Darolutamide – Uses, Dosage, Side Effects, Interaction

Mechanism of Action

The actions of androgens on androgen receptors (AR) potentiate the growth and survival of prostate cancer cells. Darolutamide competitively inhibits androgens from binding to their receptors, inhibiting AR nuclear translocation, as well as AR-mediated transcription. The end result of these processes is a decrease in prostate cancer cell proliferation and tumor size. Its main metabolite, keto-darolutamide, shows similar pharmacological activity to the parent drug, darolutamide. Darolutamide has been found to bind more tightly to the AR receptor than [apalutamide] and [enzalutamide], which are other androgen receptor antagonists. Darolutamide can act as a progesterone receptor (PR) antagonist in the laboratory setting with approximately 1% activity when compared to its actions at the androgen receptor. The clinical relevance is not known at this time.

Indications

  • This drug is indicated for the treatment of patients diagnosed with non-metastatic and castrate-resistant prostate cancer.
  • Nubeqa is indicated for the treatment of adult men with non-metastatic castration-resistant prostate cancer (nmCRPC) who are at risk of developing metastatic disease.
  • Darolutamide is approved for use concurrently with a gonadotropin-releasing hormone (GnRH) agonist or antagonist or bilateral orchiectomy in the treatment of non-metastatic castration-resistant prostate cancer (nmCRPC) in men
  • Darolutamide, through its downstream effects on cancer cell growth, treats castrate-resistant prostate cancer. It inhibits cancer cell growth and markedly lowers prostate-specific antigen (PSA) levels through potent androgen receptor antagonism.
  • Darolutamide is an androgen receptor antagonist used for castration-resistant, non-metastatic prostate cancer and metastatic hormone-sensitive prostate cancer.
  • Metastatic Hormone Sensitive Prostate Cancer
  • Non-mestatatic castrate-resistant prostate cancer

Use in Cancer

Darolutamide is approved to treat:

  • Prostate cancer. It is used in adults whose cancer:
    • Has spread to other parts of the body and responds to treatment that lowers testosterone levels. It is used with docetaxel.
    • Has not spread to other parts of the body and no longer responds to treatment that lowers testosterone levels.

Darolutamide is also being studied in the treatment of other types of cancer.

Contraindications

  • excessive fat in the blood
  • a low seizure threshold
  • high blood pressure
  • coronary artery disease
  • seizures
  • pregnancy
  • chronic kidney disease stage 4 (severe)
  • Child-Pugh class B liver impairment

Dosage

Strengths: 300 mg

Prostate Cancer

  • 600 mg orally 2 times a day
  • Patients receiving this drug should also receive a gonadotropin-releasing hormone (GnRH) analog concurrently or should have had a bilateral orchiectomy.
  • For nonmetastatic castration-resistant prostate cancer (nmCRPC)

Renal Dose Adjustments

  • Mild to moderate renal impairment (CrCl 30 to 89 mL/min): No adjustment recommended.
  • Severe renal impairment (CrCl 15 to 29 mL/min) who are not receiving hemodialysis: 300 mg orally 2 times a da
  • End-stage renal disease (CrCl 15 mL/min or less): Data not available

Liver Dose Adjustments

  • Mild (Child-Pugh A) hepatic impairment: No adjustment recommended.
  • Moderate (Child-Pugh B) hepatic impairment: 300 mg orally 2 times daily
  • Severe (Child-Pugh C) hepatic impairment: Data not available

Dose Adjustments

  • Grade 3 or greater toxicity or an intolerable adverse reaction: Withhold therapy or reduce to the dose to 300 mg 2 times a day until symptoms improve; then resume therapy at 600 mg orally 2 times a day.
  • Dose reduction below 300 mg orally 2 times a day is not recommended.

Administration advice:

  • This drug should be taken with food.
  • Swallow tablets whole; do not divide, crush, or chew.
  • If a dose is missed it should be taken as soon as it is remembered prior to the next scheduled dose; do not take 2 doses together to make up for a missed dose.

Side Effects

The Most Common

  • extreme tiredness
  • arm, leg, hand, or foot pain
  • arm, leg, hand, or foot pain
  • rash
  • blood in urine
  • fever, rapid and/or shallow breathing, or cough
  • chest pain or feeling of pressure in the chest
  • seizures
  • severe ongoing nausea or diarrhea;
  • painful or difficult urination;
  • blood in your urine;
  • severe headache, blurred vision, pounding in your neck or ears;
  • slow heart rate, weak pulse, fainting, slow breathing (breathing may stop);
  • signs of a blood clot in the lung–chest pain, sudden cough, wheezing, rapid breathing, coughing up blood; or
  • signs of a lung infection–fever, chills, cough with mucus, chest pain, shortness of breath.

More common

  • Black, tarry stools
  • bleeding gums
  • blood in the urine
  • bloody nose
  • blurred vision
  • coughing or spitting up blood
  • difficulty in breathing or swallowing
  • dizziness
  • frequent urination
  • headache
  • increased menstrual flow or vaginal bleeding
  • lower abdominal or stomach cramping
  • nausea and vomiting
  • nervousness
  • nosebleeds
  • painful urination
  • paralysis
  • pounding in the ears
  • prolonged bleeding from cuts
  • red or dark brown urine
  • red or black, tarry stools
  • slow, fast, or irregular heartbeat
  • vomiting of blood or material that looks like coffee grounds
  • unusual bleeding or bruising

Rare

  • Blood in the urine
  • chest pain or discomfort
  • pain in the shoulders, arms, jaw, or neck
  • painful or difficult urination
  • seizures
  • sweating
  • trouble breathing
  • Constipation
  • decreased appetite
  • increased weight
  • pain in the arms or legs
  • rash
  • unusual tiredness or weakness
  • Chest pain or tightness
  • cough
  • fever or chills
  • muscle or bone pain
  • sneezing
  • sore throat

Drug Interaction

Pregnancy and Lactation

AU TGA pregnancy category: D
US FDA pregnancy category: Not assigned.

Pregnancy

The safety and efficacy of this drug have not been established in females. Based on its mechanism of action, this drug can cause fetal harm and loss of pregnancy. Advise male patients with female partners of reproductive potential to use effective contraception during therapy and for 1 week after. Based on animal studies, this drug may impair fertility in males of reproductive potential.

Lactation

There are no adequate studies in women for determining infant risk when using this medication during breastfeeding. Weigh the potential benefits against the potential risks before taking this medication while breastfeeding.

How should this medicine be used?

Darolutamide comes as a tablet to take by mouth. It is usually taken with food twice a day. Take darolutamide at around the same time(s) 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 darolutamide 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 darolutamide 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 darolutamide.

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 darolutamide.

Continue to take darolutamide even if you feel well. Do not stop taking darolutamide without talking to your doctor. Ask your pharmacist or doctor for a copy of the manufacturer’s information for the patient.

What special precautions should I follow?

Before taking darolutamide,

  • tell your doctor and pharmacist if you are allergic to darolutamide, any other medications, or any of the ingredients in darolutamide 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. Your doctor may need to change the doses of your medications or monitor you carefully for side effects.
  • tell your doctor what herbal products you are taking, especially St. John’s Wort.
  • tell your doctor if you have or have ever had kidney disease, liver disease, heart disease, high blood pressure, diabetes, high blood cholesterol or history of seizures.
  • you should know that darolutamide 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, darolutamide may harm the fetus. If a pregnant woman takes darolutamide, she should call her doctor immediately. If your female partner is not pregnant but could become pregnant, you and your partner must use birth control during your treatment and for 1 week after your final dose.
  • you should know that this medication may decrease fertility in men. However, you should not assume that your female partner cannot become pregnant during your treatment.

References

  1. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/212099Orig1s000lbl.pdf
  2. https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/212099s002lbl.pdf
  3. https://go.drugbank.com/drugs/DB12941
  4. https://en.wikipedia.org/wiki/Darolutamide
  5. https://pubchem.ncbi.nlm.nih.gov/compound/Darolutamide
  6. https://www.drugs.com/mtm/darolutamide.html
  7. https://www.mayoclinic.org/drugs-supplements/darolutamide-oral-route/side-effects/drg-20470011?p=1
  8. https://medlineplus.gov/druginfo/meds/a619045.html
  9. https://www.webmd.com/drugs/2/drug-177648/darolutamide-oral/details/list-contraindications
  10. ChemIDplus Chemical Information Classification
  11. CompTox Chemicals Dashboard Chemical Lists
  12. Guide to Pharmacology Target Classification
  13. NCI Thesaurus Tree
  14. PubChem
  15. Therapeutic category of drugs in Japan
    Anatomical Therapeutic Chemical (ATC) classification
    Target-based classification of drugs

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