Antiandrogen drugs

Antiandrogens are the name given to a diverse group of medicines that counteract the effects of the male sex hormones, testosterone and dihydrotestosterone. Male sex hormones are also known as androgens; antiandrogens may also be called androgen receptor blockers. Antiandrogens are medications that act by binding to intracellular androgen receptors, preventing the effects of endogenous androgens on target tissues such as testes, hair follicles, hypothalamus, pituitary, ovaries and prostate gland. Antiandrogens are used for a variety of hyperandrogenic states such as acne, hirsutism, and paraphilias, but their major use is in therapy of prostate cancer.

Some antiandrogens work by lowering the body’s production of androgens while others block androgen receptors, limiting the body’s ability to make use of the androgens produced.

Antiandrogens are used in the treatment of various conditions and disorders including prostate cancer, precocious puberty in young males, benign prostatic hyperplasia, androgenic alopecia (male-pattern hair loss) and sexual disorders, such as hyper-sexuality, in men.

In women, antiandrogens may be used to treat polycystic ovary syndrome, hirsutism (excessive facial or body hair), amenorrhea (absence of menstrual periods), acne, and several other conditions.

Chemically, antiandrogens are classified into steroidal (such as cyproterone acetate) and nonsteroidal (including flutamide, nilutamide and bicalutamide). Cyproterone, despite evaluation in many clinical trials, has yet to receive FDA approval for use the United States, largely because of its potential for hepatotoxicity. In contrast, flutamide, nilutamide and bicalutamide are now approved and in general clinical use for therapy of prostate cancer. The largest and longest clinical experience has been with flutamide which has been shown to produce clinical remission in patients with prostate cancer, and is also used in hyperandrogenic states including acne and hirsutism. Nilutamide has been extensively studied and is indicated for use in combination with surgical castration for the treatment of metastatic prostate cancer and is recommended to be started at the time of orchiectomy. Unlike flutamide, nilutamide has not been evaluated in detail as therapy of hirsutism or acne. Bicalutamide, the most recent antiandrogen to be approved for use in the United States, is also used in therapy of prostate cancer, but has not been approved for use in nonmalignant hyperandrogenic states.

Abiraterone is a more recently developed antiandrogen used to treat prostate cancer. Abiraterone is a steroid inhibitor of CYP17, an enzyme in the pathway of androgen production which has been shown to be effective in prolonging relapse free and overall survival in men with metastatic, castration-resistant prostate cancer. Abiraterone has been linked to a moderate rate of serum aminotransferasae elevations during therapy, but the abnormalities are usually mild and transient, and instances of clinically apparent liver injury have not been linked to use of this agent, although its general use has been limited.

What is androgen?

An androgen or male sex hormone, is defined as a substance capable of developing and maintaining masculine characteristics in reproductive tissues (notably the genital tract, secondary sexual characteristics, and fertility) and contributing to the anabolic status of somatic tissues ¹. Testosterone together with its potent metabolite, dihydrotestosterone (DHT), are the principal androgens in the circulation of mature male mammals. Testosterone has a characteristic four ring C18 steroid structure and is synthesized mainly by Leydig cells, located in the interstitium of the testis between the seminiferous tubules. Leydig cell secretion creates a very high local concentration of testosterone in the testis as well as a steep downhill concentration gradient into the bloodstream maintaining circulating testosterone levels which exert characteristic androgenic effects on distant androgen sensitive target tissues. The classical biological effects of androgens are primarily mediated by binding to the androgen receptor, a member of the steroid nuclear receptor superfamily encoded by a single gene located on the X chromosome, which then leads to a characteristic patterns of gene expression by regulating the transcription of an array of androgen responsive target genes. This physiological definition of an androgen in the whole animal is now complemented by a biochemical and pharmacological definition of an androgen as a chemical that effectively competes with testosterone binding to the androgen receptor ² to stimulate post-receptor functions in isolated cells or cell-free systems. In addition, non-genomic mechanisms of androgen action involving rapid, membrane-mediated nontranscriptional processes in the cytoplasm have been described but not yet fully characterized ³.

Abiraterone

Abiraterone is an antiandrogen used to treat metastatic prostate cancer in men who have undergone castration. Abiraterone is used in combination with prednisone to treat a certain type of prostate cancer that has spread to other parts of the body. Abiraterone is in a class of medications called androgen biosynthesis inhibitors. It works by decreasing the amount of certain hormones in the body. Abiraterone acetate is a semi-synthetic steroidal inhibitor of CYP17, a crticial enzyme in the pathway of androgen production in the testes and adrenal glands. The additional inhibition of androgenic steroid synthesis inhibits the growth of the androgen-sensitive prostate cancer cells. Therapy with abiraterone has been shown to prolong relapse free as well as overall survival in men with metastatic, castration-resistant prostate cancer. Abiraterone was approved for use in the United States in 2011. It is given in combination with prednisone to prevent hypocorticoidism caused by the enzyme inhibition. Abiraterone is available as 250 mg tablets under the brand name Zytiga. The typical dose is 1000 mg daily in combination with 5 mg of prednisone twice daily.

Abiraterone common side effects include fatigue, nausea, vomiting, diarrhea and abdominal discomfort. Inhibition of CYP17 can also lead to symptoms of mineralocorticoid excess such as hypertension, hypokalemia and fluid retention.

Abiraterone special precautions

Before taking abiraterone:

• tell your doctor and pharmacist if you are allergic to abiraterone, any other medications, or any of the ingredients in abiraterone tablets. Ask your pharmacist for a list of the ingredients.
• tell your doctor and pharmacist what other prescription and nonprescription medications, vitamins, nutritional supplements, and herbal products you are taking or plan to take. Be sure to mention any of the following: dextromethorphan; certain medications for seizures such as carbamazepine (Carbatrol, Epitol, Tegretol), phenobarbital, and phenytoin (Dilantin, Phenytek); ketoconazole; nefazodone; pioglitazone (Actos); rifabutin (Mycobutin); rifampin (Rifadin, in Rifamate, in Rifater, Rimactane); rifapentine (Priftin); and thioridazine. Your doctor may need to change the doses of your medications or monitor you carefully for side effects. Many other medications may also interact with abiraterone, so be sure to tell your doctor about all the medications you are taking, even those that do not appear on this list.
• tell your doctor if you have an infection or are experiencing unusual stress, have had a recent heart attack, or if you have or have ever had adrenal or pituitary gland problems, heart failure, an irregular heartbeat, high blood pressure, a low level of potassium in your blood, or heart or liver disease.
• you should know that abiraterone is only for use in men. Women should not take this medication, especially if they are or may become pregnant or are breastfeeding. If taken by pregnant women, abiraterone may harm the fetus. Women who are, could become, or may be pregnant should not touch abiraterone tablets without protective gloves. If a pregnant woman takes or touches abiraterone tablets, she should call her doctor immediately.
• men with a female partner taking abiraterone must use effective contraception during treatment and for 3 weeks after the final dose. Talk to your doctor about the types of birth control that are right for you.
• you should know that this medication may decrease fertility in men. Talk to your doctor about the risks of taking abiraterone.

How should abiraterone be used?

Abiraterone comes as a tablet to take by mouth on an empty stomach with water, 1 hour before or 2 hours after eating any food. It is usually taken once or twice a day. Take abiraterone at around the same time every day. Follow the directions on your prescription label carefully, and ask your doctor or pharmacist to explain any part you do not understand. Take abiraterone exactly as directed. Do not take more or less of it or take it more often than prescribed by your doctor.

Swallow the tablets whole with water; do not split, chew, or crush them.

Continue to take abiraterone even if you feel well. Do not stop taking abiraterone or prednisone without talking to your doctor.

Ask your pharmacist or doctor for a copy of the manufacturer’s information for the patient.

Abiraterone side effects

Abiraterone may cause side effects. Tell your doctor if any of these symptoms are severe or do not go away:

• joint swelling or pain
• groin pain
• hot flashes (a sudden wave of mild or intense body heat)
• diarrhea
• heartburn
• cough
• difficulty falling asleep or staying asleep

Some side effects can be serious. If you experience any of these symptoms, call your doctor immediately:

• dizziness
• feeling faint or lightheaded
• headache
• confusion
• fast or irregular heartbeats
• muscle weakness or aches
• leg pain
• swelling of the hands, feet, ankles, or lower legs
• rash
• unusual bruising or bleeding
• extreme tiredness
• lack of energy
• nausea
• vomiting
• loss of appetite
• pain in the upper right part of the stomach
• yellowing of the skin or eyes
• flu-like symptoms such as fever
• blood in urine
• difficult, painful or frequent urination

Abiraterone may cause other side effects. Call your doctor if you have any unusual problems while taking abiraterone.

Apalutamide

Apalutamide is a nonsteroidal antiandrogen used to treat nonmetastatic (not spread to other parts of the body) castration-resistant prostate cancer in men who have not been helped by other medical treatments. Apalutamide is in a class of medications called androgen receptor inhibitors. It works by blocking the effects of androgen (a male reproductive hormone) to stop the growth and spread of cancer cells.

Apalutamide is a small molecule androgen receptor antagonist which binds to the intracellular receptor and prevents its translocation to the nucleus and subsequent DNA binding, thereby blocking its activity. Therapy with apalutamide lowers residual testosterone levels after surgical castration in men with prostate cancer and has been shown to prolong metastatic free survival in men with castration-resistant prostate cancer with rising levels of prostate-associated antigen (PSA) without measurable metastatic disease. Apalutamide was approved for use in the United States in 2018 and is available as tablets of 60 mg under brand name Erleada. The recommended initial dose is 240 mg daily with subsequent dose reduction for intolerance.

Apalutamide common side effects include symptoms of androgen deficiency including fatigue, diarrhea, nausea, anorexia, weight loss, constipation, joint and muscle pain, hot flushes, headaches, dizziness, and edema. Rare, but potentially serious side effects associated with long term therapy include seizures, osteoporosis, bone fractures and cardiovascular events.

Apalutamide special precautions

Before taking apalutamide:

• tell your doctor and pharmacist if you are allergic to apalutamide, any other medications, or any of the ingredients in apalutamide tablets. Ask your pharmacist for a list of the ingredients.
• tell your doctor and pharmacist what prescription and nonprescription medications, vitamins, nutritional supplements and herbal products you are taking or plan to take. Be sure to mention any of the following: anticoagulants (‘blood thinners’) such as warfarin (Coumadin), fexofenadine (Allegra), gemfibrozil (Lopid), itraconazole (Sporanox), ketoconazole (Nizoral), omeprazole (Prilosec), midazolam (Versed), rifampin (Rimactane, in Rifamate, in Rifater), rosuvastatin (Crestor). Your doctor may need to change the doses of your medications or monitor you carefully for side effects. Many other medications may also interact with apalutamide, so be sure to tell your doctor about all the medications you are taking, even those that do not appear on this list.
• tell your doctor if you have or have ever had seizures, a brain injury, a brain tumor, a stroke or ministroke, or osteoporosis.
• you should know that apalutamide is only for use in men. Women should not take this medication, especially if they are or may become pregnant or are breastfeeding. If taken by pregnant women, apalutamide may harm the fetus. If a pregnant woman takes apalutamide, she should call her doctor immediately.
• if your partner is pregnant, you must use a condom whenever you have sex during your treatment with apalutamide and for three months after your final dose. If your partner is not pregnant but could become pregnant, you must use a condom and another form of birth control whenever you have sex during your treatment and for 3 months after your final dose. Do not donate semen or sperm while you are taking apalutamide and for 3 months after your final dose.
• you should know that apalutamide may cause seizures. Do not drive a car or operate machinery until you know how this medication affects you.
• you should know that apalutamide may cause your muscles and bones to get weak, which may increase your risk of falling and breaking a bone.

How should apalutamide be used?

Apalutamide comes as a tablet to take by mouth. It is usually taken with or without food once a day. Take apalutamide at around the same time every day. Follow the directions on your prescription label carefully, and ask your doctor or pharmacist to explain any part you do not understand. Take apalutamide exactly as directed. Do not take more or less of it or take it more often than prescribed by your doctor.

Swallow the tablets whole; do not split, chew, or crush them.

Your doctor may tell you to stop taking apalutamide for a short time or decrease your dose if you experience serious side effects during your treatment. Be sure to talk to your doctor about how you are feeling during your treatment with apalutamide.

If your doctor has prescribed another medication such as goserelin (Zoladex), histrelin (Supprelin LA, Vantas), leuprolide (Eligard, Lupron), or triptorelin (Trelstar) to treat your prostate cancer, you will need to continue receiving this medication during your treatment with apalutamide.

Continue to take apalutamide even if you feel well. Do not stop taking apalutamide without talking to your doctor.

Ask your pharmacist or doctor for a copy of the manufacturer’s information for the patient.

Apalutamide side effects

Apalutamide may cause side effects. Tell your doctor if any of these symptoms are severe or do not go away:

• weakness
• tiredness
• joint pain
• muscle weakness or stiffness
• diarrhea
• nausea
• loss of appetite
• weight loss
• hot flashes

Some side effects can be serious. If you experience any of these symptoms, call your doctor immediately or get emergency medical treatment:

• seizures
• loss of consciousness
• swelling of the arms, legs, hands, or feet
• falling
• rash

Apalutamide may cause other side effects. Call your doctor if you have any unusual problems while taking apalutamide.

Bicalutamide

Bicalutamide is a nonsteroidal antiandrogen similar in structure to flutamide that is used widely in the therapy of prostate cancer. Bicalutamide works by blocking the effect of androgen (a male hormone), to stop the growth and spread of prostate cancer cells. Bicalutamide is used with another medication (gonadotropin-releasing hormone (GnRH) agonists; such as leuprolide or goserelin) to treat metastatic prostate cancer (cancer that started in the prostate and has spread to other parts of the body).

Bicalutamide is an orally available nonsteroidal antiandrogen that is similar in structure to flutamide and nilutamide. Bicalutamide acts by binding to intracellular androgen receptors and competitively inhibiting the action of endogenous androgens on sensitive tissue, including testes, prostate, breast, skin and hypothalamus. Bicalutamide was approved for use in the United States in 1995. Current indications are for the therapy of prostate cancer in combination with luteinizing hormone releasing hormone (LHRH) analogs such as leuprolide or goserelin. Bicalutamide is available in tablets of 50 mg generically and under the trade name of Casodex. The recommended dose is 50 mg once daily.

Common side effects of bicalutamide include fatigue, drowsiness, anxiety, gynecomastia and loss of libido.

Bicalutamide special precautions

Before taking bicalutamide:

• tell your doctor and pharmacist if you are allergic to bicalutamide, any other medications, or any of the ingredients in bicalutamide tablets. Ask your pharmacist for a list of the ingredients.
• tell your doctor and pharmacist what other prescription and nonprescription medications, vitamins, nutritional supplements, and herbal products you are taking or plan to take. Be sure to mention any of the following: alprazolam (Xanax); anticoagulants (‘blood thinners’) such as warfarin (Coumadin); aripiprazole (Abilify); buspirone (Buspar); calcium channel blockers such as amlodipine (Norvasc), diltiazem (Cardizem, Dilacor, Tiazac), felodipine (Plendil), nifedipine (Adalat, Procardia), nisoldipine (Sular), and verapamil (Calan, Covera, Isoptin, Verelan); chlorpheniramine; cholesterol-lowering medications (statins) such as atorvastatin (Lipitor), lovastatin (Mevacor), and simvastatin (Zocor); clarithromycin (Biaxin); cyclosporine (Neoral, Sandimmune); diazepam (Valium); erythromycin (E.E.S., E-Mycin, Erythrocin); HIV protease inhibitors such as indinavir (Crixivan), ritonavir (Norvir), and saquinavir (Invirase, Fortovase); methadone (Dolophine); midazolam (Versed); pimozide (Orap); quinidine (Quinidex, Quinaglute); quinine; sildenafil (Viagra); tacrolimus (Prograf); tamoxifen (Nolvadex); telithromycin (Ketek); trazodone (Desyrel); triazolam (Halcion); and vincristine (Vincasar). Many other medications may also interact with bicalutamide, so be sure to tell your doctor about all the medications you are taking, even those that do not appear on this list.
• tell your doctor if you have or have ever had liver disease.
• you should know that bicalutamide is only for use in men. If taken by pregnant women, bicalutamide can cause abnormalities in the fetus. Women who are or may become pregnant should not take bicalutamide. If you take bicalutamide while you are pregnant, call your doctor immediately.

How should bicalutamide be used?

Bicalutamide comes as a tablet to take by mouth. It is usually taken with or without food once a day, either in the morning or evening. Take bicalutamide at around the same time every day. You should begin taking bicalutamide on the same day you begin injecting the luteinizing hormone-releasing hormone. Follow the directions on your prescription label carefully, and ask your doctor or pharmacist to explain any part you do not understand. Take bicalutamide exactly as directed. Do not take more or less of it or take it more often than prescribed by your doctor.

Bicalutamide along with the luteinizing hormone-releasing hormone may help stop the growth and spread of cancer cells but does not cure prostate cancer. Continue to take both bicalutamide and the luteinizing hormone-releasing hormone even if you feel better. Do not stop taking these medications without talking to your doctor.

Bicalutamide side effects

Bicalutamide may cause side effects. Tell your doctor if any of these symptoms are severe or do not go away:

• hot flashes or flushing
• bone, back, or pelvic pain
• muscle weakness
• muscle or joint pain
• headache
• shortness of breath
• increased blood pressure
• swelling of the hands, feet, ankles, or lower legs
• cough
• constipation
• nausea
• vomiting
• abdominal pain
• diarrhea
• gas
• change in weight (loss or gain)
• loss of appetite
• dizziness
• pain, burning, or tingling in the hands or feet
• difficulty sleeping
• feeling of uneasiness or dread
• rash
• sweating
• inability to get or keep an erection
• need to urinate frequently during the night
• bloody urine
• painful or difficult urination
• frequent and urgent need to urinate
• difficulty emptying bladder
• painful or swollen breasts

Some side effects can be serious. If you experience any of these symptoms, call your doctor immediately:

• yellowing of the skin or eyes
• pain in the upper right part of the stomach
• extreme tiredness
• unusual bleeding or bruising
• lack of energy
• upset stomach
• loss of appetite
• flu-like symptoms
• dull or sharp side pain
• chest pain

Bicalutamide may cause other side effects. Call your doctor if you have any unusual problems while taking bicalutamide.

Cyproterone

Cyproterone is a steroidal antiandrogen that has been used in the treatment of prostate cancer in many countries of the world, but not in the United States. Cyproterone blocks the effect of the male hormone testosterone in the body. This decreases the amount of testosterone produced in the body and is one way of treating this type of cancer.

Cyproterone is available only with your doctor’s prescription.

Cyproterone is a synthetic steroidal antiandrogen that has been used to treat prostate cancer in many countries of the world, but was never approved for this use in the United States. Cyproterone is a derivative of hydroxyprogesterone and has mild progesterone-like effects. Its mechanism of action, however, appears to be via blocking of the androgen receptor. Alone or when combined with other agents, cyproterone has been found to be palliative in patients with advanced prostate cancer. Cyproterone has also been evaluated for hormonally sensitive benign conditions such as endometriosis, precocious puberty and infertility, but has not been formally recommended for these uses. Because of its potential to cause liver injury and its inferior efficacy in comparison to other antiandrogens, cyproterone is now rarely used. The typical dose regimen is 50 to 100 mg two to three times daily, often in combination with a gonadotropin releasing hormone agonist such as leuprolide, goserelin, histrelin or triptorelin.

At first, cyproterone often causes loss of strength and energy or tiredness. However, these effects are lessened after about the third month of treatment and it is very important that you continue to receive this medication.

Cyproterone should not be discontinued even if improvement of the disease occurs.

Cyproterone common side effects include hot flashes, sexual dysfunction, nausea, diarrhea, weight change and fluid retention.

Cyproterone special precautions

It is very important that your doctor check your progress at regular visits. This will allow your doctor to see if the medicine is working properly and to decide if you should continue to take it.

Cyproterone may cause some people to become drowsy, dizzy, or less alert than they are normally. Make sure you know how you react to this medicine before you drive, use machines, or do anything else that could be dangerous if you are dizzy or are not alert.

Cyproterone may cause your skin to be more sensitive to sunlight than it is normally. Exposure to sunlight, even for brief periods of time, may cause a skin rash, itching, redness or other discoloration of the skin, or a severe sunburn. When you begin taking cyproterone:

• Stay out of direct sunlight, especially between the hours of 10:00 a.m. and 3:00 p.m., if possible.
• Wear protective clothing, including a hat. Also, wear sunglasses.
• Apply a sun block product that has a skin protection factor (SPF) of at least 15. Some patients may require a product with a higher SPF number, especially if they have a fair complexion. If you have any questions about this, check with your health care professional.
• Apply a sun block lipstick that has an SPF of at least 15 to protect your lips.
• Do not use a sunlamp or tanning bed or booth.

If you have a severe reaction from the sun, check with your doctor.

While you are taking cyproterone, be careful to limit the amount of alcohol you drink.

Cyproterone side effects

Check with your doctor as soon as possible if any of the following side effects occur:

Less common

• abdominal pain or tenderness
• agitation
• back pain
• black, tarry stools
• blisters on the skin
• bloody urine
• blurred vision
• chest pain
• chills
• clay-colored stools
• confusion
• cough
• dark urine
• decreased appetite
• decreased urine output
• difficulty swallowing
• dilated neck veins
• dizziness
• drowsiness
• dry mouth
• fainting or light-headedness when getting up from a lying or sitting position suddenly
• fast heartbeat
• fatigue
• fever
• flushed, dry skin
• fruit-like breath odor
• general feeling of discomfort or illness
• hallucinations
• headache, sudden and severe
• hives
• inability to speak
• increased blood pressure
• increased hunger
• increased thirst
• increased urination
• irregular breathing
• irregular heartbeat
• itching
• loss of consciousness
• lower back or side pain
• mood or mental changes
• nausea and vomiting
• painful or difficult urination
• pains in the chest, groin, or legs, especially the calves of legs
• puffiness or swelling of the eyelids or around the eyes, face, lips or tongue
• red, thickened, or scaly skin
• seizures
• shortness of breath
• skin rash
• slurred speech
• sore throat
• sores, ulcers, or white spots on the lips or in the mouth
• stiff neck
• stomachache
• sudden loss of coordination
• sweating
• swelling of the feet or lower legs
• swollen and/or painful glands
• temporary blindness
• tightness in the chest
• unexplained weight loss
• unusual bleeding or bruising
• vision changes
• weakness in the arm and/or leg on one side of the body, sudden and severe
• wheezing
• yellow eyes or skin

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

More common

• decreased interest in sexual intercourse
• inability to have or keep an erection
• increase in sexual ability, desire, drive, or performance
• increased interest in sexual intercourse
• loss in sexual ability, desire, drive, or performance
• swelling of the breasts or breast soreness in both females and males
• unexpected or excess milk flow from breasts

Less common

• bleeding, blistering, burning, coldness, or discoloration of the skin
• change in walking and balance
• clumsiness or unsteadiness
• hair loss
• inability to move legs or arms
• increased sensitivity of skin to sunlight
• increase in bowel movements
• loose stools
• loss of strength or energy
• muscle pain or weakness
• paralysis of one side of the body
• redness or other discoloration of the skin
• severe sunburn
• soft stools
• tiredness or weakness
• unusual increase in hair growth
• weight gain

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Enzalutamide

Enzalutamide is a nonsteroidal antiandrogen used to treat prostate cancer that has spread to other parts of the body in men who have not been helped by certain other medical and surgical treatments that decrease testosterone levels. Enzalutamide is in a class of medications called androgen receptor inhibitors. It works by blocking the effects of androgen (a male reproductive hormone) to stop the growth and spread of cancer cells.

Enzalutamide is an androgen receptor antagonist which binds to the intracellular receptor and prevents its translocation to the nucleus and subsequent DNA binding thereby blocking its activity. Therapy with enzalutamide has been shown to prolong relapse free as well as overall survival in men with metastatic, castration-resistant prostate cancer who had previously failed other forms of treatment. Enzalutamide was approved for use in the United States in 2012. Enzalutamide is available as capsules of 40 mg under the brand name Xtandi, and the typical dose is 160 mg by mouth once daily.

Enzalutamide common side effects include fatigue, diarrhea, anorexia, weight loss, constipation, joint and muscle pain, hot flushes, headaches, dizziness, and edema. Rare, but potentially serious side effects include seizures and posterior reversible encephalopathy.

Enzalutamide special precautions

Before taking enzalutamide:

• tell your doctor and pharmacist if you are allergic to enzalutamide, any other medications, or any of the ingredients in enzalutamide capsules. Ask your pharmacist or check the manufacturer’s information for the patient for a list of the ingredients.
• tell your doctor and pharmacist what prescription and nonprescription medications, vitamins, and nutritional supplements you are taking or plan to take. Be sure to mention any of the following: anticoagulants (‘blood thinners’) such as warfarin (Coumadin, Jantoven), carbamazepine (Carbatrol, Equetro, Tegretol), cyclosporine (Gengraf, Neoral, Sandimmune), dihydroergotamine (D.H.E. 45, Migranal), efavirenz (Sustiva, in Atripla), ergotamine (in Migergot, in Cafergot), fentanyl (Abstral, Actiq, Duragesic, others), gemfibrozil (Lopid), itraconazole (Onmel, Sporanox), omeprazole (Prilosec), midazolam, phenobarbital, phenytoin (Dilantin, Phenytek), pimozide (Orap), quinidine (in Nuedexta), rifabutin (Mycobutin), rifampin (Rimactane, in Rifamate, in Rifater), rifapentine (Priftin), sirolimus (Rapamune), and tacrolimus (Prograf). Your doctor may need to change the doses of your medications or monitor you carefully for side effects. Many other medications may also interact with enzalutamide, so be sure to tell your doctor about all the medications you are taking, even those that do not appear on this list.
• tell your doctor what herbal products you are taking, especially St. John’s wort.
• tell your doctor if you have or have ever had seizures, a brain injury, a brain tumor, a brain arteriovenous malformation (abnormal connection between arteries and veins in the brain that forms before birth and may cause bleeding in the brain), osteoporosis (a condition in which the bones become thin and weak and break easily), heart disease, or have had a stroke or ministroke.
• you should know that enzalutamide is only for use in men. Women should not take this medication, especially if they are or may become pregnant or are breast-feeding. Women, especially those who are or who may become pregnant should not touch enzalutamide capsules. If taken by pregnant women, enzalutamide may harm the fetus. If a pregnant woman takes enzalutamide, she should call her doctor immediately.
• you should know that this medication may decrease fertility in men. However, you should not assume that your female partner cannot become pregnant. If your partner is pregnant, you must use a condom whenever you have sex during your treatment with enzalutamide and for 3 months after your final dose. If your partner is not pregnant but could become pregnant, you must use a condom and another form of birth control whenever you have sex during your treatment and for 3 months after your final dose.
• if you are having surgery, including dental surgery, tell the doctor or dentist that you are taking enzalutamide.
• you should know that enzalutamide may cause seizures. Do not drive a car or operate machinery until you know how this medication affects you.

How should enzalutamide be used?

Enzalutamide comes as a capsule to take by mouth. It is usually taken with or without food once a day. Take enzalutamide at around the same time every day. Follow the directions on your prescription label carefully, and ask your doctor or pharmacist to explain any part you do not understand. Take enzalutamide exactly as directed. Do not take more or less of it or take it more often than prescribed by your doctor.

Swallow the capsules whole; do not chew, dissolve, or open them.

Do not allow other people to touch your capsules other than a caregiver. The capsules should especially not be handled by women who are pregnant or who can become pregnant.

Your doctor may tell you to stop taking enzalutamide for a short time or decrease your dose if you experience serious side effects during your treatment. Be sure to talk to your doctor about how you are feeling during your treatment with enzalutamide.

If your doctor has prescribed another medication such as degarelix (Firmagon), goserelin (Zoladex), histrelin (Supprelin LA, Vantas), leuprolide (Eligard, Lupron), or triptorelin (Trelstar) to treat your prostate cancer, you will need to continue receiving this medication during your treatment with enzalutamide.

Continue to take enzalutamide even if you feel well. Do not stop taking enzalutamide without talking to your doctor.

Ask your pharmacist or doctor for a copy of the manufacturer’s information for the patient.

Enzalutamide side effects

Enzalutamide may cause side effects. Tell your doctor if any of these symptoms are severe or do not go away:

• weakness
• tiredness
• joint pain
• muscle weakness or stiffness
• weight loss
• headache
• dizziness
• burning, numbness, or tingling in the arms, hands, or feet
• decreased sense of touch or ability to feel sensation
• hot flashes
• difficulty falling asleep or staying asleep
• anxiety
• difficulty remembering, thinking, or paying attention
• diarrhea
• itching
• dry skin
• nosebleeds
• frequent urination

Some side effects can be serious. If you experience any of these symptoms, call your doctor immediately or get emergency medical treatment:

• seizures
• headache; confusion; or vision changes
• swelling of the face, tongue, lips, throat, arms, legs, hands, or feet
• fever, cough, sore throat, or other signs of infection
• pain in the back and/or legs
• numbness or tingling in the buttocks or legs
• difficulty controlling urination or bowel movements
• difficulty breathing
• falling
• broken bones or fractures
• hallucinating (seeing things or hearing voices that do not exist)
• pink or red urine

Enzalutamide may cause other side effects. Call your doctor if you have any unusual problems while taking enzalutamide.

Flutamide

Flutamide is a nonsteroidal antiandrogen that acts by binding to and blocking intracellular androgen receptors in target tissues including testes, prostate, skin, and hair follicle. Flutamide is used together with a luteinizing hormone-releasing hormone agonist (LHRH; a type of hormonal injection such as leuprolide [Lupron, Eligard], goserelin [Zoladex], or triptorelin [Trelstar]) to treat certain types of prostate cancer. Flutamide is in a class of medications called nonsteroidal antiandrogens. It works by blocking the effects of androgen (a male hormone) to stop the growth and spread of cancer cells.

Flutamide is a synthetic, nonsteroidal antiandrogen that acts by competitive inhibition of the binding of testosterone and dihydrotestosterone to the intracellular androgen receptor, thus blocking the effects of endogenous androgen action. Flutamide was approved for use in therapy of prostate cancer in the United States in 1989 and has been extensively used around the world. Flutamide’s antiandrogen effects have also been applied to the therapy of hyperandrogenic states both in men and women, including acne, hirsutism and benign prostatic hypertrophy. Because of the potentially serious hepatotoxicity of flutamide, its use outside of therapy of malignant disease is not recommended. The current indications for flutamide are limited to the treatment of prostate cancer in combination with luteinizing hormone-releasing hormone (LHRH) agonists (luteinizing hormone releasing hormone analogue such as leuprolide or groselin). Flutamide is available in generic forms and under the brand name of Eulexin in 125 mg capsules. The usual dose is 250 mg two to three times daily, usually in combination with other antiprostate cancer modalities such as orchiectomy or an LHRH analog.

Common side effects of flutamide are rash, drowsiness, anxiety, gynecomastia and loss of libido.

Flutamide special precautions

Before taking flutamide:

• tell your doctor and pharmacist if you are allergic to flutamide or any other medications.
• tell your doctor and pharmacist what prescription and nonprescription medications, vitamins, nutritional supplements, and herbal products you are taking or plan to take. Be sure to mention anticoagulants (”blood thinners”) such as warfarin (Coumadin).
• tell your doctor if you smoke and if you have or have ever had any inherited blood diseases such as glucose-6-phosphate dehydrogenase (G-6-PD) deficiency or hemoglobin M disease.
• you should know that flutamide is only for use in men. If taken by pregnant women, flutamide can harm the fetus. Women who are or may become pregnant should not take flutamide. If you take flutamide while you are pregnant, call your doctor.
• ask your doctor about the safe use of alcoholic beverages while you are taking flutamide. Flutamide may cause facial flushing, and drinking alcohol can make it worse.

How should flutamide be used?

Flutamide comes as a capsule to take by mouth. It is usually taken with or without food every 8 hours (three times a day.) Take flutamide at around the same times every day. Follow the directions on your prescription label carefully, and ask your doctor or pharmacist to explain any part you do not understand. Take flutamide exactly as directed. Do not take more or less of it or take it more often than prescribed by your doctor.

Continue to take flutamide along with the LHRH agonist treatment even if you feel well. Do not stop taking either medication without talking to your doctor.

Ask your pharmacist or doctor for a copy of the manufacturer’s information for the patient.

Flutamide side effects

Flutamide may cause side effects. Tell your doctor if any of these symptoms are severe or do not go away:

• diarrhea
• nausea
• vomiting
• loss of appetite
• hot flashes
• decrease in sexual ability or desire
• breast enlargement in men
• drowsiness
• confusion
• depression
• anxiety
• swelling of the hands, feet, ankles, or lower legs
• blue-green or orange-colored urine

Symptoms of overdose may include:

• breast enlargement and tenderness

Some side effects can be serious. If you experience any of the symptoms listed in the IMPORTANT WARNING section, call your doctor immediately.

Although it is rare, some men taking flutamide have developed breast cancer. Talk to your doctor about the risks of taking this medication.

Flutamide may cause other side effects. Call your doctor if you have any unusual problems while taking flutamide.

Nilutamide

Nilutamide is an oral nonsteroidal antiandrogen similar in structure to flutamide that is used widely in the therapy of prostate cancer. Nilutamide is used after surgery to treat prostate cancer. Nilutamide works by blocking the effect of androgen (a male hormone), to stop the growth and spread of cancer cells.

Nilutamide is an anilide that blocks the binding of endogenous androgens to intracellular androgen receptors blocking their effects and is used to treat prostate cancer. Nilutamide has been shown to be effective in reducing pain and disease progression in metastatic prostate cancer when administered in conjunction with orchiectomy or other antiandrogen agents such as luteinizing hormone releasing hormone (LHRH) agonists. Nilutamide was approved for use in the United States in 1996. Current indications are limited to the therapy of metastatic prostate cancer in combination with orchiectomy. Nilutamide is available under the trade name Nilandron in 150 mg tablets, and the typical recommended dose is 300 mg daily starting at the time of orchiectomy with reduction of the dose to 150 mg daily one month later. Nilutamide is not approved for nor recommended for use in hyperandrogenic states such as hirsutism or acne.

Nilutamide common side effects include dizziness, impared vision, fatigue, nausea and anorexia.

Nilutamide special precautions

Before taking nilutamide:

• tell your doctor and pharmacist if you are allergic to nilutamide, bicalutamide, flutamide, or any other medications.
• tell your doctor and pharmacist what prescription and nonprescription medications, vitamins, nutritional supplements, and herbal products you are taking or plan to take. Be sure to mention any of the following: anticoagulants (‘blood thinners’) such as warfarin (Coumadin), phenytoin (Dilantin), and theophylline (Theo-Dur, Slo-Phyllin, others). Your doctor may need to change the doses of your medications or monitor you carefully for side effects.
• tell your doctor if you have or have ever had liver or lung disease.
  you should know that nilutamide is only for use in men. Women should not take nilutamide, especially if they are pregnant or could become pregnant or are breast-feeding. If a pregnant woman takes nilutamide, she should call her doctor.
• ask your doctor about the safe use of alcoholic beverages while you are taking nilutamide. Alcohol can make the side effects from nilutamide worse.
• you should know that you may have trouble seeing for a few seconds to a few minutes when you move from a lighted area to a dark area. You should be careful driving at night or through tunnels. Wearing tinted glasses may help your eyes adjust to changes in light while you are taking nilutamide.

How should nilutamide be used?

Nilutamide comes as a tablet to take by mouth. It is usually taken with or without food once daily. Take nilutamide at around the same time every day. Follow the directions on your prescription label carefully, and ask your doctor or pharmacist to explain any part you do not understand. Take nilutamide exactly as directed. Do not take more or less of it or take it more often than prescribed by your doctor.

You should begin taking nilutamide the day of or the day after your surgery. After about 30 days of treatment, your doctor will probably decrease your dose. The length of treatment depends on how well your body responds to nilutamide. Continue to take nilutamide even if you feel well. Do not stop taking nilutamide without talking to your doctor.

Nilutamide side effects

Nilutamide may cause side effects. Tell your doctor if any of these symptoms are severe or do not go away:

• constipation
• dizziness
• hot flashes
• visual changes

Some side effects can be serious. If you experience any of these symptoms, call your doctor immediately:

• yellowing of the skin or eyes
• nausea
• vomiting
• stomach pain
• pain in the upper right part of the stomach
• extreme tiredness
• loss of appetite
• flu-like symptoms
• dark urine

Nilutamide may cause other side effects. Call your doctor if you have any unusual problems while taking nilutamide.

1. BS DJHMB. Androgen Physiology, Pharmacology and Abuse. [Updated 2016 Dec 12]. In: Feingold KR, Anawalt B, Boyce A, et al., editors. Endotext [Internet]. South Dartmouth (MA): MDText.com, Inc.; 2000-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK279000
2. Quigley CA, DeBellis A, Marschke KB, El-Awady MK, Wilson EM, French FF (1995) Androgen receptor defects: historical, clinical and molecular perspectives. Endocrine Reviews. 16: 271-321
3. Gonzalez-Montelongo MC, Marin R, Gomez T, Diaz M (2010) Androgens are powerful non-genomic inducers of calcium sensitization in visceral smooth muscle. Steroids. 75(8-9): 533-8