SYNONYM(S):

COMMON TRADE NAME(S): SUPREFACT®, SUPREFACT® DEPOT

CLASSIFICATION: hormonal agent, cytotoxic¹

Special pediatric considerations are noted when applicable, otherwise adult provisions apply.

MECHANISM OF ACTION:

Buserelin is a luteinizing hormone releasing hormone (LHRH) agonist. It is a synthetic analog of LHRH (also known as gonadotropin releasing hormone [GnRH]).² LHRH agonists (LHRHa) initially stimulate the release of luteinizing hormone (LH, gonadotropin), resulting in a transient elevation in serum androgen in men and serum estradiol in women. However, chronic administration can cause down-regulation of the LHRH receptors, thus inhibiting the secretion of LH and ultimately the sex hormones (androgen, estradiol). By decreasing the testicular production of androgen in men, LHRHa can inhibit the growth of androgen-dependent prostate cancer. Similarly, LHRHa reduce the ovarian secretion of estradiol and progesterone in women,³ leading to inhibition of estrogen-dependent cancers. In men, LHRHa can reduce serum androgen to castrate level about 21 days after initiation of therapy. Similarly, serum estradiol level is suppressed in women around 4 weeks after initiation of treatment. LHRHa are 50-100 times more potent than LHRH.⁴ In addition, they have a longer duration of action due to increased receptor affinity and greater biological stability.

PHARMACOKINETICS:

Adapted from standard reference⁶ unless specified otherwise.

USES:

*Health Canada approved indication

SPECIAL PRECAUTIONS:

Contraindications:

• history of hypersensitivity reaction to buserelin or any of its components,² other LHRHa, or LHRH¹⁰
• undiagnosed abnormal vaginal bleeding¹¹

Drug-induced disease flare: During the initial weeks of treatment, LHRHa may cause a worsening (flare) of the symptoms of prostate or breast cancer.¹⁰ Cases of spinal cord compression and/or ureteral obstruction have occurred in men with prostate cancer receiving LHRHa. These conditions require mandatory use of ketoconazole (NIZORAL®) (high dose) or anti-androgens, with LHRHa.¹² Administer with caution to patients at risk for developing these conditions; e.g., patients with vertebral metastases.¹³ For more information, see paragraph following Side Effects table.

Changes in bone density: Decreased bone mineral density (BMD) may occur with buserelin therapy.^2,13 Use with caution in patients with risk factors. For more information, see paragraph following Side Effects table.

Transient hypercalcemia may develop after initiation of LHRHa in patients with bone metastases.¹⁰

Male breast cancer: At time of writing, use of LHRHa in male breast cancer is considered experimental.^14,15

Carcinogenicity: Found to increase pituitary adenomas in rats treated with high doses of buserelin for durations >6 months.²

Mutagenicity: Not mutagenic in Ames test and mammalian in vitro mutation test.² No information found for clastogenicity.

Fertility: Ovulation is suppressed during treatment with buserelin.¹¹ Animal studies have shown decreased fertility in both males and females while receiving buserelin.

Pregnancy: Not available in the United States, therefore FDA Pregnancy Category has not been assigned. Buserelin is contraindicated in women who are pregnant, as it is not known if it can cause fetal abnormalities in humans.¹¹ Non-hormonal methods of birth control should be used during therapy.

Breastfeeding is not recommended due to the potential secretion into breast milk.¹¹

SIDE EFFECTS:

The table includes adverse events that presented during drug treatment but may not necessarily have a causal relationship with the drug. Because clinical trials are conducted under very specific conditions, the adverse event rates observed may not reflect the rates observed in clinical practice. Adverse events are generally included if they were reported in more than 1% of patients in the product monograph or pivotal trials, and/or determined to be clinically important.^16,17 When placebo-controlled trials are available, adverse events are included if the incidence is >5% higher in the treatment group.

Adapted from standard reference² unless specified otherwise.

BMD should be monitored, and calcium and vitamin D supplementation should be initiated. Lifestyle modification including regular exercise, particularly weight-bearing exercise (e.g., walking), should be encouraged. If treatment is required, consult current national guidelines^28,29 for specific recommendations. Options may include bisphosphonate therapy.²²

Drug-induced disease flare: New or worsening signs and symptoms of prostate or breast cancer may occur in the initial weeks of buserelin therapy.^10,30,31 The flare is a result of the buserelin-induced increase in androgen (in men) and estradiol (in women) during the initial weeks of therapy, prior to LHRH down-regulation.

In men, symptoms may include: acute exacerbation of bone pain, spinal cord compression⁵, urinary retention, urethral obstruction¹⁰, lymphedema.³² Blockage of flare in men can be achieved using anti-androgens (e.g., flutamide, bicalutamide, nilutamide, cyproterone) concurrent with the first administration of buserelin.^10,32 Flare is experienced significantly less frequently today due to the use of anti-androgens and the initiation of LHRHa earlier in the treatment of prostate cancer.

In women, symptoms may include^31,33: acute exacerbation of bone pain, skin erythema, increase in the size and/or number of metastatic skin nodules. There are currently no agents available to achieve blockage of flare in women.

Treatment of flare may include the use of analgesics for pain.

Vaginal bleeding, or breakthrough bleeding, may frequently occur during early buserelin therapy. The normal menstrual cycle consists of a follicular, or proliferative, phase and a luteal, or post-ovulatory, phase.^34,35 Increasing levels of estrogen in the follicular phase lead to maturation of the follicle and proliferation of the uterine mucosa, while decreasing levels of hormone in the luteal phase lead to sloughing of the endometrium (menses). At the initiation of therapy, menses may still occur as estrogen levels fall, particularly if treatment was started in the luteal phase of the menstrual cycle. It may also be possible that the initial buserelin-induced estrogen increase (flare) will induce the follicular phase of the menstrual cycle; again, menses will occur as estrogen levels fall. Therefore, one or two menses could be expected following the start of therapy. There is still potential for pregnancy to occur early after initiation.

INTERACTIONS:

No documented drug interactions.²

SUPPLY AND STORAGE:

Nasal solution¹¹: sanofi-aventis Canada Inc. supplies 1 mg/mL solution in a 10 mL bottle for intranasal administration and includes a metered-dose pump or nebulizer. Each pump action delivers 100 mcg buserelin or 0.1 mL solution. Store at room temperature in the original container; do not freeze; protect from light.

Injection: sanofi-aventis Canada Inc. supplies 3 products^2,11:

• 1 mg/mL in 5.5 mL multi-dose vials for subcutaneous administration. Selected non-medicinal ingredients: benzyl alcohol. Store at room temperature in the original container; do not freeze; protect from light.
• 6.3 mg (2-month) depot and 9.45 mg (3-month) depot for subcutaneous administration.² The 2-month depot contains 1 implantable dose consisting of 2 identical cylindrical rods. The 3-month depot contains 1 implantable dose consisting of 3 identical cylindrical rods. Both are available as a pre-filled syringe. Store at room temperature in the original container; protect from heat.

PARENTERAL ADMINISTRATION:

DOSAGE GUIDELINES:

Refer to protocol by which patient is being treated. Numerous dosing schedules exist and depend on disease, response and concomitant therapy. Guidelines for dosing also include consideration of absolute neutrophil count (ANC). Dosage may be delayed or discontinued in patients with bone marrow depression due to cytotoxic/radiation therapy or with other toxicities.

Adults:

Children: no information found for the use of buserelin in oncology

References:

1. B.C. Cancer Agency Provincial Systemic Therapy Program. Provincial Systemic Therapy Program Policy V-10: Cytotoxic Agents, Safe Handling Standards. Vancouver, British Columbia: BC Cancer Agency; 1 August 2000.

2. sanofi-aventis Canada Inc. SUPREFACT® DEPOT 2 months and SUPREFACT® DEPOT 3 months product monograph. Laval, Quebec; 26 April 2006.

3. Tyrrell JB, Findling JW, Aron DC. Hypothalamus and pituitary. In: Basic and Clinical Endocrinology. 4th ed. Norwalk, Connecticut: Appleton and Lange; 1994. p. 81-2.

4. Engel JB, Schally AV, Engel JB, et al. Drug Insight: clinical use of agonists and antagonists of luteinizing-hormone-releasing hormone. Nat Clin Pract Endocrinol Metab 2007;3(2):157-67.

5. Chabner BA, Longo DL. Cancer chemotherapy and biotherapy. 3rd ed. Philadelphia, Pennsylvania: Lippincott Williams & Wilkins; 2001. p. 95-7.

6. DRUGDEX Evaluations [database on the Internet]. Buserelin. Thomson MICROMEDEX®, 2007. Available from http://www.micromedex.com/ Accessed 2 April 2007.

7. DeVita VT, Hellman S, Rosenberg SA. Cancer Principles & Practice of Oncology. 6th ed. Philadelphia: Lippincott Williams & Wilkins; 2001. p. 483-4.

8. MARTINDALE- The Complete Drug Reference [database on the Internet]. Buserelin. Thomson MICROMEDEX®, 2007. Available from http://www.micromedex.com/ Accessed 2 April 2007.

9. B.C. Cancer Agency Breast Tumour Group. (BRAVLHRHT) BCCA Protocol Summary for Palliative Therapy for Breast Cancer Using LHRH agonist and Tamoxifen. Vancouver, British Columbia: BC Cancer Agency; 1 June 2006.

10. McEvoy GK, editor. AHFS 2006 Drug Information. Bethesda, Maryland: American Society of Health-System Pharmacists, Inc. p. 1064-6.

11. sanofi-aventis Canada Inc. SUPREFACT® product monograph; buserelin acetate injection; buserelin acetate nasal solution. Laval, Quebec; 8 May 2006.

12. Judy Sutherland, MD. BC Cancer Agency Genitourinary Tumour Group. Personal communication. Kelowna, British Columbia;16 June 2007.

13. AstraZeneca Canada Inc. ZOLADEX® product monograph. Mississauga, Ontario; 8 June 2004.

14. Giordano SH, Hortobagyi GN. Leuprolide Acetate Plus Aromatase Inhibition for Male Breast Cancer. J Clin Oncol 2006;24(21):42e-3.

15. Susan Ellard, MD. BC Cancer Agency Breast Tumour Group. Personal communication. Kelowna, British Columbia;25 June 2007.

16. Susan Ellard, MD. BC Cancer Agency Breast Tumour Group. Personal communication. Kelowna, British Columbia;10 May 2007.

17. Tom Pickles, MD. BC Cancer Agency Genitourinary Tumour Group. Personal communication. Vancouver, British Columbia;24 April 2007.

18. Keating NL, O'Malley AJ, Smith MR, et al. Diabetes and cardiovascular disease during androgen deprivation therapy for prostate cancer. J Clin Oncol 2006;24(27):4448-56.

19. B.C. Cancer Agency Provincial Systemic Therapy Program. Provincial Systemic Therapy Program Policy III-20: Prevention and management of extravasation of chemotherapy. Vancouver, British Columbia: BC Cancer Agency; 1 September 2006.

20. BC Cancer Agency. (SCNAUSEA) Guidelines for Prevention and Treatment of Chemotherapy-induced Nausea and Vomiting in Adults. Vancouver, British Columbia: BC Cancer Agency; 1 November 2005.

21. Smith MR, Lee WC, Brandman J, et al. Gonadotropin-releasing hormone agonists and fracture risk: a claims-based cohort study of men with nonmetastatic prostate cancer. J Clin Oncol 2005;23(31):7897-903.

22. Shahinian VB, Kuo YF, Freeman JL, et al. Risk of fracture after androgen deprivation for prostate cancer. N Engl J Med 2005;352(2):154-64.

23. Chabner BA, Longo DL. Cancer chemotherapy and biotherapy. 3rd ed. Philadelphia, Pennsylvania: Lippincott Williams & Wilkins; 2001. p. 116-7.

24. Mottet N, Prayer-Galetti T, Hammerer P, et al. Optimizing outcomes and quality of life in the hormonal treatment of prostate cancer. BJU International 2006;98(1):20-7.

25. Theriault RL. Strategies to prevent chemotherapy-induced bone loss in women with breast cancer. Clin Breast Cancer 2005;5 Suppl(2):S63-70.

26. Smith MR. Therapy Insight: osteoporosis during hormone therapy for prostate cancer. Nat Clin Pract Urol 2005;2(12):608-15; quiz 28.

27. Smith MR. Diagnosis and management of treatment-related osteoporosis in men with prostate carcinoma. Cancer 2003;97(3 Suppl):789-95.

28. Brown JP, Josse RG. 2002 clinical practice guidelines for the diagnosis and management of osteoporosis in Canada. CMAJ 2002;167(90100):1S-34.

29. B.C. Cancer Agency Genitourinary Tumour Group. Osteoporosis Screening Guidelines. Vancouver, British Columbia: BC Cancer Agency; 25 April 2007.

30. Emens LA, Davidson NE. Adjuvant Hormonal Therapy for Premenopausal Women with Breast Cancer. Clin Cancer Res 2003;9(1):486S-94.

31. Clarysse A. Hormone-induced Tumor Flare. Eur J Cancer Clin Oncol 1984;21(5):545-7.

32. Thompson I. Flare Associated with LHRH-Agonist Therapy. Rev Urol 2001;3 (Suppl 3 ):S10-S4.

33. Ellis M, Hayes DF. Endocrine Therapy of Metastatic Breast Cancer. In: Rose BD, editor. UpToDate. Waltham, Massachusetts: UpToDate 15.1; 11 April 2007.

34. Underwood JCE, editor. General and Systemic Pathology. 3rd ed. Edinburgh, London, New York, Philadelphia, St Louis, Sydney, Toronto: Churchill Livingstone; 2000. p. 330-40.

35. Koda-Kimble MA, Young LY, editor. Applied Therapeutics. 7th ed. Baltimore Maryland: Lippincott Williams & Wilkins; 2001. p. 43-2,3,4.

36. B.C. Cancer Agency Genitourinary Tumour Group. (GUPLHRH) BCCA Protocol Summary for Therapy for Prostate Cancer Using LHRH Agonist (Goserelin, Leuprolide or Buserelin). Vancouver, British Columbia: BC Cancer Agency; 1 February 2007.