What Is Leuprolide (Lucrin)? FDA Approval, Licensing in Turkey, and Reimbursement

• FDA Approved: Yes (Initial approval: 1985)
• Active Ingredient: Leuprolide acetate
• Brand Name: In Turkey, Lucrin (Abbvie); in the United States, Lupron (the original product)
• Route of Administration: Subcutaneous (SC)
• Class: LHRH Agonist
• Category: Hormonal Agent
• Manufacturer: TAP Pharmaceuticals 
• Distribution in Turkey: AbbVie
• Cancers for Which It Is Approved: 
  • Advanced prostate cancer
  • Off-label use: Premenopausal early-stage and stage IV breast cancer

What Is Leuprolide Acetate?

Lucrin contains leuprolide acetate, an LHRH (luteinizing hormone-releasing hormone) agonist. It initially stimulates the pituitary gland to release gonadotropins and then suppresses that release. This mechanism lowers testosterone to castration levels. A decline in testosterone is observed 2–4 weeks after treatment begins.

FDA (United States Food and Drug Administration) Approval History

Leuprolide was first approved to treat advanced prostate cancer. Its use has expanded to other indications over time.

Licensing in Turkey

Therapeutic indications for which leuprolide is licensed in Turkey:

Leuprolide Acetate Injection:

• Prostate Cancer Suitable for Hormonal Intervention: Preferred in prostate cancer cases requiring hormonal treatment.
• Assisted Reproductive Techniques: Used for controlled ovarian stimulation.

Is It Reimbursed?

It is reimbursed for prostate cancer treatment in Turkey.

• Price: As of August 2024
  • Lucrin Depot IM/SC 3.75 mg costs 5713.94 ₺. 
  • Lucrin Depot IM/SC 11.25 mg costs 8965.63 ₺. 

Off-Label Uses Permitted Without Additional TİTCK Approval

• Metastatic Adenoid Cystic Carcinoma: Appropriate for treatment line 2 and beyond in androgen receptor-positive metastatic patients.
• Early-Stage Breast Cancer: Appropriate for use in premenopausal breast cancer.
• Stage IV Breast Cancer: Appropriate for use in premenopausal breast cancer.

Mechanism of Resistance

A temporary increase in LH and FSH release during treatment may cause transient side effects such as tumor growth (flare). Antiandrogen treatment is therefore recommended before starting therapy.

Absorption

Leuprolide is not absorbed orally. Following SC injection, 90% enters the systemic circulation.

Distribution

Its distribution has not been fully characterized. Peak serum concentration is reached within 10–15 days after injection. Plasma protein binding is 45–50%.

Metabolism

Leuprolide is metabolized by hydrolysis of its C-terminal amino acids. Most of the drug is excreted unchanged in urine (> 90%). Its elimination half-life is 3–4 hours. The half-life may be prolonged in patients with impaired kidney function.

Dosing Interval

• Standard dose: 11.25 mg SC every 3 months or 3.75 mg once a month.

Drug Interactions

No well-characterized drug interaction has yet been reported.

Precautions

• Risk of Tumor Flare: At the start of leuprolide treatment, a temporary increase in LH and FSH release may cause side effects related to tumor growth. This poses a particularly critical risk for the following patients:
  • Patients at Risk of Ureteral Obstruction: May cause obstruction of urine flow.
  • Patients with Spinal Cord Compression: The risk of severe pain and neurological complications due to spinal cord compression may increase.
  • Patients with Painful Bone Metastases: Tumor flare may increase pain in these patients.

To prevent this side effect, starting antiandrogen therapy at least 2 weeks before leuprolide treatment is recommended (for example, flutamide or bicalutamide).

• Decrease in Testosterone Levels: After leuprolide treatment begins, serum testosterone falls to castration levels within 2–4 weeks. Patients should be informed about side effects during this period.
• Impaired Kidney Function: Use cautiously in patients with impaired kidney function. The drug's elimination half-life may be prolonged in these patients, increasing the risk of side effects.
• Hot Flashes: Leuprolide may frequently cause hot flashes, particularly in premenopausal women and men receiving treatment for prostate cancer. The following options may be considered to prevent or treat this symptom:
  
  • Megestrol Acetate (20 mg orally, twice daily)
• Warnings for Specific Situations
  • Patients and their families should be informed about temporary tumor growth and related symptoms that may occur during treatment.
  • Pain associated with spinal cord compression or bone metastases may worsen when treatment begins. These patients should receive close clinical monitoring.
  • Measures should be taken to address other side effects during treatment, particularly hot flashes and hormonal changes.

Side Effects

Side effects have been reported in the following order, from most to least common:

1. Hot flashes: Sudden sensations of heat and episodes of sweating may occur during treatment.
2. Impotence and gynecomastia: Loss of sexual function and enlargement of breast tissue in men may occur.
3. Tumor flare (within the first 2 weeks): Temporary increases in pain and symptoms related to tumor growth may occur at the start of treatment.
4. Injection-site discomfort: Pain, redness, or swelling may occur where the medicine is administered.
5. Increased serum cholesterol levels: Blood lipid levels may rise, potentially increasing cardiovascular risks.
6. Nausea and vomiting: Gastrointestinal problems such as nausea and vomiting may occur while taking the medicine.
7. Allergic reactions: Skin rashes, itching, or serious allergic reactions may develop.
8. Peripheral edema (due to sodium retention): Swelling due to fluid accumulation may occur in the hands, feet, or body.
9. Asthenia: General weakness and fatigue have frequently been reported.