Leuprolide

Today's med: Leuprolide (loo PROE lide)

(brand names: Eligard, Lupron Depot-Ped, Lupron Depot) Index term: Leuprolide Acetate

Drug Class: Antineoplastic agent, Gonadoptropin Releasing Hormone Agonist

Other Drugs in this class: Goserelin, Triptorelin, Nafarelin, Histrelin, Leuprolide acetate, Triptorelin Pamoate, Goserelin acetate, Nafarelin acetate, Histrelin acetate

Indications: Palliative treatment of advanced prostate cancer; management of endometriosis; treatment of anemia caused by uterine leiomyomata (fibroids); central precocious puberty

Use: Unlabeled: Treatment of breast cancer; infertility; treatment of paraphilia/hypersexuality

Action: Leuprolide, is an agonist of luteinizing hormone-releasing hormone (LHRH). Acting as a potent inhibitor of gonadotropin secretion; continuous administration results in suppression of ovarian and testicular steroidogenesis due to decreased levels of LH and FSH with subsequent decrease in testosterone (male) and estrogen (female) levels. In males, testosterone levels are reduced to below castrate levels. Leuprolide may also have a direct inhibitory effect on the testes, and act by a different mechanism not directly related to reduction in serum testosterone.

Following transient increase, testosterone suppression occurs in ~2-4 weeks of continued therapy

Contraindications:  Hypersensitivity to leuprolide, GnRH, GnRH-agonist analogs, or any component of the formulation; undiagnosed abnormal vaginal bleeding; pregnancy; breast-feeding.  Lupron Depot® 22.5 mg, 30 mg, and 45 mg are also not indicated for use in women

Adverse Effects: Children and Adults: Any formulations: Postmarketing and/or case reports (Limited to important or life-threatening): Anaphylactic/anaphylactoid reactions, asthmatic reactions, bone density decreased, coronary artery disease, diabetes; fibromyalgia-like symptoms (arthralgia/myalgia, headaches, GI distress); hemoptysis, hepatic dysfunction, hypokalemia, hypoproteinemia, injection site induration/abscess, interstitial lung disease, liver injury, MI, pelvic fibrosis, penile swelling, peripheral neuropathy, photosensitivity; pituitary apoplexy (cardiovascular collapse, mental status altered, ophthalmoplegia, sudden headache, visual changes, vomiting); prostate pain, pulmonary embolism, pulmonary infiltrate, seizure, spinal fracture/paralysis, stroke, suicidal ideation/attempt (rare), tenosynovitis-like symptoms, thrombocytopenia, transient ischemic attack, uric acid increased, WBC decreased/increased

>10%:

Cardiovascular: Edema (≤14%)

Central nervous system: Headache (≤65%), pain (<2% to 33%), depression (≤31%), insomnia (≤31%), fatigue (≤17%), dizziness/vertigo (≤16%)

Dermatologic: Skin reaction (≤12%)

Endocrine & metabolic: Hot flashes (25% to 98%), testicular atrophy (≤20%), hyperlipidemia (≤12%), libido decreased (≤11%)

Gastrointestinal: Nausea/vomiting (≤25%), bowel function altered (≤14%), weight gain/loss (≤13%)

Genitourinary: Vaginitis (11% to 28%), urinary disorder (13% to 15%)

Local: Injection site burning/stinging (transient: ≤35%)

Neuromuscular & skeletal: Weakness (≤18%), joint disorder (≤12%)

Miscellaneous: Flu-like syndrome (≤12%)

 

Adults: Note: For prostate cancer treatment, an initial rise in serum testosterone concentrations may cause “tumor flare” or worsening of symptoms, including bone pain, neuropathy, hematuria, or ureteral or bladder outlet obstruction during the first 2 weeks. Similarly, an initial increase in estradiol levels, with a temporary worsening of symptoms, may occur in women treated with leuprolide.

Lab Test Interferences: Interferes with pituitary gonadotropic and gonadal function tests during and up to 3 months after monthly administration of leuprolide therapy.

Standard Dosing: Children: Precocious puberty (consider discontinuing by age 11 for females and by age 12 for males):  I.M.:

Lupron Depot-Ped® (monthly):

≤25 kg: 7.5 mg every month

>25-37.5 kg: 11.25 mg every month

>37.5 kg: 15 mg every month

Titrate dose upward in increments of 3.75 mg every 4 weeks if down-regulation is not achieved.

Lupron Depot-Ped® (3 month): 11.25 mg or 30 mg every 12 weeks

SubQ (leuprolide acetate 5 mg/mL solution): Initial: 50 mcg/kg/day; titrate dose upward by 10 mcg/kg/day if down-regulation is not achieved. Note: Higher mg/kg doses may be required in younger children.

Adults:

Prostate cancer, advanced:

I.M.:

Lupron Depot® 7.5 mg (monthly): 7.5 mg every month or

Lupron Depot® 22.5 mg (3 month): 22.5 mg every 12 weeks or

Lupron Depot® 30 mg (4 month): 30 mg every 16 weeks or

Lupron Depot® 45 mg (6 month): 45 mg every 24 weeks

SubQ:

Eligard®: 7.5 mg monthly or 22.5 mg every 3 months or 30 mg every 4 months or 45 mg every 6 months

Leuprolide acetate 5 mg/mL solution: 1 mg/day

Endometriosis: I.M.: Initial therapy may be with leuprolide alone or in combination with norethindrone; if retreatment for an additional 6 months is necessary, concomitant norethindrone should be used. Retreatment is not recommended for longer than one additional 6-month course.

Lupron Depot®: 3.75 mg every month for up to 6 months or

Lupron Depot®-3 month: 11.25 mg every 3 months for up to 2 doses (6 months total duration of treatment)

Uterine leiomyomata (fibroids): I.M. (in combination with iron):

Lupron Depot®: 3.75 mg every month for up to 3 months or

Lupron Depot®-3 month: 11.25 mg as a single injection

Breast cancer, premenopausal ovarian ablation (unlabeled use): I.M.:

Lupron Depot®: 3.75 mg every 28 days for up to 24 months (Boccardo, 1999) or

Lupron Depot®-3 month: 11.25 mg every 3 months for up to 24 months (Boccardo, 1999; Schmid, 2007)

Adults: Males: Treatment of paraphilia/hypersexuality (unlabeled use; Guay, 2009; Reilly, 2000):

  Note: May cause an initial increase in androgen concentrations which may be treated with an antiandrogen (eg, flutamide, cyproterone) for 1-2 months (Guay, 2009). Avoid use in patients with osteoporosis or active pituitary pathology.

SubQ: Test dose: 1 mg (observe for hypersensitivity)

Depot I.M.: 3.75-7.5 mg monthly

 

Administration

I.M.: Lupron Depot®, Lupron Depot-Ped®: Administer as a single injection. Vary injection site periodically

SubQ:

Eligard®: Vary injection site; choose site with adequate subcutaneous tissue (eg, upper or mid-abdomen, upper buttocks); avoid areas that may be compressed or rubbed (eg, belt or waistband)

Leuprolide acetate 5 mg/mL solution: Vary injection site; if an alternate syringe from the syringe provided is required, insulin syringes should be used

Concerns related to adverse effects:

• Abnormal menses: Females treated for precocious puberty may experience menses or spotting during the first 2 months of treatment; notify healthcare provider if bleeding continues after the second month.

• Cardiovascular disease: Androgen-deprivation therapy (ADT) may increase the risk for cardiovascular disease (Levine, 2010). Sudden cardiac death and stroke have been reported in men receiving GnRH agonists. Long-term ADT may prolong the QT interval; consider the benefits of ADT versus the risk for QT prolongation in patients with a history of QT_c prolongation, with medications known to prolong the QT interval, or with pre-existing cardiac disease.

• Decreased bone density: Has been reported when used for ≥6 months. Use caution in patients with additional risk factors for bone loss (eg, chronic alcohol use, corticosteroid therapy).

• Endometriosis: Exacerbation of endometriosis or uterine leiomyomata may occur initially.

• Hyperglycemia: Diabetes and/or worsening of glycemic control have been reported in men receiving GnRH agonists.

• Pituitary apoplexy: Rare cases of pituitary apoplexy (frequently secondary to pituitary adenoma) have been observed with GnRH agonist administration (onset from 1 hour to usually <2 weeks); may present as sudden headache, vomiting, visual or mental status changes, and infrequently cardiovascular collapse; immediate medical attention required.

• Spinal cord compression: Has been reported when used for prostate cancer; closely observe patients for weakness and paresthesias in first few weeks of therapy. Observe patients with metastatic vertebral lesions closely.

• Tumor flare: Transient increases in testosterone (~50% above baseline) can lead to tumor flare, bone pain, hematuria, bladder outlet obstruction and neuropathy in prostate cancer patients during the first few weeks of therapy.

• Urinary tract obstruction: Has been reported when used for prostate cancer; closely observe patients for urinary tract obstruction and hematuria in first few weeks of therapy. Observe patients with urinary obstruction closely.

Disease-related concerns:

• Prostate cancer: Androgen deprivation therapy may increase the risk for cardiovascular disease, diabetes, insulin resistance, obesity, alterations in lipids, and fractures.

• Psychiatric illness: Use with caution in patients with a history of psychiatric illness; alteration in mood, memory impairment, and depression have been associated with use. 

Pregnancy Risk Factor

X

Pregnancy Considerations

Pregnancy must be excluded prior to the start of treatment. Although leuprolide usually inhibits ovulation and stops menstruation, contraception is not ensured and a nonhormonal contraceptive should be used. Fetal abnormalities and increased fetal mortality have been noted in animal studies.

 

Monitoring Parameters

Bone mineral density

Precocious puberty: GnRH testing (blood LH and FSH levels), measurement of height and bone age every 6-12 months, testosterone in males and estradiol in females (I.M. [monthly] and SubQ formulations: 1-2 months after initiation of therapy or with dosage change; I.M. [3 month] formulation: 2-3 months after initiation of therapy, month 6, and as clinically indicated thereafter); Tanner staging

Prostatic cancer: LH and FSH levels, serum testosterone (~4 weeks after initiation of therapy), PSA; weakness, paresthesias, and urinary tract obstruction in first few weeks of therapy. Screen for diabetes (blood glucose and Hb A_1c) and cardiovascular risk prior to initiating and periodically during treatment.

Treatment of paraphilia/hypersexuality (unlabeled use; Reilly, 2000): CBC (baseline, monthly for 4 months then every 6 months); serum testosterone (baseline, monthly for 4 months then every 6 months); serum LH (baseline and every 6 months), FSH (baseline), serum BUN and creatinine (baseline and every 6 months); bone density (baseline and yearly); ECG (baseline)

Drug interactions:  http://www.drugs.com/drug-interactions/leuprolide,lupron.html 

A total of 52 drugs (165 brand and generic names) are known to interact with Lupron (leuprolide).

• 52 moderate drug interactions (165 brand and generic names)

Show all medications in the database that may interact with Lupron (leuprolide).

Antidiabetic Agents: Luteinizing Hormone-Releasing Hormone Analogs may diminish the therapeutic effect of Antidiabetic Agents. Monitor therapy

IS BEING USED TO TREAT MENSTRUAL MIGRAINES!   

Links: http://www.ncbi.nlm.nih.gov/pubmed/9022620
http://www.ncbi.nlm.nih.gov/pubmed/12432971

Hormonal interventions for menstrual migraines.

Chavanu KJ, O'Donnell DC.

Source

Department of Pharmacy Practice, Chicago College of Pharmacy, Midwestern University, Downers Grove, Illinois 60515, USA.

Abstract

Menstrual migraines are a treatment challenge for both the migraineur and the health care professional. Although some women with menstrual migraines may respond to acute and preventive therapies for nonmenstrual migraines, others continue to suffer from refractory menstrual migraines. These women may respond to hormonal interventions, which may reduce the frequency of menstrual migraines, thereby lessening the need for abortive migraine therapies, decreasing migraine-related disability, and improving quality of life. Menstrual migraines have a distinct pathophysiology that differs from menstrual-related migraines. Published studies have shed light on the effectiveness of a variety of hormonal interventions, including oral contraceptives, which may be administered with an extended-dosing strategy; estrogen replacement therapy; selective estrogen receptor modifiers; danazol; and leuprolide.