Leuprorelin

Drug Approvals

(British Approved Name, rINN)

International Nonproprietary Names (INNs) in main languages (French, Latin, and Spanish): Leuprolide; Leuproreliini; Leuprorelina; Leuprorelinas; Leuproreline; Leuprorelinum.

5-Oxo-L-prolyl-L-histidyl-L-tryptophyl-L-seryl-L-tyrosyl-D-leucyl-L-leucyl-L-arginyl-N-ethyl-L-prolinamide.

C₅₉H₈₄N₁₆O_l2= 1209.4.

CAS — 53714-56-0.

ATC — L02AE02.

Pharmacopoeias. In Europe.

European Pharmacopoeia, 6th ed. (Leuprorelin). A synthetic nonapeptide analogue of the hypothalamic peptide gonadorelin. It is obtained by chemical synthesis and is available as an acetate. A white or almost white, hygroscopic, powder. Store in airtight containers at a temperature not exceeding 30°. Protect from light.

Leuprorelin Acetate

Drug Approvals

(British Approved Name Modified, rINNM)

INNs in main languages (French, Latin, and Spanish): Abbott-43818; Acetato de leuprorelina; Leuprolide Acetate (USAN); Leuproreliiniasetaatti; Leuprorelinacetat; Leuproreline, Acetate de; Leuprorelini Acetas; Loprorelin Asetat; TAP-144.

C₅₉H₈₄N_l6O_l2C₂H₄0₂ = 1269.5.

CAS — 74381-53-6.

ATC — L02AE02.

Pharmacopoeias. In US.

The United States Pharmacopeia 31, 2008 (Leuprolide Acetate). Store in airtight containers at a temperature not exceeding 30°.

Adverse Effects and Precautions

As for Gonadorelin. Thrombocytopenia and leucopenia have been reported rarely.

Benign intracranial hypertension

Increased intracranial pressure associated with leuprorelin treatment has been reported in a few isolated cases.

Effects on the eyes

Leuprorelin may be associated with blurred vision, usually lasting 1 to 2 hours after injection, but in rare instances longer. Haemorrhage or occlusion of intra-ocular blood vessels, ocular pain, and lid oedema have also been reported but the association is less well established.

Hypersensitivity

An anaphylactic reaction started within 5 minutes of the injection of a leuprorelin depot formulation in a patient with prostate cancer. Recurrent anaphylaxis developed in another patient given a depot injection of leuprorelin acetate for endometriosis, requiring both acute and chronic management.

Local reactions

Local reactions, including erythema, pain, induration, granulomas, and sterile abscess are particularly associated with depot injections of gonadorelin analogues such as leuprorelin and triptorelin they may also occur with subcutaneous daily injection. It has been suggested that the depot vehicle, a lactic acid-glycolic acid copolymer, may be responsible for many, although not all, such reactions.

Reactions are claimed to be more prevalent in children than in adults: an incidence of about 5% of patients has been suggested. Reactions are apparently idiosyncratic and may occur at any time during therapy, may be intermittent, or may never recur

Pituitary apoplexy

Pituitary apoplexy occurred shortly after the injection of a depot formulation of leuprorelin for the treatment of prostate cancer in 2 patients with occult pituitary adenomas. In a woman receiving leuprorelin daily in preparation for oocyte donation, symptoms began after the third dose. Signs and symptoms in these cases included headache, visual disturbances, generalised weakness, nausea and vomiting, and haem-orrhagic necrosis of themacroadenoma.

Interactions

As for Gonadorelin.

Pharmacokinetics

Leuprorelin acetate is not active when given orally but is well absorbed on subcutaneous or intramuscular injection. After a parenteral dose it has an elimination half-life of about 3 hours.

Uses and Administration

Leuprorelin is an analogue of gonadorelin with similar properties. Continuous administration is used for the suppression of gonadal sex hormone production in the treatment of malignant neoplasms ofthe prostate, in central precocious puberty, and in the management of endometriosis and uterine fibroids. It is also given before uterine surgery for endometrial reduction, and may be used in the treatment of breast cancer in premenopausal women. Leuprorelin is used as the acetate.

In the palliative treatment of advanced prostate cancer, leuprorelin acetate may be given by subcutaneous injection in a usual single daily dose of 1 mg. It is also given subcutaneously or intramuscularly as depot preparations but the dosage and route of these may differ between countries. In the USA, the dose is 7.5 mg monthly, 22.5 mg every 3 months, or 30 mg every 4 months, given subcutaneously or intramuscularly, depending on the preparation. A depot preparation of 45 mg given subcutaneously once every 6 months is also used. In the UK, leuprorelin acetate may also be used in advanced prostate cancer, as well as medical treatment of locally advanced cancer, as an adjuvant to surgery in locally advanced cancer at high risk of progression, or as an adjuvant to radiotherapy in high-risk localised or locally advanced disease.

A dose of 3.75 mg may be given once a month, by subcutaneous or intramuscular injection, or 11.25 mg may be given subcutaneously every 3 months. A nonbiodegradable titanium alloy implant, which is inserted subcutaneously into the inner part ofthe upper arm, is also available in the USA for advanced disease. It contains 72 mg of leuprorelin acetate and delivers the drug at a controlled rate of 120 micrograms daily. After 12 months it must be removed, but can be replaced by another implant to continue therapy. An anti-androgen such as cyproterone acetate may be given for several days before beginning leuprorelin therapy and continued for about 3 weeks, to avoid the risk of a disease flare.

For the management of endometriosis and uterine fibroids, leuprorelin acetate 3.75 mg monthly may be given as a single depot injection, intramuscularly or subcutaneously. Alternatively, 11.25 mg may be given as an intramuscular depot every 3 months. Treatment is begun during the first 5 days of the menstrual cycle, and may be continued for up to 6 months for endometriosis, while in women with anaemia due to uterine fibroids it is continued, with iron supplementation, usually for up to 3 months. To prepare for uterine surgery including endometrial ablation or resection, a single 3.75 mg depot injection may be given 5 to 6 weeks before the procedure, or monthly for 3 to 4 months before surgery for uterine fibroids.

In the management of central precocious puberty leuprorelin acetate has been given by intramuscular depot injection in a dose of 300 micrograms/kg every 4 weeks, adjusted according to response. Doses of 50 micrograms/kg daily by subcutaneous injection, adjusted according to response, have also been used. Leuprorelin acetate has also been given in other sex-hormone-related disorders.

Benign prostatic hyperplasia

For a discussion ofthe management of benign prostatic hyperplasia, including mention of the use of gonadorelin analogues and the view that they are unsatisfactory for indefinite therapy. References to the use of leuprorelin.

Disturbed behaviour

Leuprorelin has been used in the treatment of men with paraphilias. Case series have reported reductions in abnormal sexual thoughts and behaviours.

Endometriosis

Gonadorelin analogues are effective in the management of endometriosis but the need for long-term therapy to prevent recurrence limits their value because of the risk of osteoporosis ‘add-back’ hormone replacement therapy can be used to prevent this. References to the use of leuprorelin.

Fibroids

Gonadorelin analogues may be of some benefit as an adjunct or alternative to surgery in women with uterine fibroids, although there has been some concern that this might complicate the diagnosis of malignancy. References to the use of leuprorelin.

Hirsutism

The mainstay of drug treatment for hirsutism has been an anti-androgen, usually cyproterone acetate or spironolactone. Although gonadorelin analogues have been used, and are effective, they must be given parenterally or nasally and may produce menopausal effects, notably osteoporosis. References to the use of leuprorelin.

Infertility

Gonadorelin analogues are used in the treatment of infertility. References to the use of leuprorelin.

Malignant neoplasms

Gonadorelin analogues are used as an alternative to orchidectomy in the management of advanced malignant neoplasms of the prostate. Such therapy is as effective as orchidectomy in prolonging survival combination of leuprorelin or other gonadorelin analogues with nonsteroidal anti-androgens to produce maximal androgen blockade produces only modest additional benefit. Intermittent maximal androgen blockade is being studied in an attempt to improve results, and leuprorelin is also under investigation as neoadjuvant therapy in localised disease. Leuprorelin is also used for ovarian ablation in premenopausal women with breast cancer. There are also isolated reports of endometrial cancer, and ovarian cancer responding to leuprorelin, but the role of the gonadorelin analogues in these conditions is much less well established.

Precocious puberty

The gonadorelin analogues have replaced other agents as the drugs of choice for the treatment of central precocious puberty. References to the use of leuprorelin.

Premenstrual syndrome

For reference to the use of leuprorelin or other gonadorelin analogues (with HRT to prevent menopausal symptoms) in women unresponsive to other drug therapy, see under Gonadorelin.

Preparations

Proprietary Preparations

Argentina: Eligard Lectrum Lupron Reliser

Australia: Eligard Lucrin

Austria: Enantone Trenantone

Belgium: Depo-Eligard Lucrin

Brazil: Lectrum Lorelin Lupron Reliser

Canada: Eligard Lupron

Chile: Lupron

Czech Republic: Eligard Lucrin

Denmark: Enantonf Procren

Finland: Eligard Enanton Procren

France: Eligard Enantone Lucrin

Germany: Eligard Enantone Enantone-Gyn Trenantone Uno-Enantone

Greece: Daronda Elityran Leuprol

Hong Kong: Enantone Lorelin Lucrirr

Hungary: Eligard Lucrin

India: Lupride

Indonesia: Endrolin Lectrum Tapros

Ireland: Prostap

Israel: Lucrin

Italy: Enantone

Japan: Leuplin Lupron

Malaysia: Lucrin

Mexico: Lectrum Lorelin Lucrin Reliser

The Netherlands: Daronda Eligard Lucrin

Norway: Enanton Procren

New Zealand: Eligard Lucrin

Philippines: Luprolex

Poland: Eligard Lucrin Depot

Portugal: Eligard Lucrin

Russia: Lucrin

South Africa: Lucrin

Singapore: Lucrin

Spain: Eligard Ginecrin Procrin

Sweden: Eligard Enanton Procren

Switzerland: Eligard Lucrin

Thailand: Enantone

Turkey: Lucrin

UK: Prostap

USA: Eligard Lupron Viadur

Venezuela: Lupron Reliser

The symbol denotes a preparation no longer actively marketed.