Leuprorelin

Lupron "flare"

During the initial phase of luteinizing hormone-releasing hormone (LHRH) agonist therapy in male patients, there is a notable phenomenon known as the "flare." This occurs when testosterone levels temporarily surge by approximately 50% within the first 1 to 2 weeks of therapy. This increase is a response to the initial stimulation of luteinizing hormone (LH) by the LHRH agonist, leading to a rise in testosterone levels before they begin to decrease as intended. For individuals receiving LHRH agonists as part of gender-affirming care, this temporary increase in testosterone can be particularly distressing, exacerbating gender dysphoria and discomfort. To manage and mitigate these effects, healthcare providers often prescribe antiandrogens during this phase to help block the unwanted increase in testosterone and alleviate the associated distress.[24]

Mechanism of action

Leuprorelin is a gonadotropin-releasing hormone (GnRH) analogue acting as an agonist at pituitary GnRH receptors. GnRH receptor agonists initially increase the secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) by the anterior pituitary and increased serum estradiol and testosterone levels via the hypothalamic–pituitary–gonadal axis (HPG axis). However, normal functioning of this axis requires pulsatile release of GnRH from the hypothalamus. Continuous exposure to an agonist such as leuprorelin for several weeks causes pituitary GnRH receptors to become desensitised and no longer responsive (downregulation). This desensitisation is the objective of leuprorelin therapy because it ultimately reduces LH and FSH secretion, leading to hypogonadism and a dramatic reduction in estradiol and testosterone levels regardless of sex.[25][26]

Available forms

Leuprorelin is available in the following forms, among others:[27][28][29][30][31]

• Short-acting daily intramuscular injection (Lupron)[32]
• Long-acting depot intramuscular injection (Lupron Depot)[33][34][35][36]
• Long-acting depot subcutaneous injection (Eligard)
• Long-acting subcutaneous injection (Fensolvi)
• Long-acting subcutaneous implant (Viadur)
• Long-acting leuprolide mesylate (Camcevi) for the treatment of advanced prostate cancer.[37]
• Leuprolide acetate and norethindrone acetate co-packaged pack (Lupaneta Pack)[38][39]

Approvals

• Lupron injection was approved by the FDA for treatment of advanced prostate cancer on 9 April 1985.[42][32][40][41]
• Lupron depot for monthly intramuscular injection was approved by the FDA for palliative treatment of advanced prostate cancer on 26 January 1989.[33]
• Viadur was approved by the FDA for palliative treatment of advanced prostate cancer on 6 March 2000.
• Eligard was approved by the FDA for palliative treatment of advanced prostate cancer on 24 January 2002.
• Fensolvi was approved by the FDA for children with central precocious puberty on 4 May 2020.[43]

Legal status

On 24 March 2022, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Camcevi, intended for the treatment of the cancer of the prostate in adult men when the cancer is "hormone-dependent", which means that it responds to treatments that reduce the levels of the hormone testosterone. The applicant for this medicinal product is Accord Healthcare S.L.U.[44] Leuprorelin was approved for medical use in the European Union in May 2022.[4][45]

Names

Leuprorelin is the generic name of the drug and its INN and BAN, while leuprorelin acetate is its BANM and JAN, leuprolide acetate is its USAN and USP, leuprorelina is its DCIT, and leuproréline is its DCF.[46][47][48][49] It is also known by its developmental code names A-43818, Abbott-43818, DC-2-269, and TAP-144.[46][47][48][49]

Leuprorelin is marketed by Bayer AG under the brand name Viadur,[50] by Tolmar under the brand names Eligard and Fensolvi,[51][52] and by TAP Pharmaceuticals (1985–2008), by Varian Pharmed( Previously named Varian Darou Pajooh) under the brand name Leupromer and Abbott Laboratories (2008–present) under the brand name Lupron.

Legal history

In October 2001, the US Department of Justice, states attorneys general, and TAP Pharmaceutical Products, a subsidiary of Abbott Laboratories, settled criminal and civil charges against TAP related to federal and state medicare fraud and illegal marketing of the drug leuprorelin.[53] TAP paid a total of $875 million, which was a record high at the time.[54][55] The $875 million settlement broke down to $290 million for violating the Prescription Drug Marketing Act, $559.5 million to settle federal fraud charges for overcharging Medicare, and $25.5 million reimbursement to 50 states and Washington, D.C., for filing false claims with the states' Medicaid programs.[55] The case arose under the False Claims Act with claims filed by Douglas Durand, a former TAP vice president of sales, and Joseph Gerstein, a doctor at Tufts University's HMO practice.[54] Durand, Gerstein, and Tufts shared $95 million of the settlement.[54]

There have since been various suits concerning leuprorelin use, none successful.[56][57] They either concern the oversubscription of the drug or undue warning about the side effects. Between 2010 and 2013, the FDA updated the Lupron drug label to include new safety information on the risk of thromboembolism, loss of bone density and convulsions.[58] The FDA then asserted that the benefits of leuprorelin outweigh its risks when used according to its approved labeling. Since 2017, the FDA has been evaluating leuprorelin's connection to pain and discomfort in musculoskeletal and connective tissue.[59]