Leuprorelin

Leuprorelin

Systematic (IUPAC) name
N-[1-[[1-[[1-[[1-[[1-[[1-[[5-(diaminomethylideneamino)-1- [2-(ethylcarbamoyl)pyrrolidin-1-yl]-1-oxo-pentan-2- yl]carbamoyl]-3-methyl-butyl]carbamoyl]-3-methyl- butyl]carbamoyl]-2-(4-hydroxyphenyl)ethyl] carbamoyl]-2-hydroxy-ethyl]carbamoyl]-2-(1H-indol-3- yl)ethyl]carbamoyl]-2-(3H-imidazol-4-yl)ethyl]-5-oxo- pyrrolidine-2-carboxamide
Clinical data
Trade names	Lupron
AHFS/Drugs.com	Consumer Drug Information
MedlinePlus	a685040
Pregnancy category	X
Legal status	℞ (Prescription only)
Routes of administration	Implant / Injection
Pharmacokinetic data
Biological half-life	3 hours
Excretion	Renal
Identifiers
CAS Number	53714-56-0 Y
ATC code	L02AE02 (WHO)
PubChem	CID: 441410
IUPHAR/BPS	1175
DrugBank	DB00007 Y
ChemSpider	571356
UNII	EFY6W0M8TG N
KEGG	D08113 Y
ChEMBL	CHEMBL1201199 N
Chemical data
Formula	C59H84N16O12
Molecular mass	1209.4 g/mol
SMILES CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(=N)N)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CC(C)C)NC(=O)[C@H](Cc2ccc(cc2)O)NC(=O)[C@H](CO)NC(=O)[C@H](Cc3c[nH]c4c3cccc4)NC(=O)[C@H](Cc5c[nH]cn5)NC(=O)[C@@H]6CCC(=O)N6
InChI InChI=1S/C59H84N16O12/c1-6-63-57(86)48-14-10-22-75(48)58(87)41(13-9-21-64-59(60)61)68-51(80)42(23-32(2)3)69-52(81)43(24-33(4)5)70-53(82)44(25-34-15-17-37(77)18-16-34)71-56(85)47(30-76)74-54(83)45(26-35-28-65-39-12-8-7-11-38(35)39)72-55(84)46(27-36-29-62-31-66-36)73-50(79)40-19-20-49(78)67-40/h7-8,11-12,15-18,28-29,31-33,40-48,65,76-77H,6,9-10,13-14,19-27,30H2,1-5H3,(H,62,66)(H,63,86)(H,67,78)(H,68,80)(H,69,81)(H,70,82)(H,71,85)(H,72,84)(H,73,79)(H,74,83)(H4,60,61,64)/t40-,41-,42-,43+,44-,45-,46-,47-,48-/m0/s1 Key:GFIJNRVAKGFPGQ-LIJARHBVSA-N
NY (what is this?)  (verify)

Leuprorelin (INN) or leuprolide acetate (USAN) is a GnRH analog marketed under the trade name Lupron. Originally marketed for the treatment of prostate cancer or breast cancer it is now being promoted as a "puberty blocker" for children and teenagers.

The drug is very controversial. It has been at the center of a major corruption scandal as the manufacturers were paying doctors in the USA to prescribe it unnecessarily. They were fined $875 million. This sheds light on the motivation of those who promote its use as a "puberty blocker" which could recoup their losses.

There has been concern expressed about suppressed clinical trial data. The drug has also been alleged to cause birth defects.

Damages Case

The New York Times reported that "A joint venture of Abbott Laboratories and Takeda Chemical Industries agreed yesterday to pay $875 million to settle criminal and civil charges that it had illegally manipulated the Medicare and Medicaid programs. The settlement against the joint venture, TAP Pharmaceutical Products, is the largest for health care fraud. Prosecutors contended that sales representatives for TAP gave doctors free samples of Lupron, a drug used to treat prostate cancer and infertility, and then helped them get government reimbursements at hundreds of dollars for each dose. Prosecutors also indicted six current and former employees of TAP -- including Alan MacKenzie, now the president of Takeda Pharmaceuticals North America -- charging them with conspiracy to pay kickbacks to doctors if they prescribed Lupron. The kickbacks included trips to resorts, medical equipment and money offered to the doctors as educational grants, prosecutors said. Takeda Pharmaceuticals is the American subsidiary of Takeda Chemical Industries of Japan. Abbott Laboratories is based in Abbott Park, Ill.

The investigation began more than four years ago after Douglas Durand, a former vice president for sales at TAP, and Dr. Joseph Gerstein, a urologist employed by the Tufts Associated Health Maintenance Organization in Waltham, Mass., separately told federal officials about what they believed were illegal sales practices on the part of TAP. After starting to work with federal investigators, Dr. Gerstein met with TAP sales representatives who offered him $65,000 in grants that they said he could use for any purpose if he would reverse his decision to have his health maintenance organization use only Zoladex, a less expensive drug that competes with Lupron. Dr. Gerstein, Mr. Durand and Tufts are to share roughly $95 million of the settlement for serving as whistleblowers under federal law. The settlement agreement, which had been expected for months, comes as other drug companies are under scrutiny for similar practices. Bristol-Myers Squibb and Schering-Plough have said they are being investigated by the same prosecutors in Boston who announced the settlement with TAP yesterday. Those investigations also involve questions about how the companies marketed and priced drugs covered by Medicare. Both companies said yesterday that they had done nothing wrong. Michael J. Sullivan, the United States attorney for Massachusetts, said at a news conference in Boston yesterday that the settlement and indictments sent a very strong signal to the pharmaceutical industry. These types of behavior are not tolerated, Mr. Sullivan said, and are going to be investigated, even if it takes four and a half years to bring to conclusion. The $875 million settlement is more than the $840 million paid last year by HCA-the Healthcare Company, the large hospital chain, to settle health care fraud charges. It is also more than TAP's sales of Lupron last year, which were about $800 million. Thomas Watkins, the president of TAP, which is based in Lake Forest, Ill., said yesterday that the joint venture fundamentally disagreed with most of the prosecution allegations, but had decided to settle the case because the government had threatened to stop all federal reimbursements for Lupron. Those reimbursements accounted for about $450 million of the drug's sales last year, he said. We could not afford to have this drug denied to our patients, he said. Mr. Watkins added that the availability, safety and effectiveness of Lupron was never a question in the case. He said that TAP admitted it provided free samples of Lupron to a number of physicians, primarily in the early to mid-1990's, knowing that the doctors would seek reimbursement from the federal government. The billing for free samples is wrong, and it should never have happened, Mr. Watkins said. We have taken strong action so that this inappropriate marketing practice will never happen again. Takeda Pharmaceuticals said that Mr. MacKenzie had decided to take a leave of absence from the company to focus on his defense against the government's charges. We fully support him in his belief that he will be exonerated, said Matt Kuhn, a Takeda spokesman, and we look forward to his return. Medicare now covers a very limited number of drugs. Most of them are products like Lupron, which must be administered by a physician. Pharmaceutical companies supply doctors with drugs to give Medicare patients, and Medicare then repays the doctors based on a price provided by the companies called the average wholesale price. The government charged TAP with inflating that price so that doctors could be reimbursed more than TAP actually charged them for the drug. The excessive government reimbursements were cited by sales representatives, the government said, as a way to get doctors to prescribe Lupron rather than its lower-priced competitor. In addition, since the government pays just 80 percent of the price of the drug, and patients pay the rest, prosecutors said that TAP had defrauded hundreds of elderly Medicare patients, mostly men suffering from prostate cancer, by inflating Lupron's average wholesale price. At least one lawsuit has been filed against TAP to recover the excessive payments by patients. The government has also charged five doctors with health care fraud in the case. Prosecutors said that those doctors had conspired with the company to receive excessive Medicare reimbursements. Four of those doctors were charged months ago and all have pleaded guilty to the charges. The fifth doctor was indicted yesterday. As part of yesterday's settlement, TAP also agreed to comply with a 33-page corporate integrity agreement. The document requires TAP to train its employees in the proper methods of promoting and marketing drugs covered by federal health programs. The agreement also requires TAP to accurately report its true average sales price for Lupron and other drugs to the Medicare and Medicaid programs. The company would be forced to pay a fine of $2,500 for each day it fails to comply with the agreement, which is effective for the next seven years. Charles S. Prouty, special agent in charge of the F.B.I. in New England, which was part of the investigation, said that other cases were still going forward and would result in very significant settlements. Medicare frauds, he said, are an insidious kind of white-collar crime, and we have made some serious inroads in attacking them.

Reported Side Effects

Among women who took Lupron to delay puberty or grow taller, most described depression and anxiety. Several recounted their struggles with suicidal urges. There is a Lupron survivor group which collects many personal testimonies. Cases include a tragic story of a young girl who killed herself after taking it as a puberty blocker.

"Sharissa Derricott, 30, had no idea why her body seemed to be failing. At 21, a surgeon replaced her deteriorated jaw joint. None of it made sense until she discovered women online who describe similar symptoms: All had taken a drug called Lupron." Another woman reported "My body was put into a state of menopause after receiving the injection of prescription drug Lupron."

Some people allege that the drug has caused them permanent disability.

For those who take it as a puberty blocker there is no guarantee that its effects are reversible.

Lupron Survivors Groups

There are several groups for people who have had negative experiences of Lupron. One is called the Lupron Victims Support Groups Online.

There is a National Lupron Victims Network.

There is also a Lupron Victims Hub.

2 Petitions to Release Suppressed Research

In 2016 there was an on petition to President Obama to lift the gag on unpublished research about Lupron and its side-effects. The text states "LUPRON is a powerful chemotherapy drug made only and specifically for palliative care during end-stage advanced prostate cancer. Patients are not expected to recover, even prior to taking LUPRON. The singular in-depth study, conducted by leading endometriosis specialist Dr. David Redwine, analyzes the so-called clinical trials that allowed for its current uses and therein debunks the manufacturer's safety and efficacy claims. Yet, the data used by Dr. Redwine has been gagged from publication and never been made available, allowing millions of women and children to be maimed, sickened and, even, put to death through the rampant misuse of LUPRON, largely based on fabricated clinical trials furnished to the manufacturer by several physicians.

LUPRON SURVIVORS need Dr. Redwine's work published!".

A second petition has been started in England in August 2018. Its text states, "This drug causes long term health issues."

Medical uses

An LH-RH (GnRH) analog, leuprorelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), to treat precocious puberty, and to control ovarian stimulation in In Vitro Fertilization (IVF). It is considered a possible treatment for paraphilias.

Leuprorelin has been tested as a treatment for reducing sexual urges in pedophiles and other cases of paraphilia.

As of 2006 leuprorelin was under investigation for possible use in the treatment of mild to moderate Alzheimer's disease.

It also used for treatment of steroid abuse.

Leuprorelin, along with triptorelin and goserelin, are often used to delay puberty in transgender youth until they are old enough to begin hormone replacement therapy. They are also sometimes used as superior alternatives to anti-androgens like spironolactone and cyproterone acetate for suppressing testosterone production in men who wish to pass as women.

Adverse effects

Common side effects of Lupron Injection include redness/burning/stinging/pain/bruising at the injection site, hot flashes (flushing), increased sweating, night sweats, tiredness, headache, upset stomach, nausea, diarrhea, constipation, stomach pain, breast swelling or tenderness, acne, joint/muscle aches or pain, trouble sleeping (insomnia), reduced sexual interest, vaginal discomfort/dryness/itching/discharge, vaginal bleeding, swelling of the ankles/feet, increased urination at night, dizziness, breakthrough bleeding in a female child during the first 2 months of leuprorelin treatment, weakness, chills, clammy skin, skin redness, itching, or scaling, testicle pain, impotence, depression, or memory problems.

Mechanism of action

Leuprorelin acts as an agonist at pituitary GnRH receptors. By interrupting the normal pulsatile stimulation of, and thus desensitizing, the GnRH receptors, it indirectly downregulates the secretion of gonadotropins luteinizing hormone (LH) and follicle-stimulating hormone (FSH), leading to hypogonadism and thus a dramatic reduction in estradiol and testosterone levels in both sexes.

Chemical properties

The peptide sequence is Pyr-His-Trp-Ser-Tyr-D-Leu-Leu-Arg-Pro-NHEt (Pyr = L-Pyroglutamyl).

History

Approvals

• Lupron Injection (5 mg/ml for daily subcutaneous injection) was first approved by the FDA for treatment of advanced prostate cancer on April 9, 1985.
• Lupron Depot (7.5 mg/vial for monthly intramuscular depot injection) was first approved by the FDA for palliative treatment of advanced prostate cancer on January 26, 1989, and subsequently in 22.5 mg/vial and 30 mg/vial for intramuscular depot injection every 3 and 4 months, respectively. 3.75 mg/vial and 11.25 mg/vial dosage forms were subsequently approved for subcutaneous depot injection every month and every 3 months, respectively for treatment of endometriosis or fibroids. 7.5 mg/vial, 11.25 mg/vial, and 15 mg/vial dosage forms were subsequently approved for subcutaneous depot injection for treatment of children with central precocious puberty.
• Viadur (72 mg yearly subcutaneous implant) was first approved by the FDA for palliative treatment of advanced prostate cancer on March 6, 2000. Bayer will fulfill orders until current supplies are depleted, expected by the end of April 2008
• Eligard (7.5 mg for monthly subcutaneous depot injection) was first approved by the FDA for palliative treatment of advanced prostate cancer on January 24, 2002, and subsequently in 22.5 mg, 30 mg, and 45 mg doses for subcutaneous depot injection every 3, 4, and 6 months, respectively.
• Leupromer® 7.5 ( 7.5 mg, One month depot for subcutaneous injection) is the second In-situ forming injectable drug in the world. It is used for palliative treatment of advanced prostate cancer, endometriosis and fibroids. It was approved by The Ministry of Health and Medical Education Of Iran.

Leuprorelin is marketed by Bayer AG under the brand name Viadur, by Tolmar under the brand name Eligard, and by TAP Pharmaceuticals (1985–2008), by Varian Darou Pajooh under the brand name Leupromer and Abbott Laboratories (2008-current) under the brand name Lupron. It is available as a slow-release implant or subcutaneous/intramuscular injection.

In the UK and Ireland, leuprorelin is marketed by Takeda UK as Prostap SR (one-month injection) and Prostap 3 (three-month injection).

Society and culture

"Lupron protocol"

A 2005 paper suggested leuprorelin as a possible treatment for autism, the hypothetical method of action being the now defunct hypothesis that autism is caused by mercury, with the additional unfounded assumption that mercury binds irreversibly to testosterone and therefore leuprorelin can help cure autism by lowering the testosterone levels and thereby mercury levels. However, used on children or adolescents it could cause disastrous and irreversible damage to sexual functioning, and there is no scientifically valid or reliable research to show its effectiveness in treating autism. This use has been termed the "Lupron protocol" and Mark Geier, the proponent of the hypothesis, has frequently been barred from testifying in vaccine-autism related cases on the grounds of not being sufficiently expert in that particular issue and has had his medical license revoked. Medical experts have referred to Geier's claims as "junk science".

Veterinary use

Leuprorelin has been used in two cases of ferrets with chronic adrenal disease, one with primary hyperaldosteronism, and one with hyperadrenocorticism

See also

• National Women's Health Network article on Lupron Depot from November & December 2008 - "Lupron - What Does It Do To Women's Health"

External links

• Lupron Injection (package insert from abbott)
• Reforming (purportedly) Non-Punitive Responses to Sexual Offending (journal article discussing use of Lupron as a form of reforming sex offender law)
• Lupron victims hub, website against use of this drug.