Relugolix

Usage

• Relugolix is prescribed for the treatment of advanced prostate cancer in adult men.
• Pharmacological classification: Gonadotropin-releasing hormone (GnRH) receptor antagonist.
• Mechanism of Action: Relugolix works by binding to and blocking the GnRH receptors in the pituitary gland. This inhibits the release of luteinizing hormone (LH) and follicle-stimulating hormone (FSH), leading to a reduction in testosterone production in the testes. Lowering testosterone levels helps slow or stop the growth of prostate cancer cells.

Alternate Names

• International/Regional variations: The generic name is generally consistent internationally.
• Brand Name: Orgovyx.

How It Works

• Pharmacodynamics: Relugolix suppresses the hypothalamic-pituitary-gonadal (HPG) axis, leading to a significant decrease in serum testosterone levels. It achieves profound medical castration in most men.
• Pharmacokinetics:
  • Absorption: Relugolix is rapidly absorbed after oral administration, reaching peak plasma concentrations within 1-2 hours. Food does not significantly affect absorption.
  • Metabolism: Primarily metabolized by the liver, mainly via CYP3A4.
  • Elimination: Excreted in both urine and feces. The terminal half-life is approximately 27 hours.
• Mode of Action: Relugolix competitively binds to the GnRH receptors in the pituitary gland. This prevents the endogenous GnRH from stimulating LH and FSH release, resulting in decreased testosterone synthesis. It does not cause a testosterone surge, unlike GnRH agonists.
• Receptor Binding: GnRH receptor antagonist.
• Enzyme Inhibition/Neurotransmitter Modulation: Does not directly inhibit enzymes or modulate neurotransmitters in its primary mechanism of action, but its influence on testosterone levels indirectly affects multiple downstream pathways.
• Elimination Pathways: Hepatic metabolism (primarily CYP3A4), followed by excretion in urine and feces.

Dosage

Standard Dosage

Adults:

• Initial dose: 360 mg orally on day 1, followed by a maintenance dose of 120 mg orally once daily.
• Administration: Oral, with or without food, at approximately the same time each day.

Children:

• Not indicated for use in pediatric patients. Safety and efficacy have not been established.

Special Cases:

• Elderly Patients: No dose adjustment is generally required.
• Patients with Renal Impairment: Caution is advised in patients with severe renal impairment.
• Patients with Hepatic Dysfunction: Caution is recommended in patients with moderate or severe hepatic impairment.
• Patients with Comorbid Conditions: Use with caution in patients with long QT syndrome, cardiovascular disease, electrolyte abnormalities, or those taking medications that prolong the QTc interval.

Clinical Use Cases

Relugolix is specifically indicated for advanced prostate cancer and does not have clinical applications in settings like intubation, surgical procedures, mechanical ventilation, ICU use, or emergency situations.

Dosage Adjustments

• Concomitant P-gp Inhibitors: Avoid concomitant use. If unavoidable, adjust the timing of relugolix administration.
• Concomitant P-gp and Strong CYP3A Inducers: Avoid concomitant use. If unavoidable, adjust relugolix dose.

Side Effects

Common Side Effects:

• Hot flashes
• Fatigue
• Increased blood sugar
• Elevated cholesterol/triglycerides
• Decreased libido
• Erectile dysfunction
• Diarrhea/Constipation
• Musculoskeletal pain

Rare but Serious Side Effects:

• QT prolongation
• Allergic reactions (angioedema, anaphylaxis)
• Liver dysfunction

Long-Term Effects:

• Osteoporosis (bone loss)

Adverse Drug Reactions (ADR):

• QT prolongation
• Severe allergic reactions

Contraindications

• Hypersensitivity to relugolix
• Women, especially those pregnant or breastfeeding
• Use in pediatric patients

Drug Interactions

• P-gp inhibitors: Concomitant use can increase relugolix exposure.
• Combined P-gp and strong CYP3A inducers: Coadministration can decrease relugolix exposure.
• CYP3A4 inhibitors: May increase relugolix levels.
• CYP3A4 inducers: May decrease relugolix levels.
• Medications that prolong the QTc interval: Increased risk of QT prolongation when used concurrently.

Pregnancy and Breastfeeding

• Pregnancy Safety Category: X (contraindicated)
• Relugolix can cause fetal harm and pregnancy loss. Men with female partners of reproductive potential must use effective contraception during treatment and for 2 weeks after the last dose.
• Breastfeeding: Not indicated for use in lactating women. Unknown if relugolix is excreted in breast milk.

Drug Profile Summary

• Mechanism of Action: GnRH receptor antagonist, suppresses testosterone production.
• Side Effects: Hot flashes, fatigue, hyperglycemia, hyperlipidemia, decreased libido, erectile dysfunction, diarrhea/constipation, musculoskeletal pain. Serious side effects: QT prolongation, allergic reactions, liver dysfunction.
• Contraindications: Hypersensitivity, pregnancy/breastfeeding, pediatric use.
• Drug Interactions: P-gp inhibitors/inducers, CYP3A4 inhibitors/inducers, drugs that prolong the QTc interval.
• Pregnancy & Breastfeeding: Contraindicated in pregnancy. Not recommended during breastfeeding.
• Dosage: 360 mg loading dose followed by 120 mg daily.
• Monitoring Parameters: Testosterone levels, ECG (for QT prolongation), liver function tests, blood glucose, lipid panel.

Popular Combinations

Relugolix is typically used as monotherapy for advanced prostate cancer. Combination therapy may be considered in certain cases under specialist supervision.

Precautions

• General Precautions: Evaluate patients for cardiovascular risk factors, electrolyte abnormalities, and long QT syndrome before initiating therapy. Monitor liver function, blood glucose, and lipid profile.
• Specific Populations:
  • Pregnant Women: Contraindicated.
  • Breastfeeding Mothers: Not recommended.
  • Children & Elderly: Not recommended for children. Use with caution in elderly patients with severe renal impairment.
• Lifestyle Considerations: Encourage a healthy lifestyle, including regular exercise and a balanced diet. Advise patients to report any symptoms of QT prolongation, such as palpitations, dizziness, or syncope.

FAQs (Frequently Asked Questions)

Q1: What is the recommended dosage for Relugolix?

A: 360 mg loading dose on day 1, followed by 120 mg once daily.

Q2: How does Relugolix differ from GnRH agonists?

A: Relugolix does not cause a testosterone surge, unlike GnRH agonists.

Q3: What are the most common side effects?

A: Hot flashes, fatigue, hyperglycemia, hyperlipidemia, and decreased libido.

Q4: What are the serious side effects of Relugolix?

A: QT prolongation, severe allergic reactions, and liver dysfunction.

Q5: Can Relugolix be used in women?

A: No, relugolix is contraindicated in women, especially pregnant or breastfeeding women.

Q6: What are the drug interactions to be aware of with Relugolix?

A: P-gp inhibitors/inducers, strong CYP3A4 inducers, and drugs that prolong the QTc interval.

Q7: What monitoring is required during Relugolix treatment?

A: Testosterone levels, ECG (for QT prolongation), liver function tests, blood glucose, and lipid profile.

Q8: What precautions are necessary for patients with renal impairment?

A: Caution is advised in patients with severe renal impairment due to potential increased drug exposure.

Q9: Does food affect Relugolix absorption?

A: No, relugolix can be taken with or without food.

Q10: How should a missed dose of Relugolix be managed?

A: If a dose is missed within 12 hours of the scheduled time, take it as soon as possible. If more than 12 hours have passed, skip the missed dose and resume the regular dosing schedule. Do not double the dose.