) drug, received approval for the treatment of prostate cancer. It was first described in 2007 and has been in use since then. Patients with both non-metastatic castration-resistant prostate cancer (NM-CRPC) and metastatic castration-sensitive prostate cancer are treated with Apalutamide. It was one of the primary drugs approved for the treatment of NM-CRPC. This medication comes in the form of a tablet and is only accessible with a doctor's prescription.

How Does Apalutamide Work?

As an antagonist of the androgen receptors, a biological target of androgens (for example, testosterone), Apalutamide is an anti-androgen drug. This prevents the formation of these androgenic hormones from impacting the prostate gland and other body parts.

Uses of Apalutamide:

Apalutamide is prescribed under the following conditions:

• In adult men diagnosed with non-metastatic castration-resistant prostate cancer (NM-CRPC).

• In adult men diagnosed with metastatic-hormone-sensitive prostate cancer (MH-SPC).

Dosage and Administration:

Apulatamide is administered orally in the form of tablets. Each tablet constitutes 60 milligrams of Apulatamide. Patients are advised to take a single dose of four pills (240 milligrams) of Apulatamide. It can be consumed with or without food.

Warnings and Precautions:

• Seizures - Apulatimide is not advised for patients with prior history of seizures. It is also avoided if patients have an account of brain injury, stroke, or brain tumors (with or without metastasis) within a period of one year. During Apulatamide treatment, if the patient experiences seizures, the drug should be immediately stopped.

• Renal Impairment - Patients with renal impairment who have been prescribed Apulatamide should be monitored closely for adverse reactions.

• Hepatic Impairment - Apulatamide is not recommended in patients with hepatic impairment since it is eliminated from the body through the hepatic routes.

• Falls and Fractures - Patients consuming Apulatamide are susceptible to falls and fractures, and hence, the bone physiology of the patients should be thoroughly checked before the treatment starts. Studies show that Apulatamide, when given with bone-targeted medications, tends to decrease the incidence of falls and fractures in patients.

• Ischemic Heart Disease and Ischemic Cerebrovascular Disorders - Studies show that patients consuming Apulatamide have experienced ischemic heart and cerebrovascular disorders, including death. Hence, patients having risk factors for such diseases should be monitored thoroughly, and special attention should be given to their blood pressure, blood sugar, and blood lipid (cholesterol, triglycerides, low-density lipoproteins, high-density lipoproteins) levels.

• Recent History of Cardiovascular Disease - The safety of Apulatimde has not been established in patients having a history of significant cardiovascular diseases six months before the start of Apalutamide. Such patients should be monitored for risk factors such as high blood pressure, hypercholesterolemia, and hypertriglyceridemia. Cardiovascular diseases include:

  • Stable and unstable angina.
  • Myocardial infarction or heart attack.
  • Symptomatic congestive heart failure.
  • Arterial or venous thromboembolic events (such as pulmonary embolism, stroke, transient ischemic attacks, etc.).
  • Ventricular arrhythmias.

• Steven Johnson Syndrome (SJS) - Also known as toxic epidermal necrolysis or TEN, is an autoimmune disease that is often a drug-induced disease process. In this disease, the body's defense mechanism malfunctions and starts attacking cells and tissues of its own body. This results in erosions all over the body. If any symptoms and signs of steven johnson syndrome are observed, patients should be advised to stop the medication immediately and rush to the hospital. Apulatamide should be avoided in patients that are susceptible to Steven Johnson syndrome.

• Androgen Deprivation Therapy May Prolong the QT Interval - Before prescribing Apalutamide to patients having risk factors that make them susceptible to prolonged QT interval, doctors should make a thorough risk assessment.

Apulatmide is not approved for usage in children and women.

Drug Interactions:

Certain medications cannot be used together to avoid interactions; however, in some cases, sometimes these medications are prescribed by changing the dose and or taking the necessary precautions required.

Using Apalutamide with any of the following medicines is not recommended:

• Fostemsavir.

• Lopinavir.

• Mavacamten.

• Nirmatrelvir.

• Ombitasvir.

• Pacritinib.

• Paritaprevir.

• Ritonavir.

Using Apalutamide with any of the following medicines is usually not recommended. If the physician chooses to prescribe Apulatamide, then a dose modification is done in the following medications:

1. Abiraterone acetate.

2. Abrocitinib.

3. Acalabrutinib.

4. Afatinib.

5. Alpelisib.

6. Amiodarone.

7. Apixaban.

8. Avacopan.

9. Avapritinib.

10. Belumosudil.

11. Berotralstat.

12. Betrixaban.

13. Bictegravir.

14. Boceprevir.

15. Bortezomib.

16. Brigatinib.

17. Clopidogrel.

18. Clarithromycin.

19. Clozapine.

20. Ketoconazole.

21. Lemborexant.

22. Linagliptin.

23. Macitentan.

24. Glasdegib.

25. Duvelisib.

26. Estradiol.

27. Dienogest.

28. Dexamethasone.

29. Darulotamide.

Other Interactions:

Certain drugs must not be used with food since interactions might occur. Using alcohol or tobacco with certain medicines can also lead to interactions. The healthcare professional must be informed about medications, alcohol, or tobacco.

For Patients:

What Is Prostate Cancer?

The second most prevalent cancer worldwide, prostate cancer, is a type of cancer that develops in the prostate gland. The prostate gland is a small gland found in men and is located below the bladder, anterior to the rectum. It is a vital element of the male biological reproductive system. Although It is about the size and shape of a walnut, if left unchecked, this small gland can cause serious complications. Studies show that about one in nine people with the prostate gland will receive a prostate cancer diagnosis during their lifetime. This includes men, transgender women, and non-binary people with biologically male sex organs. Family history is one of the best indicators for risk assessment for prostate cancer. Men are two to three times more likely to get prostate cancer if it runs in their family. Another risk factor is age. It is most common after the age of 50. Prostate cancer can and does affect men of all backgrounds and lifestyles. Early-stage prostate cancer rarely causes symptoms, but as the disease progresses, people may experience specific warning signs, which include the following:

1. Unexplained pain in the prostate area, especially while sitting (rare but an early sign).

2. Frequent urination, especially at night.

3. Dysuria (pain or burning sensation during urination).

4. Loss of bladder control.

5. Interrupted or weak flow of urine.

6. Trouble emptying the bladder.

7. Painful ejaculation.

8. Erectile dysfunction.

9. Blood in semen or urine.

10. Lower back pain, chest pain, and hip pain (experienced when prostate cancer advances).

11. Numbness in legs and feet.

12. Dyspnea (shortness of breath).

There is no way to eliminate the risk of getting prostate cancer, but if at higher risk for developing the disease, getting regular prostate screenings, maintaining a healthy weight, eating a nutritious diet, exercising regularly, and quitting smoking will help reduce the susceptibility. It is a severe disease, but early detection is critical. When diagnosed at an early stage, or before it spreads to the other parts of the body, 97 percent of the people live at least five years post-diagnosis and treatment.

What Is Apalutamide and How Does It Work?

Apalutamide is an anti-androgenic drug. It is a class of drugs that is used in hormone therapy in patients diagnosed with prostate cancer. It works by blocking or impeding the formation of androgens (hormones responsible for male sex characteristics). Hormone therapy is a type of cancer treatment that works by stopping or removing hormones, thereby inhibiting the growth of cancer cells. In the case of prostate cancer, androgen, the male sex hormone, exacerbates cancer. This form of therapy is also known as androgen deprivation therapy or ADT. This medication tends to affect the fertility of men.

How Should Apalutamide Be Used?

Apulatamide is manufactured in the form of tablets and is taken as a single oral dose of 240 milligrams, with or without food. Each tablet constitutes 60 milligrams. Instead of breaking or chewing, the tablet should be swallowed whole. If the patient cannot swallow the tablet without crushing or chewing it, then the patient can administer the medicine in the following way:

• Take a tablet (60 milligrams of Apalutamide), place it in a container with 120 milliliters (four ounces) of apple sauce and allow it to dissolve without crushing it.

• Repeat the process for all four tablets (240 milligrams of Apalutamide) with a 15-minute interval between each tablet.

• Once all the tablets have been dissolved, drink the concentrate immediately.

• Pour some water into the container (about 60 milliliters or two ounces) to rinse its sides and drink it immediately. This ensures that no medicine is left behind.

Missed Dose: If the patient misses a dose of Apalutamide, the missed dose should be taken at the next scheduled dose. Both doses of Apalutamide should not be taken at the same time.

What Special Dietary Instructions Must Be Followed?

Unless advised otherwise, no dietary changes are required.

What Are the Side Effects of Apalutamide?

Patients using Apalutamide can experience various side effects. Common side effects include:

• Hypothyroidism (a hormonal disorder in which the thyroid gland malfunctions and does not produce the required hormones).

• Decreased appetite.

• Hypercholesterolemia (abnormal increase in cholesterol levels).

• Hypertriglyceridemia (abnormal increase in triglyceride levels).

• Dysgeusia (altered taste).

• Ischemic heart disease (a type of heart disease that is caused due to damage in the blood vessels associated with the heart).

• Hypertension (high blood pressure).

• Skin rash.

• Blurred vision.

• Headache.

• Tachycardia (fast heartbeat).

• Pruritus (itchy skin).

• Alopecia (hair loss).

• Fractures.

• Arthralgia (joint pain).

• Diarrhea (loose stools).

• Muscle spasms (muscle weakness and stiffness).

• Fatigue or tiredness.

• Weight loss.

• Nausea.

• Weakness.

• Hot flushes.

• Ischemic cerebrovascular disorders (for example, stroke).

Sometimes the side effects can be severe. The following side effects are uncommon; however, the doctor must be informed immediately if these side effects occur:

• Seizures.

• Arrhythmias (irregular heartbeats).

• Chest pain radiating to shoulders, arm, jaw, and back.

• Loss of consciousness.

• Swelling of the arms, legs, hands, and feet.

• Angina (chest pain).

• Dyspnea (shortness of breath).

• Blistering of the skin.

• Steven Johnson Syndrome.

How Is Apulatamide Stored and Discarded?

Apalutamide should be stored in an air-tight container at room temperature, away from light, heat, and moisture. It should be kept away from children. The disposal of Apalutamide should be under local guidelines and medical regulatory bodies. If not expired, unneeded medicines can also be returned to the pharmacist.

What Should Be Done in the Case of an Overdose?

In the event of an overdose, the patient should stop the medication with immediate effect and take general supportive measures until the toxicity or impact of the overdose has been resolved. As such, there is no specific antidote for the toxicity of Apalutamide. If the patient is experiencing severe complications due to the overdose, such as seizures, then the patient should be rushed to the hospital without any delay.

Who Should Not Use Apalutamide?

The use of Apulatamide is contraindicated under the following conditions:

• History of brain injury or brain tumor.

• Stroke.

• History of seizures.

• History of Steven Johnson syndrome.

• Children.

• Patients who are planning to have children.

What Should Be Informed to the Healthcare Provider Before Using Apalutamide?

Patients should ensure the following before starting the course of Apalutamide:

• They should inform the doctor of any previous history of allergies associated with Apulatamide or any other medication.

• Patients should share their medical history and inform the physician of all the prescription and non-prescription medications they might be taking. They should not forget to mention the following drugs:

• Anticoagulants or blood thinners (for example, Warfarin).

• Fexofenadine.

• Gemfibrozil.

• Ketoconazole

• Omeprazole.

• Itraconazole.

• Rosuvastatin.

• Rifampin.

• Midazolam.

• Patients should inform the physician about a history of heart diseases, such as heart attack, angina, hypertension, heart failure, and stroke. Patients should also inform about the history of seizures, brain injury, brain tumors, high blood pressure, diabetes, high cholesterol levels, and bone disorders such as osteoporosis.

• Since Apulatamide can cause seizures, dizziness, and fatigue in some patients, avoiding driving and work associated with heavy machinery is advisable.

• Apulatamide is also associated with the weakening of the bones. Hence, patients should be more careful to prevent falls and accidents and take supplements for optimal bone health.

• Men consuming Apalutamide should not donate sperm during the treatment and even three months after the treatment ceases.

• Only men can take Apalutamide. In particular, women who are breastfeeding or may become pregnant should avoid this drug. Effective birth control methods should be used (men are advised to use condoms, and women can take birth control pills). Apalutamide can cause harm to the fetus.

• Patients should consult a doctor before stopping this medication. In the case of side effects, the dose is modified, or another drug is used to replace Apalutamide.

For Doctors:

Indications -

• Non-metastatic castration-resistant prostate cancer (NM-CRPC).

• Metastatic-hormone-sensitive prostate cancer (MH-SPC).

Pharmacology:

Mechanism of Action -

Explicitly inhibiting the androgen receptor (AR), Apalutamide interacts with the ligand-binding site of the androgen receptor. By doing so, Apulatamide intercepts and inhibits nuclear translocation, DNA binding, and transcription mediated by the androgen receptor. The drug increases anti-tumor drug activity by reducing cell proliferation and increasing apoptosis of cancerous cells.

Half-Life of Apalutamide -

At a steady state, the mean approximate half-life of Apalutamide is three days.

Administration -

The drug is administered orally in the form of tablets.

Dose and Dosage Adjustments -

• Apulatamide is administered as a single dose of 240 milligrams, taken once a day.

• No dosage adjustments have been advised in patients with renal or hepatic impairment.

• When a patient experiences grade III toxicity, the medication is paused until the side effects subside or the level of toxicity decreases to grade I. Once the patient recovers, the dose is resumed at the same or an altered reduced dose of 180 or 120 milligrams.

Adverse Effects:

• Hypothyroidism (a hormonal disorder in which the thyroid gland malfunctions and does not produce the required hormones).

• Decreased appetite.

• Hypercholesterolemia (abnormal increase in cholesterol levels).

• Hypertriglyceridemia (abnormal increase in triglyceride levels).

• Dysgeusia (altered taste).

• Ischemic heart disease (a type of heart disease that is caused due to damage in the blood vessels associated with the heart).

• Hypertension (high blood pressure).

• Skin rash.

• Blurred vision.

• Headache.

• Tachycardia (fast heartbeat).

• Pruritus (itchy skin).

• Alopecia(hair loss).

• Fractures.

• Arthralgia (joint pain).

• Diarrhea (loose stools).

• Muscle spasms (muscle weakness and stiffness).

• Fatigue or tiredness.

• Weight loss.

• Nausea.

• Weakness.

• Hot flushes.

• Ischemic cerebrovascular disorders (for example, stroke).

• Seizures.

• Arrhythmias (irregular heartbeats).

• Chest pain radiating to shoulders, arm, jaw, and back.

• Loss of consciousness.

• Swelling of the arms, legs, hands, and feet.

• Angina (chest pain).

• Dyspnea (shortness of breath).

• Blistering of the skin.

• Steven Johnson Syndrome.

Apalutamide Must Be Used With Caution in the Following Conditions

• History of brain injury or brain tumor.

• Stroke.

• History of seizures.

• History of Steven Johnson syndrome.

Pharmacokinetics -

• Absorption - Peak plasma concentration is achieved after two hours of oral administration, with a mean absolute oral bioavailability of 100 %.

• Distribution - The mean volume of distribution following oral administration, at a steady state, is 276 L. This volume is greater than the total body water, thus indicating extensive extravascular distribution.

• Metabolism - Apalutamide is metabolized to form N-desmethyl Apalutamide with the help of CYP2C8 and CYP3A4 enzymes. They are further metabolized to form inactive carboxylic metabolites.

• Elimination - Apalutamide is primarily eliminated or excreted via urine as metabolites.