Leuprolide Acetate Injection

Overview of Leuprolide Acetate Injection

Dosage Strengths of Leuprolide Acetate Injection

40 mcg / 0.2 mL 10 mL Vial (Microdose)
10 mg/mL 2 mL Vial

General Information

Leuprolide is a synthetic analog of naturally occurring gonadotropin-releasing hormone (GnRH). Leuprolide is similar in activity and indications to goserelin. Leuprolide is used as a hormonal antagonist in the treatment of advanced prostatic cancer, and as hormonal therapy in the treatment of endometriosis. Off-label, there is use in premenopausal or perimenopausal women with hormone-responsive breast cancer for the purpose of ovarian ablation. Leuprolide was approved by the FDA in April 1985. Lupron injection is designated an orphan drug for the treatment of precocious puberty. Leuprolide depot injection is indicated for the treatment of uterine fibroid tumors, endometriosis, and advanced prostate cancer. Lupron Depot-Ped, a prefilled dual-chamber syringe that delivers leuprolide acetate over 1 month and is indicated for the treatment of children with central precocious puberty, was approved by the FDA in October 1995. In August 2011, the FDA approved Lupron Depot-Ped 11.25 mg and Lupron Depot-Ped 30 mg, which deliver leuprolide acetate over 3 months.1 In 2000, the FDA approved Viadur DUROS titanium alloy implant, a subcutaneous device which provided continual leuprolide therapy for one-year, for the palliative treatment of advanced prostate cancer. The manufacturer discontinued Viadur in 2007 due to diminished market demands. Eligard is a unique sterile polymeric matrix formulation of leuprolide acetate, administered by subcutaneous injection, that delivers the drug at a controlled rate over a specific time period. Three formulations of Eligard have been approved by the FDA for the palliative treatment of advanced prostate cancer: Eligard 7.5 mg, approved in January 2002, delivers leuprolide acetate over 1 month; Eligard 22.5 mg, approved in August 2002, delivers leuprolide acetate over three months; Eligard 30 mg, approved in February 2003, delivers leuprolide acetate over four months, and Eligard 45 mg, approved December 2004, delivers leuprolide acetate over 6 months.

Mechanism of Action

Leuprolide provides a medical castration for the patient and deprives hormonally-dependent tumors of testosterone or estrogen. During short-term or intermittent therapy, leuprolide has the same stimulatory action as GnRH, but long-term therapy suppresses gonadotropin release from the pituitary gland and reduces steroidogenesis in the ovaries and testicles. Normally, GnRH is released in a pulsatile fashion, but the sustained activity of leuprolide leads to downregulation of the receptor and decreased production of follicle-stimulating hormone (FSH) and luteinizing hormone (LH). In the male, this activity stops testosterone production in the testis. In the female, it stops estrogen production in the ovaries. In patients with endometriosis, this reversible hypoestrogenic state produces symptomatic relief of the pain of endometriosis and decreases the number of endometriotic lesions. Initially, there is a surge of FSH and LH, which can cause a flare reaction in prostate or breast carcinoma. Eventually, the flare reaction will diminish. Total castration can be expected in 1—2 weeks.

Pharmacokinetics

Leuprolide is administered subcutaneously or intramuscularly. Once absorbed, relatively high concentrations of the drug can be found in liver, pineal, kidney, and pituitary tissues. In vitro binding to human protein ranged 43—49%. Like the naturally occurring hormone, leuprolide can be metabolized in the anterior pituitary and hypothalamus. The plasma elimination half-life of leuprolide is estimated to be about 3 hours. Leuprolide subcutaneous injection is rapidly and completely absorbed with a bioavailability of about 94%.

Indications

For inhibiting premature leuteinizing hormone (LH) surges in women undergoing controlled ovarian hyperstimulation and subsequent in vitro fertilization (IVF) or other assisted reproductive technology (ART) for the treatment of infertility†:

NOTE: Drugs such as ganirelix and cetrorelix are now more commonly used and are FDA-approved for this purpose. Leuprolide should only be used by a qualified infertility specialist. Withhold HCG administration in cases where the ovaries are abnormally enlarged to reduce the chance of inducing ovarian hyperstimulation syndrome (OHSS).

Subcutaneous dosage for 'long-protocol' (leuprolide acetate injection solution only, do NOT use depot formulations):

Adult females: Optimal daily dosage is adjusted for the individual patient by the ART specialist; 'long-protocols' are most common but an alternative leuprolide 'flare protocol' is also used (not discussed here, note the dosage regimens for flare protocols are much different than those of long protocols). In the long protocol, leuprolide is typically started on day 21 to 24 of the menstrual cycle prior to the ovarian stimulation cycle; dosages vary but typically range 0.5 to 1 mg/day subcutaneous. Women will menstruate, continuing to use the leuprolide during oocyte stimulation with FSH, which usually begins after estradiol suppression is documented. By day 3 of the menstrual cycle, the dosage of leuprolide is typically decreased by 50%. Leuprolide and FSH (adjusting FSH dosage as needed) are administered until sufficient follicular development is attained. HCG is then administered to induce final follicular maturation for oocyte retrieval.

For inhibiting premature leutenizing hormone (LH) surges in women undergoing controlled ovarian hyperstimulation as part of the treatment of infertility:

Subcutaneous dosage: Adult females: FSH is initiated on day 2 or 3 of the cycle, followed by ganirelix acetate 250 mcg subcutaneously once daily during the mid to late portion follicular phase of the cycle (typically on day 6 of FSH administration). Continue ganirelix and FSH administration (adjust FSH dosage as needed) until the day of HCG administration. When a sufficient number of follicles of adequate size are present, as assessed by ultrasound, the final maturation of the follicles is induced by the administration of HCG. In clinical studies with ganirelix, the 250 mcg/day regimen resulted in the highest vital pregnancy and implantation rates per attempt and per embryo transfer; higher and lower dosages were associated with reduced responses. Therefore, a maximum 250 mcg/day subcutaneous is recommended.2

Contraindications/Precautions

Leuprolide injection contains benzyl alcohol; the depot formulation and implant do not. Patients who are allergic to benzyl alcohol may have an allergic reaction. Leuprolide subcutaneous injections should be used with caution in patients with known benzyl alcohol hypersensitivity.

Leuprolide is contraindicated in patients with hypersensitivity to leuprolide, GnRH, or with Gonadotropin-Releasing Hormone (GnRH) Analogs hypersensitivity; anaphylactic reactions to synthetic GnRH or GnRH agonist analogs have been reported.3 4

Leuprolide may cause a sudden onset or worsening of prostate cancer or breast cancer symptoms (flare) due to transient increases in testosterone or estrogen levels, respectively, such as bone pain, neuropathy, hematuria, or urethral or bladder outlet obstruction. Patients with urinary tract obstruction or metastatic vertebral lesions should be monitored carefully for signs of renal impairment or spinal cord compression, respectively, during initial leuprolide treatment.

Since leuprolide suppresses the pituitary-gonadal axis, diagnostic tests for pituitary insufficiency or other pituitary-gonadal function conducted during treatment and after cessation of therapy may be misleading.

Leuprolide therapy interrupts menstruation; women who continue to cycle or who experience breakthrough bleeding while receiving leuprolide should notify their physician. The drug should not be administered to women with dysfunctional uterine bleeding or undiagnosed vaginal bleeding.

Leuprolide should be used with caution in patients with osteoporosis. GnRH analog therapy increases the risk of reduced bone mineral density in men as well as women, and may have particular relevance for the geriatric population. The addition of hormone replacement therapy (estrogens and/or progestins) to leuprolide therapy for endometriosis or uterine fibroids may be effective in reducing the bone mineral loss in women. Reduced bone mineral density and osteopenia are also a concern if GnRH or LHRH analogs are used in adolescent children. LHRH-analogs (aka GnRH analogs) have been used alone or added to growth hormone (rh-GH) therapy to moderately increase adult height in adolescents with normally timed puberty and idiopathic short stature; the LHRH-analogs delay puberty and thus prolong the period of bone growth via delay of sex hormone-induced growth-plate senescence. In one study, the use of a LHRH-agonist for 4 years, the typical duration needed to see an increase in adult height, was found to decrease bone mineral density in the lumbosacral region to more than 1 standard deviation below the population mean in 82% of adolescent patients receiving the LHRH-agonist (see Adverse Reactions). The authors concluded that LHRH-agonist therapy cannot be routinely recommended to augment height in short adolescents with normally timed puberty; for most adolescents the potential benefit of treatment would not outweigh the risks.5 Leuprolide should not be used for the treatment of stuttering priapism in adolescents or children who have not yet reached full sexual maturity or adult stature.6 Prescribers must use caution and be sure to select the appropriate product for use in pediatric patients. While the Lupron Depot-Ped product is indicated for use in children, the Viadur implant and Eligard brands of leuprolide are contraindicated in children and adolescents due to limited experience.7

Although leuprolide has been used as an adjunct in fertility protocols, leuprolide is contraindicated during pregnancy because spontaneous abortion could occur once conception ensues. Leuprolide may cause fetal harm if administered to a pregnant woman; pregnancy must be ruled out before initiating treatment with leuprolide; pregnancy testing is recommended in females of childbearing potential prior to use to establish that the patient is not pregnant. When used at the recommended dose and dosing interval, leuprolide usually inhibits ovulation and stops menstruation; however, contraception is not ensured by taking leuprolide. Therefore, contraception requirements such as non-hormonal methods are required. Advise patients to notify their healthcare provider if they believe they may be pregnant. Discontinue leuprolide if a patient becomes pregnant during treatment and inform the patient of potential risk to the fetus.8 9 The higher-dose Lupron Depot products, Viadur implant and Eligard products are contraindicated in females due to limited experience and lack of an indication for use in females.7 10 8 9

Because the consequences on lactation and to the nursing infant are not known, breast-feeding should be avoided during treatment with leuprolide. The Viadur implant and Eligard brands of leuprolide are contraindicated in females due to due to a lack of indication for use and limited experience, thus these products would not be given to the lactating female.7 108 9

The use of GnRH analogs in men has been reported in association with an increased risk of myocardial infarction, sudden cardiac death, and stroke. Carefully weigh the known benefits and risks of GnRH agonists such as leuprolide when determining appropriate treatment for prostate cancer. Also, monitor patients for signs and symptoms suggestive of the development of cardiovascular disease. The risk of myocardial infarction, sudden cardiac death, and stroke appears low but needs to be evaluated carefully along with cardiovascular risk factors like cardiac disease, tobacco smoking, hypertension, hypercholesterolemia, and obesity. Manage patients according to current clinical practice.71112 At this time, there are no known comparable studies evaluating the risk of cardiovascular events in women or children taking GnRH agonists for other indications.1112

The use of GnRH analogs in men has been reported in association with hyperglycemia and an increased risk of developing diabetes mellitus. Carefully weigh the known benefits and risks of GnRH agonists such as leuprolide when determining appropriate treatment for prostate cancer. Periodically monitor patients' blood glucose concentration and/or glycosylated hemoglobin; hyperglycemia may represent diabetes mellitus development or worsening of glycemic control in patients with the condition. Manage patients according to current clinical practice.71112 At this time, there are no known comparable studies evaluating the risk of diabetes in women or children taking GnRH agonists for other indications.1112

Androgen deprivation therapy prolongs the QT interval. Consider whether the benefits of androgen deprivation treatments (e.g., leuprolide) outweigh the potential risk for QT prolongation in patients with congenital long QT syndrome, electrolyte imbalance (e,g., hypokalemia, hypomagnesemia, hypocalcemia), or congestive heart failure.13 Also use with caution in patients with cardiac disease or other conditions that may increase the risk of QT prolongation including cardiac arrhythmias, bradycardia, myocardial infarction, hypertension, coronary artery disease, or in patients receiving medications known to prolong the QT interval or cause electrolyte imbalances. Females, geriatric patients, patients with diabetes mellitus, thyroid disease, malnutrition, alcoholism, or hepatic disease may also be at increased risk for QT prolongation.14 15 16 17 18 19. Consider periodic monitoring of electrocardiogram (ECG) and electrolytes.13

Use leuprolide with caution in patients with a preexisting seizure disorder. Seizures have been reported during postmarketing surveillance in patients with a history of epilepsy, cerebrovascular disease, central nervous system anomalies or brain tumor, and patients on concomitant medications that have been associated with seizures. Seizures have also been reported in patients without any risk factors.1 13 9

Use leuprolide with caution in patients with depression and emotional instability; monitor patients for worsening of psychiatric symptoms during treatment with leuprolide. During postmarketing experience, emotional lability, such as crying, irritability, impatience, anger, and aggression were reported. Depression, including rare reports of suicidal ideation and attempt, were reported in children treated for central precocious puberty. Many, but not all, of these patients had a history of psychiatric illness or other comorbidities with an increased risk of depression.1 13

Pregnancy

Although leuprolide has been used as an adjunct in fertility protocols, leuprolide is contraindicated during pregnancy because spontaneous abortion could occur once conception ensues. Leuprolide may cause fetal harm if administered to a pregnant woman; pregnancy must be ruled out before initiating treatment with leuprolide; pregnancy testing is recommended in females of childbearing potential prior to use to establish that the patient is not pregnant. When used at the recommended dose and dosing interval, leuprolide usually inhibits ovulation and stops menstruation; however, contraception is not ensured by taking leuprolide. Therefore, contraception requirements such as non-hormonal methods are required. Advise patients to notify their healthcare provider if they believe they may be pregnant. Discontinue leuprolide if a patient becomes pregnant during treatment and inform the patient of potential risk to the fetus.8 9 The higher-dose Lupron Depot products, Viadur implant and Eligard products are contraindicated in females due to limited experience and lack of an indication for use in females.7 10 8 9

Breast-Feeding

Because the consequences on lactation and to the nursing infant are not known, breast-feeding should be avoided during treatment with leuprolide. The Viadur implant and Eligard brands of leuprolide are contraindicated in females due to due to a lack of indication for use and limited experience, thus these products would not be given to the lactating female.7 108 9

Adverse Reactions/Side Effects

General descriptions of adverse effects associated with leuprolide, in various formulations, appear below. In general, side effects and their incidence may differ with gender, age of population of use, intended indication, and other factors.

Leuprolide may cause adverse effects related to decreased testosterone and estrogen. In males, serum testosterone is reduced to castrate concentrations. In premenopausal females, circulating estrogens are reduced to postmenopausal concentrations. After leuprolide initiation, these decreases in hormonal concentrations occur within 2—4 weeks. Leuprolide may be used therapeutically to induce a hypo-estrogenic, menopause-like condition in females which is basically an induced amenorrhea that usually occurs within 3 months of initiating depot therapy; in some female patients, such a result might be considered a side effect of the drug. Examples of adverse reactions related to reduced testosterone and/or estrogen in males or females include hot flashes (8.3—73.3%), gynecomastia (2.2—7%) or breast enlargement (< 5%), testicular pain (3.8%), testicular atrophy or decreased testicular size (< 20.2%), breast pain or mastalgia (3.1%), impotence (erectile dysfunction) (< 5.4%), anemia (<= 5%), hirsutism (< 2%), hyperhidrosis or sweating (< 5.3%), prostatic disorder (< 2%), vaginitis and vaginal dryness (3%), vaginal bleeding (3%), vaginal discharge (3%), accelerated sexual maturity (< 2%), cervix disorder/neoplasm (< 2%), dysmenorrhea (< 2%), menstrual disorder (< 2%), feminization (< 2%), growth inhibition (< 2%), goiter (< 2%), prostate pain, libido decrease (3.3—5.4%), clamminess (4.4%), night sweats (2.7—3.3%), libido loss (< 2%), breast soreness or tenderness or mastalgia (< 7%), penile disorder (< 2%), reduced penis size (< 2%), thyroid enlargement (< 5%), thyroid nodule, accidental injury, pallor, sallow, a hard nodule in the throat, penis disorder (< 5%), and testis disorder (< 5%).1 8 10 20 8 In addition, hyperhidrosis and pallor were reported in a pediatric patient receiving leuprolide depot-ped for 3-month administration.1

Administration of leuprolide acetate results in an initial increase in circulating concentrations of luteinizing hormone and follicle stimulating hormone, which leads to a transient increase in concentrations of testosterone and dihydrotestosterone in males and estrone and estradiol in premenopausal females. Patients may experience worsening of symptoms or onset of new symptoms. Cases of spinal cord compression, which may contribute to muscle paralysis with or without fatal complications, have been reported with LHRH agonists such as leuprolide. If spinal cord compression or renal impairment develops, institute standard treatment of these complications. Potential exacerbations of signs and symptoms of the disease during the first few weeks of treatment are of concern in patients with vertebral metastases. If these conditions are aggravated, it may lead to neurological problems such as weakness and/or paresthesias of the lower limbs. Adverse events reported with leuprolide include paresthesias (< 8.2%), weakness (3.6%), numbness (< 5%), hyperesthesia (< 5%), peripheral neuropathy (< 5%), motor deficiency, neuromuscular disorders (< 9.6%), aggravation of preexisting tumor (< 2%), spinal fracture/paralysis, bone pain (< 5%), back pain (< 2%), general pain or musculoskeletal extremity pain (< 32.7%).1 8 10 20 7 Musculoskeletal pain and pain in extremity were also reported in a pediatric patient receiving leuprolide depot-ped for 3-month administration.1

Administration of leuprolide acetate results in an initial increase in circulating concentrations of luteinizing hormone and follicle stimulating hormone, which leads to a transient increase in concentrations of testosterone and dihydrotestosterone in males and estrone and estradiol in premenopausal females. Patients may experience worsening of symptoms or onset of new genitourinary type symptoms. Adverse events reported with leuprolide in men include aggravation of preexisting tumor (less than 2%), libido increase, blisters on penis, penile swelling, testicular soreness (less than 2%), increased or decreased prostatic acid phosphatase (5% or more), balanitis (less than 5%), hernia (less than 5%), bladder cancer or other neoplasm (less than 5%), epididymitis (less than 5%), and prostatic disorder (less than 5%). Urinary disorders (10.2% to 16.5%) were a common adverse event in males and females. Specific urinary and reported laboratory adverse events include urinary retention (less than 4.6%), hematuria (less than 6%), nocturia (less than 3.8%), increased urinary frequency (2.2% to 6%), urinary urgency (less than 6%), dysuria (less than 5%), urinary incontinence (less than 5%), urination difficulties (less than 2%), urination pain (less than 2%), scanty urination (less than 2%), bladder spasm (less than 5%), hyperuricemia (5% or more), increased BUN (5% or more), increased serum creatinine (5% or more), hyperphosphatemia (5% or more), increased calcium (less than 5%), decreased total protein (5% or more), decreased urine specific gravity (5% or more), increased urine specific gravity (5% or more), dehydration (less than 8.2%), decreased bicarbonate (5% or more), post void residual, pyuria, hypokalemia, uric aciduria, renal calculus (nephrolithiasis), and ureteral or bladder outlet obstruction such as renal tubular obstruction (less than 5%).1 8 10 20 7

Leuprolide may be associated with several central nervous system (CNS) adverse events. During postmarketing experience, emotional lability, such as crying, irritability, impatience, anger, and aggression were reported. Depression, including rare reports of suicidal ideation and attempt, were reported in children treated for central precocious puberty. Many, but not all, of these patients had a history of psychiatric illness or other comorbidities with an increased risk of depression. Counsel patients on the possibility of development or worsening of depression during leuprolide receipt, and to report any unusual changes in moods or behavior. CNS adverse reactions reported during clinical trails include depression (less than 5.3%), asthenia (less than 12.2%), headache (less than 10.2%), dizziness (less than 8.3%), insomnia (less than 8.5%), syncope (less than 5%), lethargy (less than 5%), memory impairment or disorder (less than 5%), mood swings or emotional lability (less than 5%), nervousness (less than 5%), malaise or fatigue (less than 17.5%), abnormal thinking (less than 5%), amnesia (less than 5%), confusion (less than 5%), dementia (less than 5%), delusions (less than 5%), rigors (less than 2%), anxiety (less than 5%), agitation (less than 5%), seizures (less than 5%), hyporeflexia, euphoria, and hyperreflexia. Seizures were reported in patients with a history of epilepsy, cerebrovascular disorders, CNS anomalies or tumors, and in patients on concomitant mediations that have been associated with seizures. Additionally, seizures were reported in patients without any risk factors. Tremor, gait disturbance, and tearfulness were reported in pediatric patients during postmarketing experience.7 1 8 10 20 13 Other CNS effects of leuprolide therapy include blurred vision (less than 5%), ophthalmologic disorders (unspecified, less than 5%), decreased or abnormal vision (visual impairment, less than 5%), amblyopia (less than 5%), xerophthalmia (less than 5%), smell and taste disturbance (parosmia or dysgeusia less than 5%), auditory hallucinations, tinnitus (less than 5%), decreased hearing (hearing loss), vertigo (less than2%), and loss of smell (parosmia). Hearing disorder was also reported postmarketing.7 1 8 10 20

Leuprolide receipt may cause gastrointestinal (GI) disorders: in clinical trials, 10.2—16% of patients reported GI disorders. Specific gastrointestinal adverse effects included anorexia (< 6%), eructation (< 5%), peptic ulcer (< 5%), decreased albumin (>= 5%), elevated PT and PTT (>= 5%), elevated hepatic enzymes (>= 5%), enlarged abdomen (< 5%), duodenal ulcer (< 5%), increased appetite or appetite stimulation (< 5%), thirst or xerostomia (< 5%), gum bleeding (< 5%), hepatomegaly (< 5%), intestinal or GI obstruction (< 5%), periodontal abscess (< 5%), diarrhea (< 5%), weight gain (< 2.3%), constipation (< 9.9%), weight loss (< 5%), dyspepsia (< 2%), dysphagia (< 5%), gastrointestinal disturbance (< 5%), rectal polyps (< 5%), flatulence (< 2%), gingivitis (< 5%), gastroenteritis or colitis (2.5%), vomiting (< 5%), abdominal pain (< 2%), GI bleeding (< 5%), nausea (< 5%), hepatitis, hypoproteinemia, occult blood, and rectal fistula or erythema. Hepatic dysfunction and rare cases of serious hepatic injury were reported during postmarketing.13 1 8 10 20 In addition, decreased appetite and obesity (weight gain) were reported by a patient receiving leuprolide depot-ped for 3-month administration.1

An injection site reaction can occur with leuprolide administration; the incidence may vary depending on the formulation used. For example, 9% of Lupron Depot Ped recipients, < 5% of Lupron Depot 7.5 mg recipients, 8.2—37.5% of Lupron Depot 22.5—45 mg recipients, and 16—34.6% of Eligard recipients had an injection site reaction. Injection site reactions with Eligard mainly consisted of transient burning or stinging, and most (84—100%) reactions were mild. Local skin irritation (<= 12.2%) is a more common complaint. Mild bruising, erythema, itching, induration, pain, or local skin ulcer were noted in < 3% of injections. Abscess and hematoma have been reported at the sites of injections. During post-marketing surveillance, induration and abscess were reported. Injection site ecchymosis occurred in < 5% of patients with most leuprolide formulations 1 20 8 20, but was noted in 34.6% of patients who received the Viadur implant.7 Most local reactions (e.g., pulling, pressure, itching, erythema, pain, edema, burning, and bleeding) associated with initial insertion or removal and insertion of a new Viadur implant began and resolved within the first 2 weeks; reactions persisted in 9.3% of patients, and 10.3% of patients developed application-site reactions after the first 2 weeks following insertion. Local reactions after insertion of a subsequent implant were comparable to those seen after initial insertion; < 1% of patients have been reported to have a spontaneous implant extrusion with or without associated infection. Migration of implant has been reported postmarketing.7 The Viadur implant was discontinued by the manufacturer due to diminished market demand.

Dermatological adverse reactions reported in clinical trials with the use of various leuprolide products include dermatitis or rash (unspecified) (5%), xerosis (< 5%), alopecia or hair loss disorder (< 5%), skin hyperpigmentation (< 5%), skin lesions (< 5%), impaired wound healing (< 5%), melanosis or melasma (< 5%), acneiform rash, seborrhea (3%), hair disorder (< 2%), leukoderma or skin hypopigmentation (< 2%), nail disorder (< 2%), purpura (< 2%), skin hypertrophy (< 2%), cyst (< 5%), boils, keratosis, mole, and new primary malignancy of the skin or ear including basal cell carcinoma, melanoma, and squamous cell cancer (< 5%). Hypersensitivity-related dermatologic and systemic adverse reactions reported in clinical trials include rash (unspecified) (< 3%) and allergic reaction (< 5%). Anaphylactoid reactions to synthetic GnRH or GnRH agonist analogs such as leuprolide have been reported in the literature but appear rare; urticaria, photosensitivity reactions, erythema multiforme, and symptoms consistent with an asthmatic process have also been reported rarely with an incidence rate of about 0.002%.1 20 8 20 7

As with other GnRH agonists, there have been reports of ovarian cyst formation (and ovarian enlargement) with the use of leuprolide in females during infertility protocols. When leuprolide is used in combination with gonadotropins, ovarian hyperstimulation syndrome (OHSS) has also occurred, but appears rare. (see Adverse Reactions for various gonadotropin therapies).

Pituitary apoplexy is a syndrome due to a sudden infarction or hemorrhage in the pituitary gland. Rare cases of pituitary apoplexy have been reported after the administration of gonadotropin-releasing hormone (GnRH) agonists such as leuprolide. In most cases, a pituitary adenoma was diagnosed. A majority of pituitary apoplexy cases occur within 2 weeks of the first dose and some within the first hour. In these cases, pituitary apoplexy has presented as a sudden and severe headache, nausea/vomiting, visual changes including reduction in visual field and ocular paresis, ophthalmoplegia, altered mental status, and sometimes cardiovascular collapse. The presence of acute visual loss (e.g., bitemporal hemianopia or hemianopsia) and ocular paresis (reductions in ocular movements from involvement of cranial nerves III, IV, and VI) can assist in the diagnosis. Immediate medical management may be required; management strategies include close observation, corticosteroid administration, maintenance of fluid and electrolyte balance, and possibly surgical decompression of the pituitary fossa.21 [31508]7

Decreased bone density has been reported in the medical literature in men who have had orchiectomy or who have been treated with a GnRH agonist analog. In a clinical trial, 25 men with prostate cancer, 12 of whom had been treated previously with leuprolide acetate for at least 6 months, underwent bone density studies as a result of pain. The leuprolide-treated group had lower bone density scores than the non-treated control group. Long periods of medical castration in men can be anticipated to have effects on bone density.8 GnRH analog therapy increases the risk of reduced bone mineral density and osteopenia in men as well as women and may lead to a risk for osteoporosis. In clinical trials of leuprolide with men and women, pathological bone fractures were reported in < 5%) of patients.1 8 20 10 The addition of hormone replacement therapy (e.g., estrogens) to leuprolide therapy may be effective in reducing the bone mineral loss in women. Reduced bone mineral density and osteopenia are also a concern if GnRH analogs are used for extended periods in adolescent children. LHRH-analogs (aka GnRH analogs) have been used alone or added to growth hormone (rh-GH) therapy to moderately increase adult height in adolescents with normally timed puberty and idiopathic short stature; the LHRH-analogs delay puberty and thus prolong the period of bone growth via delay of sex hormone-induced growth-plate senescence. In one study, the use of a LHRH-agonist for 4 years, the typical duration needed to see an increase in adult height, was found to decrease bone mineral density in the lumbosacral region to more than 1 standard deviation below the population mean in 82% of adolescent patients receiving the LHRH-agonist (compared to 32% of patients receiving placebo). The reduced bone mineral density during active treatment was followed by inadequate catch-up accretion of bone mineral after treatment cessation. The authors concluded that LHRH-agonist therapy cannot be routinely recommended to augment height in short adolescents with normally timed puberty; for most adolescents the potential benefit of treatment would not outweigh the risks.5

Leuprolide may cause musculoskeletal adverse effects such as arthralgia (< 9.3%), myalgia (< 8.2%), joint disorder (< 16.3%), joint pain (< 5%), myopathy (< 2%), accidental injury (< 5%), neck pain (< 5%), leg muscle cramps (< 5%), ptosis (< 5%), joint pain (< 2%), muscle atrophy (< 2%), ankylosing spondylosis, arthritis (< 2%), blurred disc margins, muscle stiffness, muscle tenderness, pelvic fibrosis, knee effusion, muscle spasms, increased sedimentation rate, or antinuclear antibody presence. Postmarketing, tenosynovitis-like symptoms (synovitis) and symptoms consistent with fibromyalgia have been reported.1 8 20 10

In men, hyperglycemia and an increased risk of developing diabetes mellitus have been reported in association with the use of GnRH analogs. Carefully weigh the known benefits and risks of GnRH agonists such as leuprolide when determining appropriate treatment for prostate cancer. Periodically monitor patients' blood glucose concentration and/or glycosylated hemoglobin; hyperglycemia may represent diabetes mellitus development or worsening of glycemic control in patients with the condition. Manage patients according to current clinical practice. In clinical trials with the depot suspension, > 5% of patients had hyperglycemia. Among leuprolide acetate solution recipients, < 5% had diabetes or hyperglycemia. Diabetes mellitus was reported during the postmarketing period.8 20 The FDA evaluated data from published studies comparing outcomes in patients undergoing androgen deprivation therapy to treat prostate cancer versus patients not undergoing this treatment; most of the studies reported small, but statistically significant, increased risks of diabetes in men receiving GnRH agonists. At this time, there are no known comparable studies evaluating the risk of diabetes in women or children taking GnRH agonists for other indications.11 12

Less than 5% of patients taking leuprolide experienced fever, chills, lymphedema, or lymphadenopathy. Infection was noted in 12.2% or less of patients who received leuprolide. Specific infections included influenza, pneumonia, strep throat, pharyngitis, rhinitis, abscess, cellulitis, herpes zoster, upper respiratory infection, urinary tract infection, and sinusitis.201 20 8

In men, an increased risk of myocardial infarction, sudden cardiac death, and stroke has been reported in association with the use of GnRH analogs. Carefully weigh the known benefits and risks of GnRH agonists such as leuprolide when determining appropriate treatment for prostate cancer. Monitor patients for signs and symptoms suggestive of the development of cardiovascular disease. The risk of myocardial infarction, sudden cardiac death, and stroke appears low but needs to be evaluated carefully along with cardiovascular risk factors (see Contraindications). Manage patients according to current clinical practice. The FDA evaluated data from published studies comparing outcomes in patients undergoing androgen deprivation therapy to treat prostate cancer versus patients not undergoing this treatment; most of the studies reported small, but statistically significant, increased risks of cardiovascular events in men receiving GnRH agonists. At this time, there are no known comparable studies evaluating the risk of cardiovascular disease in women or children taking GnRH agonists for other indications.11 12 Long-term androgen deprivation therapy can cause QT prolongation; consider whether the benefits of androgen deprivation therapy outweigh the potential risks in patients with congenital long QT syndrome, electrolyte abnormalities, or congestive heart failure and in patients taking class IA or class III antiarrhythmic medications.8Cardiovascular events noted with leuprolide include generalized edema (< 20.8%), peripheral edema (< 12%), hyperlipidemia (>= 5%), reduced HDL (>= 5%), atrial fibrillation (< 5%), deep venous thrombosis (thromboembolism) (< 5%), arrhythmia exacerbation (< 5%), sinus bradycardia (< 5%), peripheral vascular disorder (< 2%), heart failure (< 5%), hypertension (< 8%), hypotension (< 5%), ECG changes or cardiac ischemia (19%), murmur (3%), phlebitis (2%), thrombosis (2%), angina (< 5%), myocardial infarction (< 5%), pulmonary embolism (< 5%), varicose vein (< 5%), carotid bruit, extrasystole, palpitations, perivascular cuffing, ruptured aortic aneurysm, stroke, sinus tachycardia, and transient ischemic attack.10208

Respiratory disorders (4.2—10.7%) have been reported among leuprolide recipients. Cough was noted 1.3—6.6% of patients, 5% had sinus congestion, 2% had dyspnea, and < 5% had emphysema, pulmonary edema, pleural rub, pulmonary fibrosis, pleural effusion, hypoxia, asthma, hiccups, lung disorder, voice alteration (dysphonia), or increased sputum. Other adverse events noted in trials include chest tightness, decreased breathing sounds, pleuritic chest pain (pleurisy), pulmonary infiltrate, rales/rhonchi, nasal congestion, rhinorrhea, lung cancer, and wheezing/bronchitis. Postmarketing, pulmonary embolism and interstitial lung disease were reported.8 20 9

Leukopenia was noted in >= 5% of patients who received leuprolide. However, both decreased and increased white blood cell count have been reported in various clinical trials. Leuprolide may cause thrombocytopenia. Decreased and increased platelet count were reported among depot-injection recipients, and < 5% had epistaxis or hemoptysis. Hemoptysis was also noted in trials with leuprolide acetate solution.20 8 Eosinophilia has been reported on laboratory analysis in 5% or greater of patients receiving depot injections, but the relationship to the drug or any side effects is uncertain.8

Storage

Store this medication at 68°F to 77°F (20°C to 25°C) and away from heat, moisture and light. Keep all medicine out of the reach of children. Throw away any unused medicine after the beyond use date. Do not flush unused medications or pour down a sink or drain.

  • 1. a. b. c. d. e. f. g. h. i. j. k. l. m. n. o. p. q. Lupron Depot-Ped (leuprolide acetate for depot suspension) package insert. North Chicago, IL: Abbott Laboratories; 2017 May.
  • 2. Devroey P, Abyholm T, Diedrich K, et al. A double-blind, randomized, dose-finding study to assess the efficacy of the gonadotropin releasing hormone antagonist ganirelix (Org 37462) to prevent premature luteinizing hormone surges in women undergo
  • 3. Potashnik G, Lunenfeld E, Spitz E, et al. Anaphylactic reaction to gonadotropin-releasing hormone. N Engl J Med 1993;328:815.
  • 4. Letterie GS, Stevenson D, Shah A. Recurrent anaphylaxis to a depot form of GnRH analogue. Obstet Gynecol 1991;78(5 pt 2):943.
  • 5. a. b. Yanovski JA, Rose SR, Municchi G, et al. Treatment with a luteinizing hormone-releasing hormone agonist in adolescents with short stature. N Engl J Med 2003;348:908-17.
  • 6. Montague DK, Jarow J, Broderick GA, et al. American Urological Association guideline on the management of priapism. J Urol 2003;170:1318-24.
  • 7. a. b. c. d. e. f. g. h. i. j. k. l. m. n. o. Viadur (leuprolide acetate implant) package insert. Mountain View, CA: ALZA Corporation; 2010 Nov.
  • 8. a. b. c. d. e. f. g. h. i. j. k. l. m. n. o. p. q. r. s. t. u. v. w. x. y. Lupron Depot-3 month 11.25 mg (leuprolide acetate injection, powder, lyophilized, for suspension) package insert. Osaka, Japan: Takeda Pharmaceutical Company Limited; 2018 April.
  • 9. a. b. c. d. e. f. g. h. Lupron Depot (leuprolide acetate) suspension package insert. Osaka, Japan: Takeda Pharmaceutical Company Limited; 2016 June.
  • 10. a. b. c. d. e. f. g. h. i. j. k. l. m. Eligard (leuprolide acetate) package insert. Fort Collins, CO: Tolmar, Inc.; 2013 Feb.
  • 11. a. b. c. d. e. f. Food and Drug Administration (US FDA) News Release. Ongoing Safety Review of GnRH Agonists and possible increased risk of diabetes and certain cardiovascular diseases. . Retrieved May 3, 2010.
  • 12. a. b. c. d. e. f. Food and Drug Administration (US FDA) Drug Safety Communication. Updated to ongoing safety review of GnRH Agonists and notification to manufacturers of GnRH Agonists to add new safety information to labeling regarding increased risk of diabetes.
  • 13. a. b. c. d. e. f. Lupron Depot (leuprolide acetate for depot suspension) package insert. North Chicago, IL: AbbVie Inc; 2017 July.
  • 14. Roden, DM. Drug-induced prolongation of the QT interval. New Engl J Med 2004;350:1013-22.
  • 15. Crouch MA, Limon L, Cassano AT. Clinical relevance and management of drug-related QT interval prolongation. Pharmacotherapy 2003;23:881-908.
  • 16. Benoit SR, Mendelsohn AB, Nourjah P, et al. Risk factors for prolonged QTc among US adults: Third National Health and Nutrition Examination Survey. Eur J Cardiovasc Prev Rehabil 2005;12(4):363-368.
  • 17. Koide T, Ozeki K, Kaihara S, et al. Etiology of QT prolongation and T wave changes in chronic alcoholism. Jpn Heart J 1981;22:151-166.
  • 18. van Noord C, Eijgelsheim M, Stricker BH. Drug- and non-drug-associated QT interval prolongation. Br J Clin Pharmacol 2010;70(1):16-23.
  • 19. Galli-Tsinopoulou A, Chatzidimitriou A, Kyrgios I, et al. Children and adolescents with type 1 diabetes mellitus have a sixfold greater risk for prolonged QTc interval. J Pediatr Endocrinol Metab 2014;27:237-243.
  • 20. a. b. c. d. e. f. g. h. i. j. k. l. m. n. o. p. q. r. Leuprolide acetate package insert. Bedford, OH: Ben Venue Laboratories, Inc.; 2007 Dec.
  • 21. Randeva HS, Schoebel J, Byrne J, et al. Classical pituitary apoplexy: clinical features, management, and outcome. Clin Endocrinol 1999;51:181-8.

Related Medications