Version November 2024
Dosage guidance:
Dosage form information: Do not use 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.
Breast cancer, premenopausal ovarian suppression for fertility preservation during chemotherapy (off-label use):
Lupron Depot: IM: 3.75 mg every 28 days starting at least 1 week prior to the initiation of chemotherapy and continuing until the end of chemotherapy (Ref).
Breast cancer, premenopausal ovarian suppression during endocrine therapy (off-label use):
Lupron Depot: IM: 3.75 mg every 4 weeks for ~5 years (Ref).
Breast cancer in male patients, hormone receptor positive (off-label use): Note: Should be used in combination with an aromatase inhibitor (Ref).
Adva nced or metastatic disease: IM: 3.75 mg once every 4 weeks (Ref). Endocrine therapy for males with advanced or metastatic, HR+, HER2-negative breast cancer may be sequenced as in females (Ref).
Endometriosis: Note: Initial treatment (maximum 6 months) may be as monotherapy or combination therapy with norethindrone acetate (add-back therapy). 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 (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: IM: 3.75 mg every month for up to 6 months.
Lupron Depot-3 month: IM: 11.25 mg every 3 months for 1 to 2 doses (maximum 6 months).
Symptom recurrence: Administer in combination with norethindrone acetate.
Lupron Depot: IM: 3.75 mg every month for up to 6 months.
Lupron Depot-3 month: IM: 11.25 mg every 3 months for 1 to 2 doses (maximum 6 months).
Hormone therapy for transgender females, assigned male at birth (adjunctive agent) (off-label use): IM (depot) or SUBQ: 3.75 mg monthly or 11.25 mg every 3 months in combination with other appropriate agents (Ref). Lupron Depot should be administered IM and Eligard should be administered SUBQ.
Paraphilia, males (off-label use):
Note: May cause an initial increase in androgen concentrations; concomitant antiandrogen therapy (eg, cyproterone, flutamide) is recommended starting 1 week before and continued for the first month after leuprolide initiation (Ref). Avoid use in patients with osteoporosis (especially in patients with prior fracture) or active pituitary disease (Ref).
Initial test dose: SUBQ: 1 mg once; if no hypersensitivity to the test dose, may proceed to treatment dosing (Ref).
Treatment dosing: Depot IM: 3.75 to 7.5 mg monthly (Ref) or 11.25 mg every 3 months (Ref). If therapy is discontinued, rebound elevation in testosterone levels and recurrence of symptoms may occur; if symptoms recur, retreatment with leuprolide or another agent is recommended (Ref).
Prostate cancer, advanced: Note: Treatment is usually continued after development of metastatic (castration-resistant) disease.
Leuprolide acetate:
Lupron Depot 7.5 mg (monthly): IM: 7.5 mg every month.
Leuprolide Depot (generic, Cipla), Lupron Depot 22.5 mg (3 month): IM: 22.5 mg every 12 weeks.
Lupron Depot 30 mg (4 month): IM: 30 mg every 16 weeks.
Lupron Depot 45 mg (6 month): IM: 45 mg every 24 weeks.
Eligard: SUBQ: 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: SUBQ: 1 mg daily.
Zeulide Depot [Canadian product]: IM: 3.75 mg once every month or 22.5 mg once every 3 months.
Leuprolide mesylate:
Camcevi: SUBQ:42 mg leuprolide (equivalent to ~48 mg leuprolide mesylate) once every 6 months.
Uterine leiomyomata (fibroids):
Note: Prior to combination therapy with iron, consider a 1-month trial period of iron alone; the addition of leuprolide may be considered when response to iron monotherapy is inadequate.
Lupron Depot: IM: 3.75 mg every month for up to 3 months (in combination with iron).
Lupron Depot-3 month: IM: 11.25 mg as a single injection (in combination with iron).
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
The renal dosing recommendations are based upon the best available evidence and clinical expertise. Senior Editorial Team: Bruce Mueller, PharmD, FCCP, FASN, FNKF; Jason A. Roberts, PhD, BPharm (Hons), B App Sc, FSHP, FISAC; Michael Heung, MD, MS.
Altered kidney function: IM, SUBQ: No dosage adjustment necessary for any degree of kidney impairment (<5% of the drug is eliminated in the urine as parent and major metabolite) (Ref).
Hemodialysis, intermittent (thrice weekly): Not significantly dialyzed (Ref): IM, SUBQ: No supplemental dose or dosage adjustment necessary (Ref). Note: For the IR formulation, when scheduled dose falls on dialysis days, administer after hemodialysis (Ref).
Peritoneal dialysis: Unlikely to be significantly dialyzed: IM, SUBQ: No dosage adjustment necessary (Ref).
CRRT: IM, SUBQ: No dosage adjustment necessary (Ref).
PIRRT (eg, sustained, low-efficiency diafiltration): IM, SUBQ: No dosage adjustment necessary (Ref).
There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied).
Severe cutaneous adverse reactions (including Stevens-Johnson syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms, and acute generalized exanthematous pustulosis): Interrupt leuprolide therapy until cause of the reaction is determined; consult with dermatologist. Permanently discontinue leuprolide therapy if severe cutaneous adverse reaction is confirmed or other grade 4 skin reactions occur.
Refer to adult dosing.
(For additional information see "Leuprolide: Pediatric drug information")
Note: Each formulation (including different strengths) has unique release characteristics; do not use partial syringes or a combination of syringes to achieve dose. Dosing regimens and route of administration of international product(s) may vary from US dosage forms; refer to specific international product labeling.
Central precocious puberty (CPP):
Note: Pubertal maturation will resume within months (eg, ~6 to 18 months) after discontinuation of treatment, with wide variability; consider discontinuing leuprolide therapy at the appropriate age for the onset of puberty (eg, when peers would be experiencing puberty). Therapy is typically discontinued at ~10 to 12 years of age, depending on clinical circumstances (Ref).
IM: Children:
Monthly dosing:
Lupron Depot-Ped (monthly formulation):
Fixed dosing: IM: 7.5 mg every 4 weeks; titrate as needed to attain adequate suppression (Ref). A lower starting dose of 3.75 mg every 4 weeks is also effective in most children (Ref).
Weight-directed dosing: Note: Although weight-directed dosing is described by the manufacturer, some experts recommend against this approach for depot formulations (Ref).
≤25 kg: IM: 7.5 mg every 4 weeks; titrate dose in 3.75 mg increments (ie, to the next available dosage form size) every 4 weeks until clinical or laboratory tests indicate adequate suppression.
>25 to 37.5 kg: IM: 11.25 mg every 4 weeks; titrate dose in 3.75 mg increments (ie, to the next available dosage form size) every 4 weeks until clinical or laboratory tests indicate adequate suppression.
>37.5 kg: IM: 15 mg every 4 weeks; titrate dose in 3.75 mg increments (ie, to the next available dosage form size) every 4 weeks until clinical or laboratory tests indicate adequate suppression.
Every-3-month dosing:
Lupron Depot-Ped (3-month formulation) and Lupron Depot: IM: 11.25 mg, 22.5 mg, or 30 mg every 12 weeks. Note: If initiating therapy with the 3-month formulation, some experts begin with 11.25 mg dose and titrate to attain adequate suppression (Ref).
Every-6-month dosing:
Lupron Depot-Ped (6-month formulation): IM: 45 mg every 24 weeks (Ref).
SUBQ: Children ≥2 years:
Long-acting formulation: Fensolvi: SUBQ: 45 mg every 6 months (Ref).
Short-acting formulation: Leuprolide acetate 5 mg/mL solution: SUBQ: Initial: 50 mcg/kg/dose once daily; may titrate dose upward by 10 mcg/kg/day if suppression is not adequate (Ref). Note: Dosage form is no longer approved for this indication; use has been replaced by long-acting formulations which require less frequent dosing (Ref).
Endometriosis:
Note: Due to ongoing growth and bone maturation in adolescents, leuprolide use in patients <18 years of age should be reserved for patients with pain refractory to conservative surgical therapy (Ref); empiric therapy should not be used (Ref). Although the manufacturer's labeling suggest monotherapy with leuprolide as an option for initial courses, experts suggest that in adolescents, initial leuprolide therapy be in combination with norethindrone with or without conjugated estrogen (add-back therapy). Adolescent patients should also be supplemented with calcium and vitamin D (Ref).
Lupron Depot (monthly formulation): Post-menarche adolescents: IM: 3.75 mg every month for up to 6 months.
Lupron Depot (3-month formulation): Post-menarche adolescents: IM: 11.25 mg every 3 months for up to 2 doses as initial therapy; for retreatment, may repeat course for up to 2 doses; total treatment duration should not exceed 12 months.
Leuprolide (GnRHa) Stimulation Test (Female): Limited data available: Children ≥2 years: Leuprolide acetate 5 mg/mL solution: SUBQ: 20 mcg/kg once; measure LH and follicle-stimulating hormone at baseline and after administration (usually 2 spaced measurements ≤120 minutes [eg, 30 and 60 minutes or 60 and 120 minutes]) (Ref).
Uterine leiomyomata (fibroids): Note: Use in combination with iron supplementation. Due to ongoing growth and bone maturation in adolescents, consider calcium and vitamin D supplementation with therapy based on experience in adolescents with leuprolide use for endometriosis.
Lupron Depot (monthly formulation): Post-menarche adolescents: IM: 3.75 mg every month for up to 3 months.
Lupron Depot (3-month formulation): Post-menarche adolescents: IM: 11.25 mg as a single injection.
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
Dosing adjustment for toxicity: Delayed hypersensitivity (including severe cutaneous adverse reactions of Stevens-Johnson syndrome and toxic epidermal necrolysis): Discontinue future leuprolide therapy at first signs/symptoms of a delayed hypersensitivity reaction and manage as clinically indicated.
There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).
There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).
Leuprolide may cause decreased bone mineral density (BMD). Data in pediatric patients with central precocious puberty are conflicting (Ref). Data from use of gonadotropin-releasing hormone (GnRH) agonist therapy in males with prostate cancer show a 2% to 3% decrease in BMD of the hip and spine per year during initial therapy (Ref). Postmarketing claim-based studies show a bone fracture rate of 19.4% in males with prostate cancer receiving androgen deprivation therapy compared to 12.6% to those not receiving therapy (Ref). Bone loss with GnRH agonist therapy in females is less quantified but described as significant and may exceed 1% per month (Ref). In adult females, discontinuation of therapy did not ensure complete recovery of the bone loss (Ref).
Mechanism: Time-related; fundamentally, it is the increase in bone turnover and decrease in BMD that causes adverse skeletal effects (Ref). The imbalance of osteoclast and osteoblast activity is secondary to parathyroid hormone, estrogen, and other sex hormone level changes (Ref).
Onset: Varied; remarkable bone loss may occur after 3 to 6 months of GnRH agonist therapy but is more commonly associated with long-term GnRH therapy (Ref).
Risk factors:
• Treatment duration (Ref)
• Family history of osteoporosis
• Concurrent administration of medications associated with bone loss (eg, antiseizure medications, long-term corticosteroids, aromatase inhibitors) (Ref)
• Lifestyle factors (eg, chronic tobacco or alcohol use, sedentary nature) (Ref)
• Low calcium intake (Ref)
• Vitamin D deficiency (Ref)
• Hypogonadism (Ref)
Immediate hypersensitivity reactions (urticaria, angioedema, anaphylaxis) have been reported (Ref). Recurrent anaphylaxis in response to depot leuprolide has been reported (Ref); with recurrent anaphylaxis or a history of anaphylaxis to multiple unrelated drugs (eg, leuprolide acetate depot and triamcinolone), a reaction to the excipient carboxymethylcellulose should be considered. Delayed hypersensitivity reactions have also been reported, including maculopapular skin rash, mycosis-fungoides-like eruption, serum sickness, and hypersensitivity angiitis (Ref). Injection site granuloma may occur (Ref). Acute generalized exanthematous pustulosis, bullous dermatitis, erythema multiforme, exfoliative dermatitis, drug reaction with eosinophilia and systemic symptoms, Stevens-Johnson syndrome, and toxic epidermal necrolysis have also been reported.
Mechanism:
Immediate hypersensitivity reactions: Non–dose-related; likely immunologic (ie, IgE mediated, with specific antibodies formed against a drug allergen following initial exposure) or due to histamine-releasing activity (Ref). In addition, leuprolide appears to be a peptide ligand for MRGPRX2 receptor on mast cells and a cause for non-IgE–mediated mast cell activation (Ref).
Delayed hypersensitivity reactions: Non–dose-related; immunologic (involving a T-cell–mediated drug-specific immune response or immune complex-mediated) (Ref).
Granuloma: Non–dose-related; may be caused by a foreign-body reaction against polymers used as a vehicle for leuprolide injection or a reaction to leuprolide (Ref).
Onset:
Immediate hypersensitivity reactions: Rapid; generally occurs within 1 hour of administration but may occur up to 14 days after injection of the depot (Ref). Reactions have occurred with the first injection up to the 25th injection (Ref).
Delayed hypersensitivity reactions: Varied; typically occur days to 6 weeks after drug exposure (Ref).
Granulomas: Delayed; usually appear weeks to months after injection (Ref).
Risk factors:
• Cross-reactivity with other gonadotropin-releasing hormone analogues, including triptorelin and goserelin, may occur (Ref)
• Leuprolide acetate depot contains both carboxymethylcellulose (carmellose in Australia/Asia, E466 in Europe) and polysorbate 80, which are excipients that have independently been associated with anaphylaxis (Ref)
Metabolic changes with androgen deprivation therapy (ADT) are concerning due to increased risk of both arterial and venous thromboembolic events (Ref). Gonadotropin releasing hormone (GnRH) agonists, such as leuprolide, may increase risk of a major cardiovascular and cerebrovascular event (20%) vs GnRH antagonists (3%) (Ref). Additionally, ischemic heart disease was found to be the most common cardiac disorder in a phase 3 randomized clinical trial with an incidence of 10% (Ref).
Mechanism: Dose-related; ADT decreases testosterone levels which elicits metabolic changes, such as decreased lean muscle mass, increased visceral fat, insulin resistance, and dyslipidemia, leading to a prothrombotic state that expedites atherosclerosis (Ref). Immunomodulatory changes, such as activation of atherosclerotic plaque T-cell GnRH receptors leading to plaque destabilization, are also being explored (Ref).
Onset: Delayed; risk increases during the first 6 months of ADT (Ref).
Risk factors:
• Duration of therapy (Ref)
• Prior cardiovascular disease/event or preexisting risk factors (Ref)
• Age ≥65 years (Ref)
Gonadotropin-releasing hormone (GnRH) analogues have rarely been associated with pituitary apoplexy (Ref). Presentation is generally a sudden severe headache associated with visual impairment (photophobia, diplopia, or blurry vision), headache, vomiting, hyponatremia, and ophthalmoplegia (Ref). Immediate care ranging from medical management to surgical invention may be required (Ref).
Mechanism: Dose related; pituitary stimulation to underlying adenoma causes ischemic necrosis and subsequent hemorrhage, or compression of vessels may lead to infarction in the nonadenomatous gland (Ref).
Onset: Varied; most commonly occurs within hours (<4 hours) of first administration; has also been observed up to 14 days after administration (Ref).
Risk factors:
• Elderly males with underlying gonadotropin-secreting adenoma (Ref)
• Presence of pituitary macroadenoma (Ref)
Leuprolide has rarely been associated with acute mania and psychiatric signs and symptoms (Ref). There are very few case reports in the literature; however, the development of such events can require hospitalization and initiation of antidepressants and/or neuroleptic medications (Ref). Presentation is more common in those without prior history of psychiatric events, but exacerbations of existing pathology have been reported (Ref). In 23% of women taking a gonadotropin-releasing hormone agonist, depression was reported (Ref).
Mechanism: Unknown; however, estrogen withdrawal or deficit in central serotonin transmission is postulated (Ref).
Onset: Dose- and time-related; symptoms appear after several injections have been received (Ref).
Cardiac arrhythmias associated with leuprolide therapy are very rare with incidence limited to clinical trials until a recent case report of prolonged QT interval on ECG and torsades de pointes (TdP) (Ref). In a phase 3 randomized clinical trial, supraventricular arrhythmias occurred in 4% of patients and prolonged QT interval occurred in 1% of patients (Ref).
Risk factors: Drug-induced QTc prolongation/TdP (in general):
• Females (Ref)
• Age >65 years (Ref)
• Structural heart disease (eg, history of myocardial infarction or heart failure with reduced ejection fraction) (Ref)
• Genetic defects of cardiac ion channels (Ref)
• History of drug-induced TdP (Ref)
• Congenital long QT syndrome (Ref)
• Baseline QTc interval prolongation (eg, >500 msec) or lengthening of the QTc by ≥60 msec (Ref)
• Electrolyte disturbances (eg, hypocalcemia, hypokalemia, hypomagnesemia) (Ref)
• Bradycardia (Ref)
• Hepatic impairment (Ref)
• Kidney impairment (Ref)
• Loop diuretic use (Ref)
• Sepsis (Ref)
• Concurrent administration of multiple medications (≥2) that prolong the QT interval or medications with drug interactions that increase serum concentrations of QT-prolonging medications (Ref)
There are postmarketing reports of seizures with the use of long-acting leuprolide (Ref). While most seizures are classified as unspecified, cases of generalized, partial, and absence seizures are noted (Ref). Reports were mostly in females (average age 25 years) receiving therapy for endometriosis (Ref). There are 2 reports of seizure in pediatric patients with preexisting brain damage; resolution of seizure activity occurred with discontinuation of leuprolide therapy and initiation of treatment (Ref).
Mechanism: Postulated to be dose-related; related to pharmacological action. Potentially same mechanism as catamenial seizures since leuprolide causes transient increase in hormones (Ref).
Onset: Delayed; average onset is 41 days (Ref)
Risk factors:
• History of catamenial seizures (Ref)
• Preexisting brain damage (Ref)
A tumor flare or transient increase in prostate cancer symptoms, especially in patients with advanced disease, presents as an exacerbation of initial symptoms, such as ureteral obstruction, urinary retention, spinal cord compression, and/or lymphedema (Ref). Sudden death during tumor flare has been reported (Ref). At one time, the incidence was estimated to be as high as 11%; however, advances in screening, earlier treatment, and the concurrent use of antiandrogen therapy have decreased the rate of tumor flare (Ref).
Mechanism: An initial increase in testosterone peaks ~3 days after administration, exacerbating symptoms (Ref).
Onset: Intermediate; symptoms observed within the first 1 to 3 weeks of receiving leuprolide (Ref).
Risk factors:
• Advanced disease (Ref)
• High prostate-specific antigen levels (Ref)
• Impending cord compression (Ref)
• Urethral obstruction (Ref)
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Adverse reactions reported in adults, unless otherwise indicated.
>10%:
Cardiovascular: ECG changes (≤19%), edema (5% to 21%), flushing (children: 5%; adults: ≤78%), hypertension (children, adults: ≤15%), ischemia (≤19%) (table 1), peripheral edema (children, adults: ≤12%)
|
Drug (Leuprolide) |
Comparator (Diethylstilbestrol) |
Population |
Dose |
Dosage Form |
Indication |
Number of Patients (Leuprolide) |
Number of Patients (Diethylstilbestrol) |
Comments |
|---|---|---|---|---|---|---|---|---|
|
19% |
22% |
Adult males |
1 mg/day |
SUBQ injection |
Prostate cancer |
98 |
101 |
Described as "ECG changes/ischemia" |
Dermatologic: Diaphoresis (≤98%), pruritus (children: 11%; adults: 2% to 3%)
Endocrine & metabolic: Decreased libido (3% to 11%), hot flash (≤98%), increased serum cholesterol (23%), increased serum triglycerides (12% to 32%), weight gain (children, adults: ≤13%), weight loss (≤13%)
Gastrointestinal: Abdominal pain (children: 9% to 18%; adults: <1%), constipation (children: 6%; adults: ≤14%), diarrhea (children, adults: ≤16%), hematochezia (children: ≤13%), nausea (children: ≤13%; adults: ≤25%), vomiting (children: ≤13%; adults: ≤25%)
Genitourinary: Testicular atrophy (4% to 20%), vaginitis (children: ≤3%; adults: 11% to 28%)
Hematologic & oncologic: Bruise (children: ≤13%)
Local: Bruising at injection site (children: ≤78%; adults: 3% to 12%), discomfort at injection site (children: ≤78%; adults: ≤19%), erythema at injection site (children: ≤78%; adults: 2% to 38%), injection-site reaction (children: ≤78%; adults: ≤14%, including abscess at injection site), pain at injection site (children: ≤78%; adults: ≤19%), swelling at injection site (children: ≤78%), warm sensation at injection site (children: ≤78%)
Nervous system: Asthenia (children: <1%; adults: ≤18%), depression (children: ≤22%; adults: ≤31%) (table 2), dizziness (children: <1%; adults: ≤16%), emotional lability (children: ≤22%; adults: ≤31%), fatigue (≤18%), headache (children: 2% to 33%; adults: ≤65%), insomnia (children, adults: ≤31%), lethargy (≤13%), malaise (≤18%), migraine (≤65%), mood changes (children: ≤22%; adults: ≤5%), pain (3% to 33%), psychiatric signs and symptoms (children: ≤22%, including affective disorder, aggressive behavior, auditory hallucinations, crying, disruptive mood dysregulation disorder, trichotillomania), sleep disorder (≤31%), vertigo (≤16%)
|
Drug (Leuprolide) |
Comparator (Danazol) |
Placebo |
Dosage Form |
Indication |
Number of Patients (Leuprolide) |
Number of Patients (Danazol) |
Number of Patients (Placebo) |
Comments |
|---|---|---|---|---|---|---|---|---|
|
22% |
N/A |
N/A |
40 mg IM injection |
Central precocious puberty in children |
45 |
N/A |
N/A |
Described as “psychiatric event including depression” |
|
31% |
N/A |
N/A |
3.75 mg IM injection |
Endometriosis in adults |
51 |
N/A |
N/A |
Described as "depression/emotional lability" |
|
22% |
20% |
3% |
3.75 mg IM injection |
Endometriosis in adults |
166 |
136 |
31 |
Described as "depression/emotional lability" |
|
11% |
N/A |
4% |
3.75 mg IM injection |
Uterine fibroids in adults |
166 |
N/A |
163 |
Described as "depression/emotional lability" |
Neuromuscular & skeletal: Arthropathy (children: <2%; adults: 4% to 16%), increased creatinine phosphokinase in blood specimen, musculoskeletal pain (children: <1%; adults: ≤11%)
Respiratory: Cough (children, adults: 1% to 13%), epistaxis (children, adults: ≤13%), flu-like symptoms (children: <2%; adults: ≤21%), nasopharyngitis (children, adults: ≤22%), upper respiratory tract infection (children: 6%; adults: ≤21%)
Miscellaneous: Fever (children: 13% to 17%; adult: <5%)
1% to 10%:
Cardiovascular: Acute myocardial infarction (<5%), angina pectoris (<5%), atrial fibrillation (<5%), bradycardia (children, adults: <5%), cardiac arrhythmia (<5%), chest pain (children: 4%), coronary artery disease (≤6%), deep vein thrombophlebitis (<5%), heart failure (1%), heart murmur (3%), hypotension (children; adults: <5%), palpitations (<5%), peripheral vascular disease (<2%), phlebitis (≤2%), pitting edema (≤5%), syncope (children, adults: <5%), tachycardia (<5%), thrombosis (≤2%), varicose veins (<5%), vasodilation (children: 2%)
Dermatologic: Acne vulgaris (children: ≤3%; adults: ≤10%), allergic skin reaction (≤10%), alopecia (children, adults: ≤4%), body odor (children, adults: <5%), cellulitis (<5%), cold and clammy skin (4%), dermatitis (5%), ecchymoses (<5%), erythema multiforme (children: ≤3%), hair disease (<5%), hyperhidrosis (children: 4%), hyperpigmentation (including dyschromia: <5%), leukoderma (children: <2%), malignant melanoma, nail disease (children, adults: <5%), night sweats (3%), seborrhea (children: ≤3%), skin carcinoma (including ear: <5%), skin hypertrophy (children: <2%), skin lesion (<5%), skin rash (children, adults: 7%), xeroderma (<5%)
Endocrine & metabolic: Androgen-like effect (females: ≤4%), decreased HDL cholesterol (2% to 10%), decreased serum albumin (≥5%), decreased serum bicarbonate (≥5%), decreased serum total protein (≥5%), dehydration (8%), diabetes mellitus (children; adults: <5%), feminization (children: <2%), goiter (children, adults: <5%), growth retardation (children: <2%), gynecomastia (children, adults: ≤7%), hirsutism (children: <2%), hyperglycemia (≥5%), hyperphosphatemia (≥5%), hyperuricemia (≥5%), hypoglycemia (<5%), increased lactate dehydrogenase (≥5%), increased LDL cholesterol (8%), increased serum calcium (<5%), increased thirst (<5%), increased uric acid (≥5%), loss of libido (<2%), menstrual disease (children, adults: ≤2%)
Gastrointestinal: Abdominal distention (<5%), anorexia (6%), change in appetite (4%), colitis (≤3%), duodenal ulcer (<5%), dysgeusia (<5%), dyspepsia (children, adults: <4%), dysphagia (children, adults: <5%), eructation (<5%), flatulence (≤4%), gastroenteritis (≤3%), gastrointestinal hemorrhage (<5%), gingival hemorrhage (<5%), gingivitis (children, adults: <5%), hernia of abdominal cavity (<5%), hiccups (<5%), increased appetite (children, adults: <5%), intestinal obstruction (<5%), melanosis (<5%), mucous membrane abnormality (reaction: ≤4%), peptic ulcer (<5%), periodontal abscess (<5%), rectal polyp (<5%), xerostomia (<5%)
Genitourinary: Balanitis (<5%), bladder carcinoma (<5%), bladder spasm (<5%), breast changes (≤6%), breast disease (children: <2%), breast hypertrophy (children; adults: <5%), breast tenderness (children, adults: ≤7%), cervical neoplasm (children: <2%), cervix disease (children: <2%), decreased prostatic acid phosphatase (≥5%), difficulty in micturition (<2%), dysmenorrhea (children: <2%), dysuria (≤6%), epididymitis (<5%), erectile dysfunction (4% to 5%), hematuria (≤6%), hemorrhagic cystitis (including cystitis: ≤6%), increased prostatic acid phosphatase (≥5%), lactation (<5%), mastalgia (≤7%), nocturia (1% to 6%), oliguria (<2%), penile disease (<5%), pollakiuria (2%), prostatic disease (<5%), reduction in penile size (<2%), sexual disorder (accelerated sexual maturity: children: <2%), testicular disease (<5%), testicular pain (2%), urinary frequency (≤6%), urinary incontinence (children, adults: <5%), urinary retention (<2%), urinary tract infection (≤6%), urinary tract obstruction (<5%), urinary tract pain (1%), urinary urgency (≤6%), vaginal discharge (children: ≤3%), vaginal hemorrhage (children: ≤3%)
Hematologic & oncologic: Anemia (≤6%), carcinoma (<5%), eosinophilia (≥5%), increased erythrocyte sedimentation rate (children: <2%), leukopenia (≥5%), lymphadenopathy (<5%), lymphedema (<5%), neoplasm (<5%), prolonged partial thromboplastin time (≥5%), prolonged prothrombin time (≥5%), purpuric disease (children: <2%), second primary malignant neoplasm (including basal cell carcinoma of skin, malignant melanoma, non-Hodgkin lymphoma, pulmonary neoplasm), squamous cell carcinoma (7%), thrombocytosis (≥5%), tumor flare (children: <2%)
Hepatic: Abnormal hepatic function tests (≥5%), hepatomegaly (<5%), increased gamma-glutamyl transferase (≥5%), increased serum alanine aminotransferase (≥5%), increased serum aspartate aminotransferase (≥5%), increased serum transaminases (3%)
Hypersensitivity: Hypersensitivity reaction (children, adults: <5%)
Immunologic: Increased ANA titer (children: <2%)
Infection: Abscess (<5%), herpes zoster infection (<5%), infection (children, adults: ≤5%)
Local: Induration at injection site (children, adults: <3%), injection-site pruritus (≤9%)
Nervous system: Abnormality in thinking (<5%), agitation (<5%), altered sense of smell (<2%), amnesia (<5%), anxiety (≤8%), chills (<5%), confusion (<5%), delusion (<5%), dementia (<5%), drowsiness (children: <2%), hypoesthesia (<5%), irritability (including impatience: 2%), loss of consciousness (<5%), memory impairment (6%), nervousness (children: <2%; adults: ≤8%), neuropathy (<5%), numbness (<5%), paralysis (children; adults: <5%), paresthesia (≤8%), peripheral neuropathy (children; adults: <5%), personality disorder (<5%), rigors (<2%), tremor (<2%), voice disorder (<5%)
Neuromuscular & skeletal: Amyotrophy (<2%), arthralgia (children: <2%; adults: ≤9%), arthritis (≤1%), back pain (children, adults: ≤7%), bone disease (temporal bone swelling: <5%), hyperkinetic muscle activity (children: <2%), limb pain (children, adults: ≤10%), lower limb cramp (≤2%), myalgia (can be severe: children: <2%; adults: ≤8%), myopathy (children: <2%), neck pain (<5%), ostealgia (2% to 5%), pathological fracture (children, adults: <5%)
Ophthalmic: Amblyopia (<5%), blepharoptosis (<5%), blurred vision (<5%), conjunctivitis (<5%), dry eye syndrome (<5%), visual disturbance (children, adults: <5%)
Otic: Tinnitus (<5%)
Renal: Decreased urine specific gravity (≥5%), increased blood urea nitrogen, increased serum creatinine, increased urine specific gravity (≥5%)
Respiratory: Asthma (children, adults: <5%), bronchitis (<5%), bronchospasm (children: 6%), chronic obstructive pulmonary disease (5%), dyspnea (≤5%), dyspnea on exertion (1% to 5%), hemoptysis (<5%), hypoxia (<5%), increased bronchial secretions (<5%), paranasal sinus congestion (5%), pharyngitis (children, adults: <5%), pleural effusion (<5%), pleural rub (<5%), pneumonia (<5%), productive cough (children: 6%), pulmonary edema (<5%), pulmonary emphysema (<5%), pulmonary fibrosis (<5%), rhinitis (children, adults: <5%), sinus headache (≤8%), sinusitis (children, adults: <5%)
Miscellaneous: Abnormal healing (<5%), cyst (<5%), inflammation (<5%)
<1%:
Dermatologic: Pallor (children)
Endocrine & metabolic: Obesity (children)
Gastrointestinal: Abdominal distress, decreased appetite (children)
Genitourinary: Exacerbation of hematuria
Local: Hematoma at injection site (children)
Nervous system: Abnormal gait (children)
Frequency not defined (all populations):
Cardiovascular: Aortic aneurysm (ruptured), carotid stenosis, chest tightness, extrasystoles
Dermatologic: Hyperkeratosis, spider telangiectasia
Endocrine & metabolic: Decreased serum potassium, galactorrhea not associated with childbirth (females), hyperkalemia, increased libido, increased testosterone level, pituitary insufficiency (suppression of pituitary-gonadal system), thyroid nodule
Gastrointestinal: Occult blood in stools, rectal fistula, rectal irritation (erythema)
Genitourinary: Blisters on penis, increased post-void residual urine volume, penile swelling, pyuria, ureteral obstruction
Hematologic & oncologic: Hypoproteinemia, leukocytosis, thrombocytopenia
Hepatic: Hepatitis
Hypersensitivity: Facial edema, facial swelling
Local: Burning sensation at injection site (including stinging), skin ulceration at injection site
Nervous system: Anosmia, burning sensation of feet, cerebrovascular accident, euphoria, hyperreflexia, hyporeflexia, motor dysfunction, spinal cord compression, transient ischemic attacks
Neuromuscular & skeletal: Ankylosing spondylitis, knee effusion, muscle cramps, muscle rigidity, muscle tenderness
Ophthalmic: Eyelid edema, retinal vascular disease (perivascular cuffing)
Otic: Auditory disturbance (including decreased hearing)
Renal: Nephrolithiasis, pyelonephritis
Respiratory: Abnormal breath sounds (decreased), dry throat, pleuritic chest pain, pulmonary infiltrates, rales, rhonchi, streptococcal pharyngitis, wheezing
Miscellaneous: Fibrosis (pelvic), mass
Postmarketing (all populations):
Cardiovascular: Deep vein thrombosis, prolonged QT interval on ECG (Abbasi 2020), pulmonary embolism, torsades de pointes (Abbasi 2020)
Dermatologic: Acute generalized exanthematous pustulosis, bullous dermatitis, exfoliative dermatitis, hypertrichosis, skin photosensitivity, Stevens-Johnson syndrome, toxic epidermal necrolysis, urticaria (Okdemir 2015)
Endocrine & metabolic: Diabetes mellitus with hyperosmolar coma (Saad 2022), pituitary apoplexy (Fabiano 2016; Tanios 2017)
Genitourinary: Prostate pain
Hematologic & oncologic: Adenoma (pituitary), decreased white blood cell count
Hepatic: Acute hepatotoxicity, hepatic impairment, liver steatosis, severe hepatotoxicity
Hypersensitivity: Anaphylaxis (Fujisaki 2012), angioedema (Kirkgoz 2020), drug reaction with eosinophilia and systemic symptoms, hypersensitivity angiitis (Gnanaraj 2010), nonimmune anaphylaxis, serum sickness (Gnanaraj 2010)
Local: Injection site granuloma (Yasukawa 2005)
Nervous system: Fibromyalgia syndrome, intracranial hypertension (including idiopathic intracranial hypertension) (Tan 2019), mania (Pong 2014), outbursts of anger (Chavez 2010), seizure (Akaboshi 2000), suicidal ideation, suicidal tendencies
Neuromuscular & skeletal: Bone fracture (including spinal) (Shahinian 2005), decreased bone mineral density (Dawood 1995; Kaya 2015; Smith 2006), muscle spasm, slipped capital femoral epiphysis, tenosynovitis (symptoms)
Respiratory: Interstitial lung disease (interstitial pneumonitis) (Villalba-Cuesta 2022)
Miscellaneous: Nodule (throat)
Hypersensitivity to leuprolide, GnRH, GnRH-agonist analogs, or any component of the formulation.
Fensolvi, Lupron-Depot-Ped: Additional contraindications: pregnancy.
Lupron Depot 3.75 mg (monthly) and Lupron Depot 11.25 mg (3-month): Additional contraindications: patients with undiagnosed uterine bleeding; pregnancy.
Canadian labeling: Additional contraindications (not in US labeling): Patients who are or who could become pregnant; breastfeeding. Zeulide Depot (Canadian product) is also contraindicated in females.
Concerns related to adverse effects:
• Metabolic syndrome: Metabolic changes (such as hyperglycemia, diabetes, hyperlipidemia) may occur; metabolic dysfunction–associated steatotic liver disease, including cirrhosis, has also been reported. Hyperglycemia may manifest as new-onset diabetes or worsening of glycemic control in patients with preexisting diabetes.
• Pseudotumor cerebri: Pseudotumor cerebri (idiopathic intracranial hypertension) has been reported in pediatric patients receiving GnRH agonists, including leuprolide acetate, but is very rare (Omar 2020).
Disease-related concerns:
• Asthma: Asthma exacerbations have been reported with therapy in patients with histories of asthma, sinusitis, or environmental or drug allergies.
• Central precocious puberty: Children treated for precocious puberty may experience signs and symptoms of puberty, including vaginal bleeding, during the first weeks of treatment or after subsequent doses due to the initial stimulatory effect of leuprolide before suppression occurs; health care provider should be notified if symptoms continue after the second month.
• Depression: Monitor for new or worsening depression, especially in patients with a history of depression.
• Endometriosis: Due to the physiologic effects of the drug, exacerbation of endometriosis symptoms may occur after the first dose of leuprolide.
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 suggest 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) (Tang 2007). Do not use 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. The Atrigel delivery system (used in Eligard/Fensolvi) 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.
Other warnings/precautions:
• Appropriate use: For the treatment of endometriosis, leuprolide can be used in combination with norethindrone acetate (referred to as add-back therapy) to reduce bone mineral density loss and reduce vasomotor symptoms associated with use of leuprolide acetate. Leuprolide in combination with norethindrone acetate (add-back therapy) is not indicated for the preoperative hematologic improvement of patients with anemia caused by heavy menstrual bleeding due to uterine fibroids.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Injectable, Intramuscular, as acetate:
Generic: 22.5 mg (1 ea)
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]
Lupron Depot-Ped (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
Eligard: 7.5 mg, 22.5 mg, 30 mg, 45 mg [contains methylpyrrolidone, polylactide-coglycolide]
Fensolvi (6 Month): 45 mg
Fensolvi (6 Month): 45 mg [contains methylpyrrolidone, polylactide-coglycolide]
Kit, Subcutaneous, as acetate [preservative free]:
Eligard: 30 mg [contains methylpyrrolidone, polylactide-coglycolide]
Prefilled Syringe, Subcutaneous, as mesylate [preservative free]:
Camcevi: 42 mg (1 ea) [latex free]
May be product dependent
Injection (Leuprolide Acetate (3 Month) Intramuscular)
22.5 mg (per each): $1,626.08
Kit (Eligard Subcutaneous)
7.5 mg (per each): $542.03
22.5 mg (per each): $1,626.08
30 mg (per each): $2,168.11
45 mg (per each): $3,252.16
Kit (Fensolvi (6 Month) Subcutaneous)
45 mg (per each): $31,363.51
Kit (Leuprolide Acetate Injection)
1 mg/0.2 mL (per each): $808.80 - $891.00
Kit (Lupron Depot (1-Month) Intramuscular)
3.75 mg (per each): $2,058.41
7.5 mg (per each): $2,452.92
Kit (Lupron Depot (3-Month) Intramuscular)
11.25 mg (per each): $6,175.28
22.5 mg (per each): $7,358.72
Kit (Lupron Depot (4-Month) Intramuscular)
30 mg (per each): $9,811.66
Kit (Lupron Depot (6-Month) Intramuscular)
45 mg (per each): $14,717.70
Kit (Lupron Depot-Ped (1-Month) Intramuscular)
7.5 mg (per each): $2,476.28
11.25 mg (per each): $4,495.63
15 mg (per each): $4,951.49
Kit (Lupron Depot-Ped (3-Month) Intramuscular)
11.25 mg (per each): $13,486.94
30 mg (per each): $14,854.52
Kit (Lupron Depot-Ped (6-Month) Intramuscular)
45 mg (per each): $29,709.02
Prefilled Syringe (Camcevi Subcutaneous)
42 mg (per each): $5,124.08
Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product
Injectable, Intramuscular:
Lupron Depot: 30 mg (1 ea) [contains polysorbate 80]
Kit, Intramuscular, as acetate:
Lupron Depot (1-Month): 3.75 mg, 7.5 mg [contains polysorbate 80]
Lupron Depot (3-Month): 11.25 mg [contains polysorbate 80]
Lupron Depot 3 Month Kit: 22.5 mg [contains polysorbate 80]
Zeulide Depot: 3.75 mg, 22.5 mg [contains polysorbate 80]
Kit, Subcutaneous, as acetate:
Eligard: 7.5 mg, 22.5 mg, 30 mg, 45 mg
Solution, Subcutaneous:
Lupron: 1 mg/0.2 mL ([DSC]) [contains benzyl alcohol]
Do not use 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. Do not administer IV.
IM:
Leuprolide Depot (generic, Cipla): Administer as a single injection into the gluteal area, anterior thigh, or deltoid. Injection site should be alternated. Administer immediately after preparation.
Lupron Depot: Must be administered by a health care provider. Administer as a single injection into the gluteal area, anterior thigh, or deltoid. Injection site should be alternated. Administer within 2 hours of preparation.
Zeulide Depot [Canadian product]: Allow product to reach room temperature before administration. Inject into the upper outer quadrant of the gluteus.
SUBQ:
Camcevi: Select an injection site in the upper or mid abdominal area with sufficient soft or loose SUBQ tissue that has not been used recently; do not administer into areas with brawny or fibrous SUBQ tissue or locations that could be rubbed or compressed (eg, belt or waistband). Bunch skin around injection site, insert needle at a 90-degree angle to the skin surface, release skin, and slowly and steadily inject full contents; remove needle at the same 90-degree angle. Avoid applying heat directly to the injection site.
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 (1 mg/0.2 mL): Vary injection site; if an alternate syringe from the syringe provided is required, insulin syringes should be used.
Parenteral: Note: Do not use 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. Do not administer IV.
IM: Lupron Depot, Lupron Depot-Ped: Administer as a single injection into the gluteal area, anterior thigh, or deltoid; rotate administration site periodically. Reconstituted solution does not contain preservatives and should be used immediately. Lupron Depot-Ped should be administered by a health care professional.
SUBQ:
Long-acting formulation: Fensolvi: Should be administered by a health care professional. Administer as a single SUBQ injection into the abdomen, upper buttocks, or other location with adequate SUBQ tissue that does not have excessive pigment, nodules, lesions, or hair. Avoid areas for injection with brawny or fibrous SUBQ tissue or areas of skin that may be rubbed or compressed (belts or clothing waistband). Rotate injection sites.
Short-acting formulation: Leuprolide acetate 5 mg/mL solution: Administer undiluted into areas on the arm, thigh, or abdomen; rotate injection site. If an alternate syringe from the manufacturer-provided syringe is required, insulin syringes should be used.
Hazardous agent (NIOSH 2016 [group 1]).
Use appropriate precautions for receiving, handling, storage, preparation, dispensing, transporting, administration, and disposal. Follow NIOSH and USP 800 recommendations and institution-specific policies/procedures for appropriate containment strategy (NIOSH 2016; USP-NF 2020).
An FDA-approved patient medication guide, which is available with the product information, and as follows, must be dispensed with this medication:
Fensolvi: https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/213150s002lbl.pdf#page=15
Lupron Injection: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/019010s038lbl.pdf#page=27
Lupron Depot-Ped: https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/020263s053lbl.pdf#page=26
Central precocious puberty: Treatment of pediatric patients with central precocious puberty.
Endometriosis: For use in the management of endometriosis, either as monotherapy (for pain relief and reduction of endometriotic lesions) or as combination therapy with norethindrone acetate (for the initial management of the painful symptoms of endometriosis and management of symptom recurrence).
Limitations of use: Not for use prior to menarche or post-menopause. Monotherapy is not recommended for retreatment.
Prostate cancer, advanced: Treatment of advanced prostate cancer.
Uterine leiomyomata (fibroids): For use in combination with iron for the preoperative hematologic improvement of patients with anemia caused by fibroids when 3 months of hormonal suppression is deemed necessary.
Limitations of use: Not for use prior to menarche or post-menopause. Leuprolide acetate is not indicated for combination use with norethindrone acetate for the preoperative hematologic improvement of patients with anemia caused by heavy menstrual bleeding due to fibroids.
Breast cancer, premenopausal ovarian suppression for fertility preservation during chemotherapy; Breast cancer, premenopausal ovarian suppression during endocrine therapy; Breast cancer in male patients, hormone receptor–positive; Hormone therapy for transgender females (assigned male at birth); Paraphilia, males
Lupron Depot (1-month, 3-month, or 6-month formulation) may be confused with Lupron Depot-Ped (1-month, 3-month, or 6-month formulation).
Lupron Depot-Ped is available in three formulations, a 1-month formulation, a 3-month formulation, and a 6-month formulation. Both the 1-month and 3-month formulations offer an 11.25 mg strength, which may further add confusion.
The Institute for Safe Medication Practices (ISMP) includes this medication among its list of drugs (chemotherapeutic agent, parenteral and oral; contraindicated in pregnancy [Fensolvi, Lupron Depot]) which have a heightened risk of causing significant patient harm when used in error (High-Alert Medications in Acute Care and Community/Ambulatory Care Settings).
Leuprolide is available as different salt formulations (leuprolide acetate and leuprolide mesylate). Use caution when selecting a leuprolide formulation, as indications and dosing vary between the products.
None known.
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the drug interactions program by clicking on the “Launch drug interactions program” link above.
Antidiabetic Agents: Hyperglycemia-Associated Agents may diminish the therapeutic effect of Antidiabetic Agents. Risk C: Monitor therapy
Choline C 11: Luteinizing Hormone-Releasing Hormone Analogs may diminish the therapeutic effect of Choline C 11. Risk C: Monitor therapy
Corifollitropin Alfa: Luteinizing Hormone-Releasing Hormone Analogs may enhance the therapeutic effect of Corifollitropin Alfa. Risk X: Avoid combination
Flotufolastat F18: Androgen Deprivation Therapy Agents may diminish the diagnostic effect of Flotufolastat F18. Management: Androgen deprivation therapy (ADT) may result in changes in the uptake of flotufolastat F18 in prostate cancer. The impact of ADT on the performance of flotufolastat F18 is unknown, but use of alternative agents should be considered. Risk D: Consider therapy modification
Gallium Ga 68 PSMA-11: Androgen Deprivation Therapy Agents may diminish the therapeutic effect of Gallium Ga 68 PSMA-11. Management: Androgen deprivation therapy (ADT) may result in changes in the uptake of gallium Ga 68 PSMA-11 (gozetotide) in prostate cancer. The impact of ADT on the performance of gallium Ga 68 PSMA-11 is unknown, but use of alternative agents should be considered. Risk D: Consider therapy modification
Haloperidol: QT-prolonging Agents (Indeterminate Risk - Caution) may enhance the QTc-prolonging effect of Haloperidol. Risk C: Monitor therapy
Indium 111 Capromab Pendetide: Luteinizing Hormone-Releasing Hormone Analogs may diminish the diagnostic effect of Indium 111 Capromab Pendetide. Risk X: Avoid combination
Piflufolastat F18: Androgen Deprivation Therapy Agents may diminish the diagnostic effect of Piflufolastat F18. Management: Androgen deprivation therapy (ADT) may result in changes in the uptake of piflufolastat F18 in prostate cancer. The impact of ADT on the performance of piflufolastat F18 is unknown, but use of alternative agents should be considered. Risk D: Consider therapy modification
QT-prolonging Agents (Highest Risk): QT-prolonging Agents (Indeterminate Risk - Caution) may enhance the QTc-prolonging effect of QT-prolonging Agents (Highest Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy
Evaluate pregnancy status prior to use and throughout treatment in patients who could become pregnant; pregnancy should be excluded prior to use.
Treatment with leuprolide usually inhibits ovulation and stops menstruation; however, contraception is not ensured. When contraception is indicated, a nonhormonal contraceptive should be used during leuprolide therapy.
Leuprolide suppresses ovarian and testicular steroidogenesis. Decreased libido, impotence, erectile dysfunction, and menstrual disorders may result and fertility may be impaired. Suppression of fertility is reversible following discontinuation of leuprolide. Pregnancy rates are not expected to be affected once leuprolide is discontinued. When used to treat pain associated with endometriosis in patients who are infertile, fertility is not improved by leuprolide treatment (ASRM 2012).
Leuprolide is used off label to suppress menstruation and preserve ovarian function and fertility in patients undergoing chemotherapy; however, leuprolide is not considered to be an effective contraceptive; a nonhormonal contraceptive is recommended when leuprolide is used during chemotherapy (ACOG 2018; ACOG 2021).
Based on the mechanism of action and data from animal reproduction studies, in utero exposure to leuprolide may cause fetal harm. Use is contraindicated during pregnancy.
It is not known if leuprolide is present in breast milk.
According to the manufacturer, the decision to breastfeed during therapy should consider the risk of infant exposure, the benefits of breastfeeding to the infant, and the benefits of treatment to the mother.
Monitor bone mineral density. Monitor for signs/symptoms of hypersensitivity (including delayed hypersensitivity), severe cutaneous adverse reactions (including Stevens-Johnson syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms, and acute generalized exanthematous pustulosis), and pseudotumor cerebri. Monitor for development or worsening of psychiatric symptoms. Evaluate pregnancy status in patients who could become pregnant (prior to use and during therapy).
Endometriosis: Endometrial-related pain.
Paraphilia: CBC (baseline, monthly for 4 months then every 6 months); serum testosterone (baseline, monthly for 4 months then every 6 months); serum luteinizing hormone (LH) (baseline and every 6 months), follicle-stimulating hormone (FSH) (baseline), serum BUN and creatinine (baseline and every 6 months); bone density (baseline and yearly); ECG (baseline) (Reilly 2000).
Precocious puberty:
Response to treatment (GnRH agonist stimulation test, basal serum luteinizing hormone levels or serum sex steroid levels), height, bone age.
Prostate cancer: LH and FSH levels, serum testosterone (~4 weeks after initiation of therapy), prostate specific antigen. Screen for diabetes (monitor blood glucose and HbA1c; periodically and as clinically necessary), serum lipids, and cardiovascular risk prior to initiating and periodically during treatment. Consider periodic monitoring of electrocardiograms and electrolytes in patients at risk for QT prolongation. Monitor for signs/symptoms of emerging cardiovascular disease, tumor flare, urinary tract, and spinal cord compression (observe patients with metastatic vertebral lesions closely, particularly in the first few weeks of treatment).
Transgender hormone therapy: Serum testosterone levels (goal <50 ng/dL) every 3 months during the first year and then annually or biannually; serum LH, FSH, and prolactin levels at baseline and annually; routine cancer and laboratory screening as in non-transgender individuals for all tissues present (ES [Hembree 2017]; Gava 2016).
Cardiovascular monitoring for patients with prostate cancer: Comprehensive assessment prior to treatment including a history and physical examination, screening for cardiovascular disease risk factors such as hypertension, diabetes, dyslipidemia, obesity, and smoking; baseline and serial ECGs are recommended in patients at risk of QTc prolongation during androgen deprivation therapy (ADT); estimate 10-year cardiovascular disease risk in patients without cardiovascular disease at baseline; assess cardiovascular risk annually during ADT (ASCO [Armenian 2017]; ESC [Lyon 2022]).
Testosterone, castrate levels: ≤50 ng/dL (SI: ≤1.7 nmol/L).
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.
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.
Distribution: Males: Vd: 27 L.
Protein binding: 43% to 49%.
Metabolism: Metabolized to smaller inactive peptides, then may be further catabolized; Major metabolite, pentapeptide (M-1).
Bioavailability: SUBQ: 94%.
Half-life elimination: ~3 hours.
Time to peak: Camcevi: 3.2 hours (first dose) and 2.1 hours (second dose); Eligard: ~5 hours (7.5 mg), ~3.3 hours (30 mg), or ~4.5 hours (45 mg).
Excretion: Urine (<5% as parent and major metabolite).
Clearance: Camcevi: 7.6 L/hour; Eligard: 8.34 L/hour.
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