Leuprorelin

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Leuprorelin or leuprolide acetate is a GnRH analog used in the treatment of prostate and breast cancer, endometriosis, uterine fibroids, precocious puberty and in in vitro fertilization (IVF)

Contents

[edit] BRAND NAMES

[edit] STRUCTURE

Pyr-His-Trp-Ser-Tyr-D-Leu-Leu-Arg-Pro-NHEt

Leuprorelin is a peptide consisting of nine aminoacids

[edit] MECHANISM OF ACTION

Leuprorelin is a synthetic nonapeptide analog of naturally occurring gonadotropin-releasing hormone [GnRH, also known as luteinizing hormone-releasing hormone (LHRH)] which posseses greater potency than natural hormone.

Normally, the hypothalamus controls the pituitary production of gonadotropins through secretion of GnRH. The hypothalamus releases GnRH in a pulsatile fashion every 90–120 min into the portal circulation connecting the hypothalamus and anterior pituitary. When the pulsatile GnRH binds to the gonadotropes in the anterior pituitary, it stimulates release of LH and FSH into the general circulation.

Leuprorelin acts like GnRH by binding to the gonadotropin releasing hormone receptor; following an initial stimulation of gonadotropins, chronic stimulation with Leuprorelin interrupt the normal pulsatile stimulation of GnRH receptors by GnRH, and thus desensitize the GnRH receptors and 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.

This causes the ovaries to enter a state of rest, putting the woman in a temporary “menopausal state” and, in males, androgens are reduced to castrate or pre-pubertal levels. These decreases occur within a month of initiating treatment and are maintained as long as treatment continues.

This effect is reversible on discontinuation of therapy.

[edit] INDICATIONS

  • Prostate Cancer:
    • Adjuvant treatment to radical prostatectomy in patients with locally advanced prostate cancer at high risk of disease progression
    • Adjuvant treatment to radiotherapy in patients with high-risk localised or locally advanced prostate cancer
    • Locally advanced prostate cancer as an alternative to surgical castration
    • Metastatic prostate cancer
  • Breast Cancer: Leuprorelin is used to reduce the risk of early-stage, hormone-receptor-positive breast cancer coming back in premenopausal women after surgery. Leuprorelin shut down the ovaries and stop them from producing estrogen so there is less estrogen to fuel the growth of hormone-receptor-positive breast cancer.
  • Uterine fibroids: Leuprorelin is indicated in the treatment of uterine fibroids to reduce their size and associated bleeding. Therapy may be preoperative prior to myomectomy or hysterectomy, or it may provide symptomatic relief for the perimenopausal woman who does not desire surgery. Leuprorelin can be used along with an iron supplement
  • Endometriosis: Leuprorelin is indicated for management of endometriosis, including pain relief and reduction of endometriotic lesions. It can be used as sole therapy or as an adjunct to surgery. Leuprorelin can be used along with norethindrone acetate 5 mg tablets (Lupaneta Pack Website), norethindrone is a progestin, it will help with hot flashes and bone loss associated with Leuprorelin.
  • To control ovarian stimulation in In Vitro Fertilization (IVF): Leuprorelin prevent the LH surge that occurs right before ovulation. This action helps prevent the premature release of the eggs before they can be harvested for assisted reproductive technologies.
  • Central precocious puberty (LUPRON DEPOT-PED): Treatment of children ( girls and boys) with central precocious puberty (CPP). CPP is defined as early onset of secondary sexual characteristics (generally earlier than 8 years of age in girls and 9 years of age in boys) associated with pubertal pituitary gonadotropin activation. Leuprorelin will delay the puberty process.

[edit] DOSAGE

  • Prostate Cancer
    • Depot formulations:
      • 3.75-7,5 mg administered every month as a single intramuscular or subcutaneous injection
      • 11.25-22,5 mg every 3 months as a single intramuscular or subcutaneous injection.
      • 30 mg every 4 months as a single intramuscular or subcutaneous injection
      • 45 mg every 6 months as a single intramuscular or subcutaneous injection
    • Implant (Viadur): The recommended dose is one implant (65 mg leuprolide) every 12 months. The implant is inserted subcutaneously in the inner aspect of the upper arm and provides continuous release of Leuprorelin for 12 months of hormonal therapy. The implant must be removed after 12 months of therapy. At the time an implant is removed, another implant may be inserted to continue therapy.

In prostate cancer anti-androgens are commonly used during the first weeks of GnRH agonist therapy in order to prevent the initial and temporary rise in serum testosterone (flare up effect)


  • Endometriosis
    • Depot formulations:
      • 3.75 mg administered as a single subcutaneous or intramuscular injection every month or
      • 11.25 every 3 months as a single intramuscular or subcutaneous injection.
        Treatment should be for a period of 6 months only and initiated during the first 5 days of the menstrual cycle.


  • Uterine Fibroids
    • Depot formulations:
      • 3.75 administered every month for up to 3 months as a single intramuscular or subcutaneous injection
      • 11.25 depot formulation only once as a single intramuscular or subcutaneous injection.


  • Breast Cancer
    • Depot formulations:
      • 3.75 administered every month as a single intramuscular or subcutaneous injection
      • 11.25 every 3 months as a single intramuscular or subcutaneous injection.
        Treatment should be for up to 24 months


  • Central precocious puberty (CPP)

7.5 mg, 11.25 mg, or 15 mg for 1-month administration: The starting dose will be dictated by the child's weight

Body Weight

Recommended Dose

≤ 25 kg

7.5 mg

> 25-37.5 kg

11.25 mg

> 37.5 kg

15 mg

If adequate hormonal and clinical suppression is not achieved with the starting dose, it should be increased to the next available higher dose (e.g. 11.25 mg or 15 mg at the next monthly injection). Hormonal and clinical parameters should be monitored after 1–2 months of initiating therapy and with each dose change to ensure adequate pituitary gonadotropin suppression. Once a dose that results in adequate hormonal suppression is found, it can often be maintained for the duration of therapy in most children. It is recommended, however, that adequate hormonal suppression be verified in such patients as weight can increase significantly while on therapy. Leuprorelin should be discontinued at the appropriate age of onset of puberty at the discretion of the physician.

[edit] CONTRAINDICATIONS

  • Endometriosis or Uterine Fibroids: Leuprorelin is contraindicated in case of Hypersensitivity to leuprorelin acetate or to other GnRH agonists, undiagnosed abnormal vaginal bleeding, in Women who are or may become pregnant and in women who are breast-feeding.
  • Children with central precocious puberty: Leuprorelin is contraindicated in case of Hypersensitivity to leuprorelin acetate or to other GnRH agonists, and in Women who are or may become pregnant
  • Prostate cancer: Leuprorelin is contraindicated in case of Hypersensitivity to leuprorelin acetate or to other GnRH agonists

[edit] PRECAUTIONS

  • For prostate cancer treatment:
    • Transient increase in serum levels of testosterone during treatment may result in worsening of symptoms or onset of new signs and symptoms during the first few weeks of treatment, including bone pain, neuropathy, and hematuria. Isolated cases of ureteral obstruction and spinal cord compression have been observed, which may contribute to paralysis with or without fatal complications. Patients with metastatic vertebral lesions and/or with urinary tract obstruction should be closely observed during the first few weeks of therapy.
    • Hyperglycemia and diabetes: Hyperglycemia and an increased risk of developing diabetes have been reported in men receiving GnRH analogs. blood glucose level should be monitered
    • Cardiovascular diseases: Increased risk of myocardial infarction, sudden cardiac death and stroke has been reported in men. Patients receiving a Leuprorelin should be monitored for symptoms and signs suggestive of development of cardiovascular disease and be managed according to current clinical practice.
    • Effect on QT/QTc Interval: Androgen deprivation therapy may prolong the QT interval. Consider risks in patients with congenital long QT syndrome, congestive heart failure, frequent electrolyte abnormalities, and in patients taking drugs known to prolong the QT interval. Electrolyte abnormalities should be corrected. Consider periodic monitoring of electrocardiograms and electrolytes.
    • Convulsions have been observed in patients with or without a history of predisposing factors.

[edit] INTERACTIONS

Drug interactions: because Leuprorelin is a peptide that is primarily degraded by peptidase and not by cytochrome P-450 enzymes as noted in specific studies, and the drug is only about 46% bound to plasma proteins, drug interactions would not be expected to occur.

[edit] PREGNANCY AND LACTATION

  • Pregnancy Category X (US). Leuprorelin may cause fetal harm when administered to a pregnant woman. It is contraindicated in women who are or may become pregnant. If Leuprorelin is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus and potential risk for pregnancy loss.
  • Nursing Mothers: It is not known if Leuprorelin is excreted in human milk. A decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

[edit] SIDE EFFECTS

Most common adverse reactions in clinical studies (incidence ≥5%) in men: Malaise, fatigue, hot flashes/sweats, and testicular atrophy.

As with other GnRH agonist, other adverse reactions, including decreased bone density and rare cases of pituitary apoplexy have been reported

In women Leuprorelin can cause menopause-like symptoms such as hot flashes, irritability, depression and vaginal dryness.

[edit] RELATED LINKS

Hormone Therapy for Prostate Cancer

[edit] BIBLIOGRAPHY

[edit] REFERENCES