Medically reviewed on Sep 10, 2018
(loo PROE lide)
- Leuprolide Acetate
- Leuprorelin Acetate
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Kit, Injection, as acetate:
Generic: 1 mg/0.2 mL
Kit, Intramuscular, as acetate:
Lupron Depot (1-Month): 7.5 mg [latex free; contains polysorbate 80]
Lupron Depot (6-Month): 45 mg [latex free; contains polysorbate 80]
Kit, Intramuscular, as acetate [preservative free]:
Lupron Depot (1-Month): 3.75 mg [latex free; contains polysorbate 80]
Lupron Depot (3-Month): 11.25 mg, 22.5 mg [latex free; contains polysorbate 80]
Lupron Depot (4-Month): 30 mg [latex free; contains polysorbate 80]
Lupron Depot-Ped (1-Month): 7.5 mg, 11.25 mg, 15 mg [latex free; contains polysorbate 80]
Lupron Depot-Ped (3-Month): 30 mg (Ped), 11.25 mg (Ped) [latex free; contains polysorbate 80]
Kit, Subcutaneous, as acetate:
Eligard: 7.5 mg, 22.5 mg, 30 mg, 45 mg
Brand Names: U.S.
- Lupron Depot (1-Month)
- Lupron Depot (3-Month)
- Lupron Depot (4-Month)
- Lupron Depot (6-Month)
- Lupron Depot-Ped (1-Month)
- Lupron Depot-Ped (3-Month)
- Antineoplastic Agent, Gonadotropin-Releasing Hormone Agonist
- Gonadotropin Releasing Hormone Agonist
Leuprolide, is an agonist of gonadotropin releasing hormone (GnRH) receptors. Acting as a potent inhibitor of gonadotropin secretion, leuprolide produces an initial increase in luteinizing hormone (LH) and follicle stimulating hormone (FSH), which leads to a transient increase (5 to 12 days [Cook 2000]) in testosterone and dihydrotestosterone (in males) and estrone and estradione (in premenopausal females). Continuous leuprolide administration then 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.
Males: Vd: 27 L
Major metabolite, pentapeptide (M-1)
Urine (<5% as parent and major metabolite)
Onset of Action
Onset of action: Following transient increase, testosterone suppression occurs in ~2 to 4 weeks of continued therapy
Onset of therapeutic suppression for precocious puberty: Leuprolide: 2 to 4 weeks; Leuprolide depot: 1 month
43% to 49%
Use: Labeled Indications
Central precocious puberty: Treatment of children with central precocious puberty (CPP). CPP is defined as early onset of secondary sexual characteristics (usually <8 years of age in girls and <9 years of age in boys) associated with pubertal pituitary gonadotropin activation; may have a significantly advanced bone age resulting in diminished adult height.
Limitations of use: Prior to treatment initiation, confirm clinical diagnosis of CPP with blood concentrations of luteinizing hormone (LH) (basal or stimulated with a gonadotropin-releasing hormone [GnRH] analog), sex steroids, and bone age assessment (versus chronological age). Baseline evaluations should include height and weight measurements, diagnostic brain imaging (to rule out intracranial tumor), pelvic/testicular/adrenal ultrasound (to rule out steroid-secreting tumors), human chorionic gonadotropin levels (to rule out a chorionic gonadotropin-secreting tumor), and adrenal steroid measurements (to exclude congenital adrenal hyperplasia).
Endometriosis: Management of endometriosis, including pain relief and reduction of endometriotic lesions. Initial management of endometriosis and symptom recurrence (in combination with norethindrone acetate as add-back therapy).
Limitations of use: Initial treatment (maximum 6 months) may be as monotherapy or combination therapy with norethindrone acetate (used as add-back therapy to reduce the loss of bone mineral density). A single retreatment course (maximum 6 months) of leuprolide in combination with norethindrone acetate may be considered if symptoms recur. Monotherapy is not recommended for retreatment. Total duration of therapy should not exceed 12 months.
Prostate cancer, advanced: Palliative treatment of advanced prostate cancer
Uterine leiomyomata (fibroids): Treatment (preoperative) of anemia caused by uterine leiomyomata (fibroids).
Limitations of use: For use in combination with supplemental iron in females with inadequate response to iron alone.
Off Label Uses
Breast cancer, premenopausal ovarian suppression
Data from a large randomized phase III trial, as well as from a smaller randomized study, support the use of leuprolide in premenopausal patients for ovarian suppression in the management of breast cancer [Boccardo 1999], [ Schmid 2007].
Guidelines from the American Society of Clinical Oncology (ASCO) for Endocrine Therapy in Hormone Receptor-Positive Metastatic Breast Cancer recommend that premenopausal women with ER-positive metastatic breast cancer start ovarian suppression, preferably in combination with hormonal therapy. While premenopausal patients without prior hormone therapy exposure can be treated with tamoxifen, or ovarian suppression, or ablation alone, combination therapy is preferred. In metastatic breast cancer, ovarian suppression with GnRH agonists or ablation with oophorectomy appear to achieve similar results.
The ASCO Guideline Update on Ovarian Suppression for Adjuvant Endocrine Therapy for Women With Hormone Receptor-Positive Breast Cancer recommends that premenopausal women with higher-risk disease receive ovarian suppression (in addition to adjuvant endocrine therapy) although lower-risk patients should not; premenopausal women with stage II or stage III breast cancers who would ordinarily be advised to receive adjuvant chemotherapy should also receive ovarian suppression (in addition to endocrine therapy). Additionally, women with stage I or II breast cancers at higher risk of recurrence who might consider chemotherapy may be offered ovarian suppression (in addition to endocrine therapy).
Clinical experience based on multiple clinical trials suggest that leuprolide may be useful in the treatment of paraphilia [Guay 2009], [Reilly 2000]. Additional trials may be necessary to further define the role of leuprolide in this condition.
Hypersensitivity to leuprolide, GnRH, GnRH-agonist analogs, or any component of the formulation; women who are or may become pregnant; breastfeeding (Lupron Depot 3.75 mg [monthly] and Lupron Depot 11.25 mg [3-month]); undiagnosed abnormal vaginal bleeding (Lupron Depot 3.75 mg [monthly] and Lupron Depot 11.25 mg [3-month]).
Lupron Depot 22.5 mg, 30 mg, and 45 mg and Eligard (all strengths) are also not indicated for use in women
Prostate cancer, advanced: Note: Treatment is usually continued after development of metastatic (castration-resistant) disease.
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
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 daily
Endometriosis: IM: Note: Total duration of therapy (initial plus re-treatment for symptom recurrence) should not exceed 12 months.
Initial therapy: May be used as monotherapy or in combination with norethindrone acetate.
Lupron Depot: 3.75 mg every month for up to 6 months or
Lupron Depot-3 month: 11.25 mg every 3 months for 1 to 2 doses (maximum 6 months)
Symptom recurrence: Administer in combination with norethindrone acetate.
Lupron Depot: 3.75 mg every month for up to 6 months or
Lupron Depot-3 month: 11.25 mg every 3 months for 1 to 2 doses (maximum 6 months)
Uterine leiomyomata (fibroids): IM (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 supression (off-label use): IM:
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)
Treatment of paraphilia/hypersexuality (off-label use; Guay 2009; Reilly 2000): Males: IM:
Note: Additional trials may be necessary to further define the role of leuprolide in this condition. May cause an initial increase in androgen concentrations which may be treated with an antiandrogen (eg, flutamide, cyproterone) for 1 to 2 months (Guay 2009). Avoid use in patients with osteoporosis or active pituitary pathology.
SubQ: Test dose: 1 mg (observe for hypersensitivity)
Depot IM: 3.75 to 7.5 mg monthly
Refer to adult dosing.
Precocious puberty (consider discontinuing by age 11 for females and by age 12 for males):
Lupron Depot-Ped (monthly):
≤25 kg: 7.5 mg every month
>25 to 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.
Dosing: Renal Impairment
There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied).
Dosing: Hepatic Impairment
There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied).
Eligard: Packaged in two syringes; one contains the Atrigel polymer system and the second contains leuprolide acetate powder; follow package instructions for mixing. Administer within 30 minutes of preparation (discard if not used within 30 minutes).
Lupron Depot, Lupron Depot-Ped: Reconstitute only with diluent provided. Administer within 2 hours of preparation (discard if not used within 2 hours).
Do not use concurrently a fractional dose of the 3-, 4-, or 6-month depot formulation, or a combination of doses of the monthly depot formulation or any depot formulation due to different release characteristics. Do not use a combination of syringes to achieve a particular dose.
IM: Lupron Depot, Lupron Depot-Ped: Administer as a single injection into the gluteal area, anterior thigh, or deltoid. Vary injection site periodically. Administer within 2 hours of preparation.
Eligard: Vary/rotate injection site; choose site with adequate subcutaneous tissue (eg, upper or mid-abdomen, upper buttocks) that does not have excessive pigment, nodules, lesions, or hair. Avoid areas with brawny or fibrous tissues or areas that may be compressed or rubbed (eg, belt or waistband). Administer within 30 minutes of preparation.
Leuprolide acetate 5 mg/mL solution: Vary injection site; if an alternate syringe from the syringe provided is required, insulin syringes should be used
Eligard: Store at 2°C to 8°C (36°F to 46°F). Allow to reach room temperature prior to using. Once outside the refrigerator, the kit may be stored (in its original packaging) at 15°C to 30°C (59°F to 86°F) for up to 8 weeks prior to mixing and administration. Once mixed, must be administered within 30 minutes (discard if not used within 30 minutes).
Lupron Depot, Lupron Depot-Ped: Store at room temperature of 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). Upon reconstitution, the suspension does not contain a preservative and should be used immediately; discard if not used within 2 hours.
Leuprolide acetate 5 mg/mL solution: Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). Protect from light and store vial in carton until use. Do not freeze.
Antidiabetic Agents: Hyperglycemia-Associated Agents may diminish the therapeutic effect of Antidiabetic Agents. Monitor therapy
Choline C 11: Luteinizing Hormone-Releasing Hormone Analogs may diminish the therapeutic effect of Choline C 11. Monitor therapy
Corifollitropin Alfa: Luteinizing Hormone-Releasing Hormone Analogs may enhance the therapeutic effect of Corifollitropin Alfa. Avoid combination
FLUoxetine: May enhance the QTc-prolonging effect of QTc-Prolonging Agents (Moderate Risk). Monitor therapy
Hydroxychloroquine: May enhance the QTc-prolonging effect of QTc-Prolonging Agents (Moderate Risk). Avoid combination
Indium 111 Capromab Pendetide: Luteinizing Hormone-Releasing Hormone Analogs may diminish the diagnostic effect of Indium 111 Capromab Pendetide. Avoid combination
Macimorelin: May enhance the QTc-prolonging effect of QTc-Prolonging Agents (Moderate Risk). Avoid combination
MiFEPRIStone: May enhance the QTc-prolonging effect of QTc-Prolonging Agents (Moderate Risk). Avoid combination
Probucol: May enhance the QTc-prolonging effect of QTc-Prolonging Agents (Moderate Risk). Avoid combination
Promazine: May enhance the QTc-prolonging effect of QTc-Prolonging Agents (Moderate Risk). Avoid combination
QTc-Prolonging Agents (Highest Risk): QTc-Prolonging Agents (Moderate Risk) may enhance the QTc-prolonging effect of QTc-Prolonging Agents (Highest Risk). Avoid combination
QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying): May enhance the QTc-prolonging effect of QTc-Prolonging Agents (Moderate Risk). Monitor therapy
QTc-Prolonging Agents (Moderate Risk): May enhance the QTc-prolonging effect of other QTc-Prolonging Agents (Moderate Risk). Management: Avoid such combinations when possible. Use should be accompanied by close monitoring for evidence of QT prolongation or other alterations of cardiac rhythm. Consider therapy modification
Vinflunine: May enhance the QTc-prolonging effect of QTc-Prolonging Agents (Moderate Risk). Avoid combination
Xipamide: May enhance the QTc-prolonging effect of QTc-Prolonging Agents (Moderate Risk). Monitor therapy
Interferes with pituitary gonadotropic and gonadal function tests during and up to 3 months after monthly administration of leuprolide therapy.
Children (percentages based on 1-month and 3-month pediatric formulations combined):
>10%: Local: Pain at injection site (≤20%)
2% to 10%:
Cardiovascular: Vasodilatation (2%)
Central nervous system: Emotional lability (5%), mood changes (5%), headache (3% to 5%), pain (3%)
Dermatologic: Acne vulgaris (3%), seborrhea (3%), skin rash (3% including erythema multiforme)
Endocrine & metabolic: Weight gain (≤7%)
Genitourinary: Vaginal discharge (3%), vaginal hemorrhage (3%), vaginitis (3%)
Local: Injection site reaction (≤9%)
<2%: Abnormal gait, alopecia, arthralgia, asthma, body odor, bradycardia, cervix disease, constipation, cough, decreased appetite, decreased visual acuity, depression, dizziness, drowsiness, dysmenorrhea, dyspepsia, dysphagia, epistaxis, excessive crying, feminization, fever, flu-like symptoms, gingivitis, goiter, growth suppression, gynecomastia, hirsutism, hyperhidrosis, hyperkinesia, hypersensitivity reaction, hypertension, increased appetite, infection, lacrimation, leukoderma, limb pain, musculoskeletal pain, myalgia, myopathy, nausea, nervousness, obesity, pallor, peripheral edema, personality disorder, pharyngitis, precocious puberty, purpura, rhinitis, sinusitis, skin striae, syncope, urinary incontinence, vomiting, weakness
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.
Delayed release formulations:
Cardiovascular: Edema (≤14%)
Central nervous system: Headache (≤65%), pain (<2% to 33%), depression (≤31%), insomnia (≤31%), fatigue (≤17%), dizziness (≤16%)
Dermatologic: Allergic skin reaction (≤12%)
Endocrine & metabolic: Hot flash (25% to 98%), weight changes (≤13%), hyperlipidemia (≤12%), decreased libido (≤11%)
Gastrointestinal: Nausea and vomiting (≤25%), gastrointestinal disease (14%), change in bowel habits (≤14%)
Genitourinary: Vaginitis (11% to 28%), testicular atrophy (≤20%), genitourinary complaint (13% to 15%)
Local: Burning sensation at injection site burning (transient: ≤35%)
Neuromuscular & skeletal: Weakness (≤18%), arthropathy (≤12%)
Respiratory: Flu-like symptoms (≤12%), respiratory tract disease (11%)
1% to 10% (limited to important or life-threatening):
Cardiovascular: Angina pectoris (<5%), atrial fibrillation (<5%), bradycardia (<5%), cardiac arrhythmia (<5%), cardiac failure (<5%), deep thrombophlebitis (<5%), hyper-/hypotension (<5%), palpitations (<5%), syncope (<5%), tachycardia (<5%)
Central nervous system: Nervousness (≤8%), paresthesia (≤8%), anxiety (≤6%), agitation (<5%), confusion (<5%), delusions (<5%), dementia (<5%), neuropathy (<5%), paralysis (<5%), seizure (<5%), ostealgia (<2%)
Dermatologic: Acne vulgaris (≤10%), alopecia (≤5%), diaphoresis (≤5%), cellulitis (<5%), hair disease (<5%), pruritus (≤3%), skin rash (≤2%)
Endocrine & metabolic: Dehydration (≤8%), gynecomastia (≤7%), decreased serum bicarbonate (≥5%), hypercholesterolemia (≥5%), hyperglycemia (≥5%), hyperphosphatemia (≥5%), hyperuricemia (≥5%), hypoalbuminemia (≥5%), hypocholesterolemia (≥5%), hypoproteinemia (≥5%), increased lactate dehydrogenase (≥5%), increased prostatic acid phosphatase (≥5%), menstrual disorder (≤2%), hirsutism (<2%)
Gastrointestinal: Anorexia (<5%), dysphagia (<5%), eructation (<5%), gastric ulcer (<5%), gastrointestinal hemorrhage (<5%), intestinal obstruction (<5%), peptic ulcer (<5%), constipation (≤3%), gastroenteritis (≤3%), diarrhea (≤2%)
Genitourinary: Mastalgia (≤6%), impotence (≤5%), balanitis (<5%), breast hypertrophy (<5%), lactation (<5%), penile disease (<5%), testicular disease (<5%), urinary incontinence (<5%), urinary tract infection (<5%), nocturia (≤4%), testicular pain (≤4%), dysuria (≤2%), bladder spasm (<2%), erectile dysfunction (<2%), hematuria (<2%), urinary retention (<2%), urinary urgency (<2%)
Hematologic & oncologic: Change in platelet count (increased; ≥5%), decreased prostatic acid phosphatase (≥5%), eosinophilia (≥5%), leukopenia (≥5%), bruise (≤5%), ecchymoses (<5%), lymphadenopathy (<5%), neoplasm (<5%), anemia, decreased hematocrit, decreased hemoglobin
Hepatic: Abnormal hepatic function tests (≥5%), increased serum AST (≥5%), prolonged partial thromboplastin time (≥5%), prolonged prothrombin time (≥5%), hepatomegaly (<5%)
Hypersensitivity: Hypersensitivity reaction (<5%)
Infection: Infection (5%)
Local: Pain at injection site (2% to 5%), injection site reaction (<5%), erythema at injection site (1% to 3%)
Neuromuscular & skeletal: Myalgia (≤8%), neuromuscular disease (<5%), pathological fracture (<5%), arthralgia (≤1%)
Renal: Decreased urine specific gravity (≥5%), increased blood urea nitrogen (≥5%), increased serum creatinine (≥5%), increased urine specific gravity (≥5%), polyuria (2% to 4%)
Respiratory: Emphysema (<5%), epistaxis (<5%), hemoptysis (<5%), increased bronchial secretions (<5%), pleural effusion (<5%), pulmonary edema (<5%), dyspnea (≤2%), cough (≤1%)
Miscellaneous: Fever (<5%)
Immediate release formulation:
Cardiovascular: ECG changes (19%), peripheral edema (12%)
Central nervous system: Pain (13%)
Endocrine & metabolic: Hot flash (55%)
1% to 10% (limited to important or life-threatening):
Cardiovascular: Hypertension (8%), heart murmur (3%), thrombophlebitis (2%), cardiac failure (1%), angina pectoris, cardiac arrhythmia, myocardial infarction, pulmonary embolism, syncope
Central nervous system: Headache (7%), insomnia (7%), dizziness (5%), ostealgia (5%), anxiety, depression, fatigue, fever, nervousness, peripheral neuropathy
Dermatologic: Dermatitis (5%), alopecia, hyperpigmentation, pruritus, skin lesion
Endocrine & metabolic: Decreased libido, diabetes mellitus, goiter, gynecomastia, hypercalcemia, hypoglycemia
Gastrointestinal: Constipation (7%), anorexia (6%), nausea and vomiting (5%), diarrhea, dysphagia, gastrointestinal hemorrhage, peptic ulcer, rectal polyps
Genitourinary: Decreased testicular size (7%), hematuria (6%), urinary frequency (6%), impotence (4%), urinary tract infection (3%), bladder spasm, dysuria, incontinence, mastalgia, testicular pain, urinary tract obstruction
Hematologic & oncologic: Anemia (5%), bruise
Local: Injection site reaction
Neuromuscular & skeletal: Weakness (10%)
Ophthalmic: Blurred vision
Renal: Increased blood urea nitrogen, increased serum creatinine
Respiratory: Dyspnea (2%), cough, pneumonia, pulmonary fibrosis
Miscellaneous: Fever, inflammation
Children and Adults: Any formulations: Postmarketing and/or case reports: Abdominal pain, abscess at injection site, anaphylaxis, anaphylactoid reaction, asthma, bone fracture (spine), cerebrovascular accident, convulsions, coronary artery disease, decreased white blood cell count, diabetes mellitus, fibromyalgia syndrome (arthralgia/myalgia, headaches, GI distress), flushing, hemoptysis, hepatic injury, hepatic insufficiency, hepatotoxicity, hyperuricemia, hypokalemia, hypoproteinemia, induration at injection site, interstitial pulmonary disease, leukocytosis, myocardial infarction, osteopenia, paralysis, penile swelling, peripheral neuropathy, pituitary apoplexy (cardiovascular collapse, mental status altered, ophthalmoplegia, sudden headache, visual changes, vomiting), prolonged QT interval on ECG, prostate pain, pulmonary embolism, pulmonary infiltrates, retroperitoneal fibrosis (pelvic), seizure, skin photosensitivity, suicidal ideation (rare), tenosynovitis (symptoms), thrombocytopenia, transient ischemic attacks, urticaria
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 health care provider if bleeding continues after the second month.
• Allergic reactions: Anaphylactoid reactions and asthma exacerbations have been reported with therapy in patients with histories of asthma, sinusitis, or environmental or drug allergies.
• Cardiovascular effects: 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. ADT may prolong the QT/QTc interval; consider the benefits of ADT versus the risk for QT prolongation in patients with a history of QTc prolongation, congenital long QT syndrome, heart failure, frequent electrolyte abnormalities, and in patients with medications known to prolong the QT interval, or with preexisting cardiac disease. Consider periodic monitoring of electrocardiograms and electrolytes in at-risk patients.
• 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 or tobacco use, strong family history of osteoporosis, and chronic therapy that may decrease BMD such as corticosteroid or anticonvulsant therapy).
• Endometriosis: Due to the physiologic effects of the drug, exacerbation of endometriosis symptoms may occur after the first dose of leuprolide.
• Hyperglycemia: Diabetes and/or worsening of glycemic control have been reported in men receiving GnRH agonists. Monitor blood glucose and/or glycosylated hemoglobin (HbA1c) as clinically necessary.
• 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.
• Psychiatric events: Psychiatric events have been described with GnRH agonists, including leuprolide; symptoms of emotional lability, irritability, impatience, anger, and aggression have been reported in postmarketing accounts. Monitor for development or worsening of psychiatric symptoms. Use with caution in patients with a history of psychiatric illness.
• Seizures: Convulsions have been observed in postmarketing reports in patients receiving GnRH agonists, including leuprolide; patients affected included both those with and without a history of cerebrovascular disorders, CNS anomalies or tumors, epilepsy, seizures, and those on concomitant medications which may lower the seizure threshold (eg, bupropion, SSRIs). If seizures occur, manage accordingly.
• 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.
• Depression: Use with caution in patients with depression. Depression may occur or worsen during norethindrone acetate therapy; discontinue if serious depression recurs.
• Prostate cancer: Androgen deprivation therapy may increase the risk for cardiovascular disease, diabetes, insulin resistance, obesity, alterations in lipids, and fractures.
• Uterine fibroids: Fibroid symptoms will recur after therapy cessation; treatment is limited to 3 months’ duration.
• Elderly: Not for use in postmenopausal women.
Concomitant drug therapy issues:
• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.
Dosage form specific issues:
• Benzyl alcohol and derivatives: Some dosage forms may contain benzyl alcohol; large amounts of benzyl alcohol (≥99 mg/kg/day) have been associated with a potentially fatal toxicity (“gasping syndrome”) in neonates; the “gasping syndrome” consists of metabolic acidosis, respiratory distress, gasping respirations, CNS dysfunction (including convulsions, intracranial hemorrhage), hypotension, and cardiovascular collapse (AAP ["Inactive" 1997]; CDC 1982); some data suggests that benzoate displaces bilirubin from protein binding sites (Ahlfors 2001); avoid or use dosage forms containing benzyl alcohol with caution in neonates. See manufacturer’s labeling.
• Depot formulations: Vehicle used in injectable (polylactide-co-glycolide microspheres) has rarely been associated with retinal artery occlusion in patients with abnormal arteriovenous anastomosis (eg, patent foramen ovale). Due to different release properties, combinations of dosage forms or fractions of dosage forms should not be interchanged.
• Eligard Atrigel delivery system: The Atrigel delivery system is a nongelatin-based, biodegradable, polymer matrix.
• Polysorbate 80: Some dosage forms may contain polysorbate 80 (also known as Tweens). Hypersensitivity reactions, usually a delayed reaction, have been reported following exposure to pharmaceutical products containing polysorbate 80 in certain individuals (Isaksson 2002; Lucente 2000; Shelley 1995). Thrombocytopenia, ascites, pulmonary deterioration, and renal and hepatic failure have been reported in premature neonates after receiving parenteral products containing polysorbate 80 (Alade 1986; CDC 1984). See manufacturer’s labeling.
• Appropriate use: Breast cancer: The American Society of Clinical Oncology (ASCO) Guideline Update on Ovarian Suppression for Adjuvant Endocrine Therapy for Women With Hormone Receptor-Positive Breast Cancer (Burstein 2016) recommends that premenopausal women with higher-risk disease receive ovarian suppression (in addition to adjuvant endocrine therapy), although lower-risk patients should not; premenopausal women with stage II or stage III breast cancers who would ordinarily be advised to receive adjuvant chemotherapy should also receive ovarian suppression (in addition to endocrine therapy). Additionally, women with stage I or II breast cancers at higher risk of recurrence who might consider chemotherapy may be offered ovarian suppression (in addition to endocrine therapy). Women with stage 1 disease which does not require chemotherapy should receive endocrine therapy, but not ovarian suppression. Likewise, women with node-negative cancers 1 cm or less (T1a, T1b) should receive endocrine therapy, but not ovarian suppression. Guidelines from ASCO for Endocrine Therapy in Hormone Receptor-Positive Metastatic Breast Cancer (Rugo 2016) recommend that premenopausal women with ER-positive metastatic breast cancer start ovarian suppression, preferably in combination with hormonal therapy. While premenopausal patients without prior hormone therapy exposure can be treated with tamoxifen, or ovarian suppression, or ablation alone, combination therapy is preferred. In metastatic breast cancer, ovarian suppression with GnRH agonists or ablation with oophorectomy appear to achieve similar results.
• Appropriate use: Prostate cancer: Guidelines from the American Society of Clinical Oncology (ASCO) for hormonal management of advanced prostate cancer which is androgen-sensitive (Loblaw 2007) recommend either orchiectomy or luteinizing hormone-releasing hormone (LHRH) agonists as initial treatment for androgen deprivation.
Bone mineral density; development or worsening of psychiatric symptoms
Endometriosis: Pregnancy test (prior to therapy); endometrial-related pain
Precocious puberty: GnRH testing (blood LH and FSH levels), measurement of height and bone age every 6 to 12 months, testosterone in males and estradiol in females (IM [monthly] and SubQ formulations: 1 to 2 months after initiation of therapy or with dosage change; IM [3 month] formulation: 2 to 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 HbA1c) and cardiovascular risk prior to initiating and periodically during treatment. Consider periodic monitoring of electrocardiograms and electrolytes.
Treatment of paraphilia/hypersexuality (off-label 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)
Pregnancy Risk Factor
Use is contraindicated in pregnant females or females who may become pregnant.
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.
• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)
• Patient may experience lack of appetite, constipation, breast pain or soreness, testicle changes, sexual dysfunction, hot flashes, sweating, enlarged breasts, nausea, vomiting, insomnia, injection site irritation, joint pain, acne, muscle pain, anxiety, or weight loss. Have patient report immediately to prescriber signs of infection, signs of severe cerebrovascular disease (change in strength on one side is greater than the other, difficulty speaking or thinking, change in balance, or vision changes), signs of pituitary apoplexy (sudden headache, vomiting, passing out, mood changes, eye weakness, unable to move eyes, or vision changes), signs of high blood sugar (confusion, fatigue, increased thirst, increased hunger, polyuria, flushing, fast breathing, or breath that smells like fruit), angina, severe headache, severe dizziness, passing out, vision changes, bone pain; urinary retention; change in amount of urine passed; severe back pain; seizures; hematuria; burning or numbness feeling; shortness of breath, bradycardia, tachycardia, abnormal heartbeat, excessive weight gain, swelling of arms or legs, difficulty moving, severe loss of strength and energy, behavioral changes, mood changes, menstruation, vaginitis, or vaginal irritation (HCAHPS).
• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.
Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.
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