Leuprolide may cause adverse effects related to decreased testosterone and estrogen. In males, serum testosterone is reduced to castrate concentrations (less than 50 ng/dL). In premenopausal females, circulating estrogens are reduced to postmenopausal concentrations. After leuprolide initiation, these decreases in hormonal concentrations occur within 2 to 4 weeks. Leuprolide may be used therapeutically to induce a hypo-estrogenic, menopause-like condition in females, which is 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 (74% to 98%). Women treated with leuprolide also reported vaginitis (11% to 28%) and unspecified menstrual disorders (2% to 5%).[42683] [51299] Hot flashes occurred in 25% to 98% of men with prostate cancer who received leuprolide; in a small study (n = 74), hot flashes were less common in men who had been orchiectomized (8.3%). Hot flashes also occurred in 73% to 98% of women with endometriosis or fibroids treated with leuprolide; 5% of pediatric patients treated with leuprolide reported hot flushes in 1 trial, 2% reported vasodilation in another, and flushing was reported in postmarketing experience. Gynecomastia occurred in 7.1% or less of men with prostate cancer who received leuprolide; breast enlargement was reported separately in less than 5% of men as well as in postmarketing reports of pediatric patients treated with leuprolide. Less than 2% of pediatric patients reported gynecomastia/breast disorders. Breast soreness or tenderness (mastalgia) occurred in 7% or fewer men, 6% of women with endometriosis, and 4% of children who received leuprolide. Lactation occurred in less than 5% of women in 1 study.[66721] [43800] [41676] [42683] [51299] [45097] [66709] [65368] [68727] Additional adverse reactions in men with prostate cancer related to reduced testosterone include testicular pain (less than 5%), testicular atrophy or decreased testicular size (20.2% or less), impotence (erectile dysfunction) (5.4% or less), hyperhidrosis or sweating (2% or less), clamminess (4.4% or less), night sweats (3.3% or less), penis disorder (less than 5%), reduced penis size (less than 2%), and testis disorder (less than 5%). Prostate pain was reported in postmarketing experience with men receiving leuprolide for the treatment of prostate cancer. Libido decrease (5.4% or less) or loss of libido (less than 2%) was reported in men treated with leuprolide; additionally, 10% to 11% of women receiving treatment for fibroids reported decreased libido.[66721] [43800] [45097] [66709] [68727] In pediatric patients, accelerated sexual maturity, dysmenorrhea, feminization, growth inhibition, hirsutism, and unspecified menstrual disorders each occurred in less than 2% of patients; hyperhidrosis was reported in 4% of patients.[65368] [41676]

Administration of leuprolide 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 (to approximately 50% above baseline) and dihydrotestosterone in males during the first 2 weeks of treatment; testosterone concentrations typically decline to baseline or below by the end of the second week of treatment and to castrate levels within 2 to 4 weeks after starting treatment. Patients with prostate cancer may experience worsening of symptoms or onset of new symptoms (tumor flare). Cases of urinary tract obstruction and spinal cord compression, which may contribute to muscle paralysis with or without fatal complications, have been reported with LHRH agonists such as leuprolide. Monitor patients for symptoms of tumor flare during the first few weeks of treatment; closely monitor patients with urinary tract obstruction or metastatic vertebral lesions for new or worsening symptoms. If spinal cord compression or renal impairment develops, institute standard treatment of these complications. This transient increase in testosterone concentrations is usually manifested by an increase in bone pain (7% or less), but may also include neuropathy, hematuria (6.1% or less), or renal tubular obstruction/bladder outlet obstruction (less than 5%); temporary weakness (3.6% or less) and lower limb paresthesia have been reported in a few cases. Additional possible testosterone-related adverse events reported with leuprolide treatment in men with prostate cancer include increased prostatic acid phosphatase (5% or more), balanitis (less than 5%), epididymitis (less than 5%), prostate disorder (less than 5%), testicular soreness/pain (less than 2%), libido increase, and penile swelling; decreased prostatic acid phosphatase occurred in at least 5% of men in 1 study. Spinal fracture/paralysis was reported in postmarketing experience with leuprolide in prostate cancer patients. Aggravation of a preexisting tumor occurred in less than 2% of pediatric patients who received leuprolide.[41676] [45097] [66709] [43800] [66721] [68727]

Unspecified urinary disorders occurred in 10.2% to 16.5% of men with prostate cancer treated with leuprolide in 2 clinical trials. Specific urinary and related laboratory adverse events occurring in men with prostate cancer in various clinical trials include urinary retention (less than 2%), nocturia (9% or less), increased urinary frequency (2.2% to 12%), urinary urgency (less than 2%), frequency/urgency (6.1% or less), dysuria (less than 5%), micturition urgency which included dysuria (6% or less), urinary incontinence (less than 5%), urination difficulty (less than 2%), urination pain (8% or less), scanty urination (less than 2%), bladder spasm (less than 5%), increased or decreased urine specific gravity (5% or more), dehydration (8.2% or less), post void residual, pyuria, and uric aciduria (5% or more).[45097] [66709] [66721] [43800] [68727] Dysuria was also reported in less than 5% of women receiving leuprolide for the treatment of endometriosis, as a possible effect related to decreased estrogen concentrations; renal calculus (nephrolithiasis) occurred in 0.7% of these women. Urinary incontinence occurred in less than 5% of women treated with leuprolide for fibroids and in less than 2% of pediatric patients receiving leuprolide.[42683] [51299] [41676]

Emotional lability or mood swings, and depression have been reported with leuprolide treatment. There have been very rare reports of suicidal ideation and attempt. Many, but not all, of these patients had a history of depression or other psychiatric illness. Patients should be counseled on the possibility of development or worsening of depression during treatment with leuprolide. Monitor patients for worsening of psychiatric symptoms during treatment with leuprolide. Refer patients with new or worsening depression to a mental health professional, as appropriate.[43800] [41676] [65368] [42683] [51299] Depression and mood swings each occurred in less than 5% of men with prostate cancer treated with leuprolide; suicidal ideation and attempt was reported in postmarketing experience.[45097] [66721] [43800] [66709] [68727]. Depression and/or emotional lability was reported in 11% to 31% of women with endometriosis or fibroids treated with leuprolide, and is thought to be a possible effect of decreased estrogen in these patients; serious cases of depression were reported in 0.7% of patients, and both mood swings and suicidal ideation/attempt were reported in postmarketing experience.[42683] [51299] Psychiatric events, including affect lability, affective disorder, aggression, crying, depressed mood, disruptive mood dysregulation disorder, auditory hallucination, altered mood, mood swings, and trichotillomania were reported in 22% of pediatric patients with central precocious puberty (CPP) receiving leuprolide every 6 months. Altered mood occurred in 5% and depression in less than 2% of pediatric patients with CPP treated with leuprolide, while emotional lability (5%), a general emotional disorder (2%), crying, and tearfulness were also reported in this patient population.[41676] [65368] Additional psychiatric effects that occurred in women and were thought to be a possible effect of deceased estrogen included insomnia (31% or less) and anxiety/nervousness (8% or less).[42683] [51299] Anxiety and nervousness were also reported in less than 5% of men with prostate cancer who received leuprolide, and in less than 2% of children with CPP. Insomnia was reported in 8.5% or fewer men with prostate cancer treated with leuprolide, and was reported in 4% of children.[45097] [66709] [66721] [41676] [65368] [43800] Amnesia (6% or fewer) and delusions (less than 5%) were reported in both men and women treated with leuprolide; unspecified memory disorders (memory impairment) were separately reported in less than 5% of men who received leuprolide.[66721] [43800] [42683] [51299] Abnormal thinking, agitation, auditory hallucinations/tinnitus, confusion, dementia, euphoria, and were each reported in less than 5% of men treated with leuprolide.[66721] [43800] Irritability was reported in 2% of leuprolide-treated children, and unspecified personality disorder in less than 5% of treated women.[65368] [42683] [51299]

Nausea/vomiting occurred in 5% to 25% of women with endometriosis or fibroids treated with leuprolide; it was less commonly reported in men with prostate cancer (9% or less). In children with central precocious puberty (CPP), less than 2% of patients experienced nausea and/or vomiting with monthly leuprolide administration compared to 13% with leuprolide administration every 6 months.[45097] [66721] [65368] [41676] [42683] [51299] [68727] Altered bowel function was reported in 14% of women treated with leuprolide.[42683] [51299] Diarrhea was reported in 13% or fewer men with prostate cancer and in 16% of children with CPP receiving leuprolide every 6 months. Constipation was reported by 9% or fewer men and children who received leuprolide.[66721] [45097] [43800] [65368] [41676] [68727] Unspecified GI disturbances were reported in 7% or fewer patients treated with leuprolide. Changes in appetite were reported in 13% or less of treated women, while anorexia occurred in 6% or fewer men and appetite stimulation was reported in less than 5% of men and less than 2% of children; decreased appetite was reported in postmarketing experience in children with CPP who received leuprolide. Weight gain was reported in up to 7% of children and less than 2% of men treated with leuprolide, and was reported in 12% of women; conversely, weight loss occurred in less than 5% of men who received leuprolide.[42683] [51299] [66721] [43800] [65368] [41676] Additional gastrointestinal adverse reactions reported in men and children treated with leuprolide include dyspepsia (less than 2%), dysphagia (less than 5%), and gingivitis (less than 5%).[45097] [66721] [43800] [41676] Xerostomia and thirst occurred in less than 5% of men and women treated with leuprolide.[42683] [51299] [66721] [43800] Adverse reactions only reported in men with prostate cancer who received leuprolide include gum hemorrhage (less than 5%), periodontal abscess (less than 5%), duodenal ulcer (less than 5%), peptic ulcer (less than 5%), abdominal distension (less than 5%), eructation (less than 5%), flatulence (less than 2%), gastroenteritis/colitis (2.5% or less), GI bleeding (less than 5%), occult blood on rectal exam, GI obstruction (less than 5%), rectal fistula/erythema, rectal polyps (less than 5%), and unspecified GI disorders which included dyspepsia and flatulence (0.2% to 16%).[43800] [66721] [45097] Abdominal pain was reported in 8% of men with prostate cancer in 1 study and in up to 18% of children with CPP treated with leuprolide.[65368] [41676] [68727]

A localized injection site reaction including induration and abscess has been reported with leuprolide administration.[66721] [43800] [42683] [51299] [41676] [65368] Reactions including pain, erythema, hemorrhage, nodule, paresthesia, pruritus, and warmth at the site occurred in 6% to 37.5% of men with prostate cancer treated with Lupron Depot doses 22.5 mg and higher or Camcevi; the incidence was less than 5% in men receiving the 7.5 mg dose of Lupron Depot and in women with endometriosis or fibroids who also received Lupron Depot (3.75 mg or 11.25 mg doses). A general skin reaction and ecchymosis were each reported in 8.5% or fewer men and women treated with leuprolide; in 1 small study, a general skin was reported in 12.2% of nonorchiectomized men who received leuprolide 30 mg and in 0% of orchiectomized men.[66721] [43800] [66709] [42683] [51299] [68727] Out of 1,338 Eligard injections administered to men with prostate cancer, injection site reactions included mostly brief and mild burning/stinging (16% to 34.6%), pain (2.3% to 4.6%), erythema (0.9% to 2.6%), and bruising (1.7% to 2.5%); pruritus (0.4% to 2.6%), induration (0.4%), and skin ulcer (0.1%) were also reported.[45097] Injection site reactions, including injection site pain, erythema, warmth, bruising, discomfort, and swelling, were reported in 78% of pediatric patients receiving leuprolide every 6 months for central precocious puberty. Mostly mild to moderate injection site reactions including abscess were reported in 9% of pediatric patients receiving leuprolide every month, while injection site pain (19% to 21%) and swelling (2%) were reported in patients receiving leuprolide every 3 months. Sterile abscess, hematoma, induration, and warmth at the injection site were listed as less common injection site reactions. Pruritus (11%) was also reported in this population.[65368] [41676]

Symptoms consistent with anaphylactoid reactions have rarely been reported (0.002%) with leuprolide treatment; anaphylactic reactions to Gonadotropin Releasing Hormone (GnRH) agonists have been reported in the medical literature. General reports of allergic reaction have been reported with leuprolide during clinical trials (estimated incidence less than 2%). Allergic reactions have included rash (less than 2%), urticaria, and photosensitivity reactions.[41676] [42683] [43800] [45097] [51299] [66709] [66721] [65368] Rash, including erythema multiforme, occurred in 3% of pediatric patients treated with leuprolide monthly and in 7% of patients receiving leuprolide every 6 months. Androgen-like effects of leuprolide in women have included acne (10%) and alopecia (less than 5%). Acneiform rash/seborrhea (3%), alopecia (less than 2%), and hair disorder (less than 2%) were also reported children. Drug-induced body odor and nail disorders were reported in women (less than 5% each) and as less common adverse reactions in children receiving leuprolide.[41676] [42683] [51299] Skin hypopigmentation (leukoderma) and purpura occurred in less than 2% of children; pallor was reported as a less common adverse reaction. Hyperkeratosis and skin hypertrophy were also reported.[41676] Alopecia/hair disorder (less than 5%), cysts (less than 5%), dermatitis (5%), impaired wound healing (less than 5%), melanosis/melasma (less than 5%), skin hyperpigmentation (less than 5%), skin lesions (less than 5%), xerosis (less than 5%), hyperkeratosis, skin hypertrophy, pallor, blisters on penis, hives, moles, pubic boils, and spiders have been reported in men who received leuprolide for prostate cancer; hair growth was reported in postmarketing experience.[45097] [43800] [41676] [66709] [66721] [65368]

As with other GnRH agonists, there have been reports of ovarian cyst formation (and ovarian enlargement) with the use of leuprolide in females during various types of infertility protocols. When leuprolide is used in combination with gonadotropins, ovarian hyperstimulation syndrome (OHSS) has also occurred.[63289]

Pituitary apoplexy is a syndrome due to a sudden infarction in the pituitary gland. Rare cases of pituitary apoplexy have been reported after the administration of Gonadotropin Releasing Hormone (GnRH) agonists including leuprolide during postmarketing surveillance. 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 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.[31507] [31508] [66709] [45097] [66721] [43800] [65368] [41676] [42683] [51299] [68727]

Treatment with leuprolide can cause decreased bone mineral density (BMD) which can result in osteopenia and a risk for osteoporosis. In women with endometriosis treated with leuprolide, the mean change in BMD of the lumbar spine from baseline at week 24 (n = 41) was -3.2% and at week 52 (n = 29) was -6.3%; in patients who received leuprolide plus norethindrone, the mean change from baseline at week 24 (n = 42) was -0.3% and at week 52 (n = 32) was -1%. Eight months after discontinuation of therapy, the mean change from baseline in patients treated with leuprolide was -3.3% compared with -0.9% for those who received leuprolide/norethindrone; at 12 months, the mean change from baseline was -2.2% versus -0.7%, respectively. In patients receiving leuprolide for the treatment of uterine fibroids, vertebral trabecular BMD showed a mean decrease of 2.7% from baseline at 3 months; a trend toward recovery was observed 6 months after discontinuation of therapy.[51299] [42683] Reduced BMD has also been reported in published literature and postmarketing in pediatric patients with central precocious puberty treated with leuprolide. Published studies have indicated that after discontinuation of leuprolide therapy in children, subsequent bone mass accrual is preserved and peak bone mass in late adolescence does not seem to be affected.[41676] Long periods of medical castration in men can be anticipated to have effects on bone density. Decreased BMD has been reported in men treated with a Gonadotropin Releasing Hormone (GnRH) or a Luteinising Hormone-Releasing Hormone (LHRH) 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 BMD studies as a result of pain. The leuprolide-treated group had lower bone density scores than the non-treated control group. Pathological bone fractures were reported in less than 5% of men with prostate cancer treated with leuprolide.[45097] [66721] [43800] [66709] [68727]

General complaints of pain (4.2% to 32.7%) and joint disorders (8% to 16.3%) were reported in men with prostate cancer and women with endometriosis or fibroids who were treated with leuprolide in clinical trials; joint disorders were considered to be a possible effect of decreased estrogen status in women.[42683] Arthralgia (1.3% to 11%), extremity pain (10% or less), musculoskeletal pain including back pain and bone pain (11% or less), myalgia (8.2% or less) occurred in men who received leuprolide for prostate cancer in clinical trials. Additional musculoskeletal adverse reactions reported in men treated with leuprolide include ankylosing spondylosis, arthritis, back pain (less than 2%), blurred disc margins, disc hernia (less than 5%), inguinal hernia, joint pain (less than 5%), leg cramps (less than 5%), limb pain (2.7% or less), muscle atrophy (less than 2%), muscle stiffness, muscle tenderness, neck pain (less than 5%), pelvic fibrosis, accidental injury, and knee effusion. Muscle cramps/spasms were reported postmarketing.[66709] [66721] [43800] [51299] [68727] Fibromyalgia and tenosynovitis-like symptoms have been reported postmarketing in both men and women.[66709] [66721] [43800] [42683] [51299] General pain (3%), extremity pain (9%), back pain (7%), ligament sprain (7%), fracture, including ankle and tibia fractures (4%), arthralgia (less than 2%), myalgia (less than 2%), and joint disorders (less than 2%) were reported in pediatric patients with central precocious puberty (CPP). Hyperkinesis, myopathy, antinuclear antibody present, and increased sedimentation rate were also reported in less than 2% of pediatric patients who received leuprolide; synovitis and epiphysiolysis have been reported in postmarketing experience.[65368] [41676]

Hyperglycemia (at least 5% in some studies; less than 5% in others) and an increased risk of developing diabetes mellitus have been reported with the use of Gonadotropin Releasing Hormone (GnRH) agonists in men; diabetes has also been reported in postmarketing experience in pediatric studies with leuprolide. The risk for diabetes in women is unknown due to a lack of data. Periodically monitor blood glucose concentration and/or glycosylated hemoglobin (HbA1c) in those receiving leuprolide therapy. Manage patients according to current clinical practice.[40127] [42683] [66709] [45097] [66721] [43800] [65368] [41676] [68727]

Leukopenia was noted in at least 5% of men with prostate cancer who received leuprolide; leukopenia occurred in more than 10% of men with prostate cancer who received 1 formulation of leuprolide (Lutrate Depot), while decreased white blood cells (WBC) have also been reported in postmarketing experience with all other populations treated with leuprolide products. Increased WBC and eosinophilia have each occurred in at least 5% of men treated with leuprolide. Decreased red blood cells, hematocrit, and hemoglobin were reported in less than 5% of men who received leuprolide; anemia was reported in 5% or less of these patients and in more than 10% of patients treated with Lutrate Depot. In one study, 13.9% of men had a grade 1 or 2 decreased hemoglobin at baseline; during treatment with Lupron Depot, grade 1 (42.4%), grade 2, (2%), and grade 3 or 4 (1.3%) hemoglobin reductions were reported. Thrombocytopenia and decreased platelets were each reported in at least 5% of men; increased platelets were also reported in at least 5% of patients in this population. Additionally, prolonged bleeding time (increased PT and PTT) occurred in at least 5% of men with prostate cancer treated with leuprolide in one clinical trial.[41676] [42683] [43800] [45097] [51299] [65368] [66709] [66721] [68727]

Fever/chills was reported in less than 5% of men with prostate cancer treated with leuprolide and fever in 17% or fewer children with central precocious puberty (CPP) treated with leuprolide. General reports of infection or inflammation were reported in 5.4% or fewer men who received leuprolide and was a reported as a less common adverse reaction in patients with CPP.[66721] [43800] [65368] [41676] Urinary tract infection (UTI) occurred in 7% or fewer men treated with leuprolide; in one small study, 6.6% of men reported UTI/cystitis during treatment but was not felt to be related to treatment in any patient. Serious cases of UTI were reported in 1.9% of women with endometriosis who received leuprolide; pyelonephritis was reported in women with fibroids treated with leuprolide 7.5 mg monthly but not in those who received 3.75 mg monthly.[66721] [43800] [42683] [51299] [68727] Upper respiratory infection (URI) was reported in 17% or fewer men with prostate cancer and children with CPP treated with leuprolide in clinical trials; in one trial, URI occurred in 21.2% of men who received leuprolide but was not felt to be related to therapy in any patient.[66709] [43800] [65368] [68727] In all populations treated with leuprolide including women with endometriosis or fibroids, influenza (less than 5%), rhinitis (less than 5%), and sinusitis (less than 5%) were reported.[66721] [43800] [41676] [42683] [51299] Pharyngitis occurred in less than 5% of men while strep throat was also reported; nasopharyngitis occurred in 22% or fewer pediatric patients.[43800] [41676] [65368] Additional infection-related events reported in men who received leuprolide include abscess (less than 5%), bronchitis (less than 5%), cellulitis (less than 5%), lymphadenopathy (less than 5%), pneumonia (less than 5%; serious cases, at least 2%), pulmonary infiltrates, and shingles/herpes zoster (less than 5%).[66721] [43800]

Respiratory disorders (10.7% or less) reported in men with prostate cancer treated with leuprolide, included: asthma (less than 5%), chest tightness, decreased breath sounds, cough (less than 5%), dysphonia (less than 5%), dyspnea (less than 2%) emphysema (less than 5%), epistaxis (less than 5%), hemoptysis (less than 5%), hiccups (less than 5%), hypoxia (less than 5%), lung disorder (less than 5%), pleuritic chest pain, pleural effusion (less than 5%), pleural rub (less than 5%), pulmonary edema (less than 5%), pulmonary fibrosis (less than 5%), rales/rhonchi, sinus/nasal congestion (5% or less), wheezing (less than 5% and often associated with URI), and increased sputum (less than 5%); interstitial lung disease was reported in postmarketing experience with leuprolide. Cough (13% or less), productive cough (6% or less), bronchospasm (6% or less), and asthma (less than 2%) were also reported in children with central precocious puberty treated with leuprolide, along with epistaxis (less common), and dyspnea (postmarketing). Asthma or wheezing was also reported in leuprolide-treated women with pre-existing histories of asthma or environmental or drug allergies.[42683] [51299] [66721] [43800] [41676] [65368] [68727]

In men, an increased risk of myocardial infarction, sudden cardiac death, and stroke has been reported in association with the use of Gonadotropin Releasing Hormone (GnRH) agonists; the risk appears to be low based on the reported odds ratios. Carefully evaluate cardiovascular risk factors when determining the treatment plan for men with prostate cancer. Monitor patients for signs and symptoms suggestive of the development of cardiovascular disease; if cardiac disease develops, manage patients according to current clinical practice.[66721] [43800] [45097] [66709] [68727] 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.[42122] Leuprolide may cause QT prolongation. Ischemia/ECG changes occurred in up to 19% of men with prostate cancer treated with leuprolide.[66721] [68727] Palpitations and sinus tachycardia were each reported in less than 5% of adults (men and women) treated with leuprolide while myocardial infarction occurred in less than 5% of men and in postmarketing experience with women. Stroke and transient ischemic attack (TIA) were reported in men who received leuprolide and in postmarketing experience with women; serious cases of stroke/TIA occurred in at least 2% of men who received Lupron Depot in one study. Phlebitis/thrombosis occurred in 2% or fewer men who received leuprolide. Deep thrombophlebitis/DVT/thromboembolism and pulmonary embolism each occurred in less than 5% of men and in postmarketing experience with women. Ruptured aortic aneurysm, atrial fibrillation (less than 5%), cardiac arrhythmias (less than 5%), carotid bruit, extrasystole, heart failure (less than 5%), and murmur (3% or less) were also reported in leuprolide-treated men.[66721] [43800] [42683] [51299] Hypertension occurred in 15% of men with prostate cancer treated with leuprolide mesylate (Camcevi), in 8.3% or fewer men receiving leuprolide acetate, in less than 2% of children with central precocious puberty (CPP) who received leuprolide acetate, and in postmarketing experience with women with endometriosis or fibroids treated with leuprolide acetate. Hypotension occurred in less than 5% of men and in postmarketing experience with leuprolide in other populations; syncope was reported in less than 5% of adults and in less than 2% of children treated with leuprolide.[66709] [45097] [66721] [43800] [65368] [41676] [42683] [51299] [68727] Angina related to treatment was reported in less than 5% of leuprolide-treated men while chest pain (unspecified) was reported in 4% of children.[66721] [43800] [65368] [41676] Bradycardia occurred in less than 5% of men and less than 2% of children who received leuprolide; varicose veins were reported in less than 5% of men and peripheral vascular disorder in less than 2% of children.[66721] [43800] [41676]

Although the relationship to drug treatment is difficult to assess in this population, various laboratory abnormalities were reported in men with prostate cancer treated with leuprolide, including decreased bicarbonate (5% or more), hyperphosphatemia (5% or more), hyperuricemia (5% or more), increased BUN (Lupron Depot, 5% or more; Lupron, less than 5%), increased creatinine (Lupron Depot, 5% or more; Lupron, less than 5%), and increased calcium (hypercalcemia) (less than 5%). Decreased potassium concentrations (hypokalemia) was also reported in clinical trials and postmarketing experience.[43800] [66721]

During the early phase of therapy, because gonadotropins and sex steroids rise above baseline because of the initial stimulatory effect of the drug, an increase in clinical signs and symptoms of puberty may also be observed in pediatric patients during the first weeks of therapy or after subsequent doses; vaginitis/vaginal bleeding/vaginal discharge occurred in 3% of pediatric patients with central precocious puberty in one study; vaginal bleeding was reported in postmarketing experience with pediatric patients receiving leuprolide.[41676] [65368] In women receiving leuprolide for endometriosis or uterine fibroids, an increase in symptoms may be observed during the initial days of therapy, but these should dissipate with continued therapy. Endocrine adverse effects in women treated with leuprolide have included menstrual irregularity (changes in vaginal bleeding patterns or other menstrual disorders) and lactation (galactorrhea).[42683]

Seizures occurred in less than 5% of men with prostate cancer treated with leuprolide in one clinical trial and 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. Manage patients receiving leuprolide who experience convulsions according to current clinical practice.[41676] [43800] [51299] [66709] [42683] [65368] [45097] [66721] [68727]Pseudotumor cerebri (idiopathic intracranial hypertension) has been reported in pediatric patients during postmarketing experience.[41676] [65368] Dizziness (including vertigo) was reported in 2% to 8.3% (grade 3 or 4, 0.7% or less) of men with prostate cancer treated with leuprolide; dizziness was also individually reported in 3.3% to 7% and vertigo in less than 2%.[45097] [66709] [66721] [43800] Dizziness and/or vertigo occurred in 11% to 16% of women treated with leuprolide for endometriosis or fibroids, and was reported as a less common adverse reaction in pediatric patients treated for central precocious puberty.[51299] [42683] [41676] Taste perversion or disorders (dysgeusia) were reported in less than 5% of men and women treated with leuprolide.[66721] [51299] [42683] [45097] Additional CNS-related adverse reactions reported in men with prostate cancer included hyperreflexia (less than 5%), hyporeflexia (less than 5%), loss of smell (parosmia, less than 5%), rigors (less than 2%), and tremor (less than 2%).[66721] [45097] Gait disturbance was a less commonly reported adverse reaction in pediatric patients treated with leuprolide.[41676]

Ocular adverse reactions occurring in less than 5% of men with prostate cancer treated with leuprolide include visual impairment, amblyopia, blurred vision, ptosis, and xerophthalmia; eyelid growth and perivascular cuffing of the eye were also reported in men treated with leuprolide.[43800] [66721] Unspecified ophthalmologic disorders that were possibly an effect of decreased estrogen and conjunctivitis were also reported in less than 5% of women with endometriosis or fibroids treated with leuprolide.[42683] [51299] Decreased vision was a less common adverse reaction reported in pediatric patients with central precocious puberty treated with leuprolide.[41676]

Paresthesias occurred in 8.2% or fewer men with prostate cancer treated with leuprolide in clinical trials; they also occurred in 7% of women with endometriosis who received lower doses of leuprolide in one study.[66721] [43800] [42683] [51299] Neuromuscular disorders (i.e., leg cramps, paresthesia) were reported in less than 9.6% of men with prostate cancer who received leuprolide and in 2% to 7% of women with endometriosis in 2 studies as a possible effect of decreased estrogen.[43800] [42683] [51299] Additional adverse events reported in men with prostate cancer treated with leuprolide include hyperesthesia (less than 5%), motor deficiency (less than 5%), neuropathy (less than 5%), numbness (less than 5%), peripheral neuropathy (less than 5%), weakness (3.6% or less), and "feet burning".[45097] [66721] [43800] [66709] Peripheral neuropathy also occurred in postmarketing experience with women treated with leuprolide.[42683] [51299]

Headache (26% to 65%) was commonly reported in women with endometriosis or fibroids treated with leuprolide in clinical trials, possibly as an effect of decreased estrogen; it was less common in men with prostate cancer treated with leuprolide (10.2% or less) and in children with central precocious puberty (CPP) who received leuprolide treatment.[42683] [51299] [66721] [43800] [65368] [41676] [68727] Asthenia (12.2% or less), fatigue (including asthenia) (15% or less), fatigue/malaise (17.5% or less), fatigue/lethargy (11.9% or less), fatigue as a stand-alone term (less than 5%), and lethargy as a stand-alone term (less than 5%) were also reported in men who received leuprolide across clinical trials.[66721] [43800] [66709] [45097] [68727] Asthenia occurred in 8% to 18% of women treated with leuprolide, and was a less commonly reported adverse reaction in children with CPP; somnolence occurred in less than 2% of children with CPP who received leuprolide and fatigue was reported in postmarketing experience.[65368] [41676] [42683] [51299] Decreased hearing/hearing loss and hearing disorders were reported in postmarketing experience in men treated with leuprolide.[66721]

Elevated hepatic enzymes (2 x baseline and above the upper limit of normal) occurred in 1% to 3% of women with endometriosis or fibroids treated with leuprolide; the increases observed in most (83.3%) of the women with endometriosis occurred beyond 6 months of treatment.[42683] [51299] Increased liver function tests (e.g., ALT, AST, GGTP, LDH) were also reported in at least 5% of men with prostate cancer treated with leuprolide, along with hypoalbuminemia (5% or more) and decreased total protein (5% or more). Hepatomegaly occurred in less than 5% of men treated with leuprolide, while hepatitis and hepatic dysfunction were also reported. Serious drug-induced liver injury (hepatotoxicity) was reported in both men and women treated with leuprolide in postmarketing experience.[66709] [66721] [43800] [42683] [51299] [68727]

Hypercholesterolemia has been reported with leuprolide treatment. In women with normal baseline cholesterol, the mean cholesterol increase was 16 to 17 mg/dL in women with endometriosis (p less than 0.03) and 11 to 29 mg/dL in women with uterine fibroids; after 24 weeks of follow-up, the percent-change from baseline was 9.2% for total cholesterol, 7.4% for HDL, 10.9% for LDL, 5% for the LDL/HDL ratio, and 17.5% for triglycerides; the major impact of adding norethindrone to treatment was a decrease in HDL cholesterol and an increase in the LDL/HDL ratio. Lipid concentrations outside the normal range at week 0 and week 24 of leuprolide treatment in women included total cholesterol (more than 240 mg/dL; 15% and 23%), HDL cholesterol (less than 40 mg/dL; 15% and 10%), LDL cholesterol (more than 160 mg/dL; 0% and 8%), LDL/HDL ratio (more than 4; 0% and 3%); the percentage of women with triglyceride concentrations outside the normal range (hypertriglyceridemia) was unchanged (13%). Changes from baseline tended to be greater at week 52; after treatment, mean serum lipid concentrations in women with follow-up data returned to pretreatment values.[42683] [51299] At least 5% of men with prostate cancer treated with leuprolide experienced hyperlipidemia (total cholesterol, LDL cholesterol, triglycerides) and/or decreased HDL cholesterol. In men treated with Lupron Depot 45 mg every 6 months, 28.5% had grade 1 or 2 increases in cholesterol at baseline; grade 1 or 2 increases (200 to 300 mg/dL) during the study occurred in 55%, grade 2 increases (301 to 400 mg/dL) in 3.3%, and grade 3 increases (greater than 400 mg/dL) in 0.7% of men.[43800] [68727]

A goiter occurred in less than 2% of children with central precocious puberty treated with leuprolide in one clinical trial.[41676] Thyroid enlargement, thyroid nodule, and a hard nodule in the throat were each reported in less than 5% of men with prostate cancer treated with leuprolide.[66721]

Edema was generally reported in 14.3% or fewer men with prostate cancer and women with endometriosis or fibroids who received leuprolide, although 1 small study suggested the incidence was higher in orchiectomized men compared to nonorchiectomized (20.8% vs. 8.2%). Swelling of the temporal bone occurred in less than 5% of men, while facial swelling/edema was also reported. Peripheral edema occurred in 12% or fewer men treated with leuprolide and in less than 2% of children.[66709] [45097] [66721] [43800] [65368] [41676] [42683] [51299]

New primary malignancy has been reported in men with prostate cancer treated with leuprolide including bladder cancer (less than 5%), cancer of the skin/ear (less than 5%), and a generalized mass.[41676] [66721] [66709] In one study, a second primary neoplasm was emergent in 7.3% of men who received leuprolide including basal cell carcinoma, bladder transitional cell carcinoma, lung cancer, malignant melanoma, non-Hodgkin's lymphoma, and squamous cell carcinoma; however, none of these cases were felt to be related to treatment.[43800] A cervix disorder/neoplasm occurred in less than 2% of children with central precocious puberty who received leuprolide.[41676]

Severe cutaneous adverse reactions (SCARs), including toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome (SJS), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP) occurred in patients treated with leuprolide; some cases also had visceral involvement and/or required skin grafts. Monitor patients for SCARs and educate patients about the signs and symptoms (e.g., a prodrome of fever, flu-like symptoms, mucosal lesions, progressive skin rash, or lymphadenopathy). If a SCAR is suspected, interrupt therapy until the etiology has been determined; a dermatology consult is recommended. Permanently discontinue leuprolide for grade 4 skin reactions or confirmed SCARs.[43800]

Patients with benzyl alcohol hypersensitivity should use caution when treated with leuprolide acetate solution for injection as it is formulated with benzyl alcohol. Symptoms of hypersensitivity are usually local, in the form of erythema and induration at the injection site.[66721]

Leuprolide is contraindicated in patients with Gonadotropin-Releasing Hormone (GnRH) analogs hypersensitivity, hypersensitivity to leuprolide, or hypersensitivity to GnRH; anaphylactic reactions to synthetic GnRH or GnRH agonists have been reported.[30370] [30371] [65368] [41676] [42683] [43800] [45097] [66709] [66721] [51299]

Leuprolide may cause a sudden onset or worsening of prostate cancer (flare) due to transient increases in testosterone levels. Some patients may experience a temporary worsening of symptoms during the first few weeks for treatment, including bone pain, neuropathy, hematuria, or bladder outlet obstruction, which can be managed symptomatically. As with other LH-RH agonists, isolated cases of spinal cord compression have been observed, which may contribute to paralysis with or without fatal complications. Monitor patients for symptoms of tumor flare during the first few weeks of treatment; closely monitor patients with urinary tract obstruction or metastatic vertebral lesions for new or worsening symptoms.[66721] [43800] [45097] [66709] [68727]

Since leuprolide suppresses the pituitary-gonadal axis, laboratory test interference may occur with diagnostic tests for pituitary insufficiency or other pituitary-gonadal function conducted during treatment and after cessation of therapy.[45097] [66721] [43800] Normal function of the pituitary-gonadal system is usually restored within 4 to 12 weeks after treatment is discontinued;[66721] [43800] [68727] in pediatric patients, normal function may be restored within 6 months.[41676]

Leuprolide therapy should not be administered to women with dysfunctional uterine bleeding or undiagnosed vaginal bleeding. During the early phase of leuprolide therapy or after subsequent doses, sex steroids temporarily rise above baseline because of a transient stimulatory effect of the drug; an increase in symptoms may be observed during the first weeks of therapy.[41676] [42683] [51299] In pediatric patients, an increase in clinical signs and symptoms of puberty, including vaginal bleeding, may be observed during this time.[41676]

Carefully weigh the risks and benefits of leuprolide therapy in patients with osteopenia or osteoporosis, as well as in patients with risk factors for decreased bone mineral density (BMD) such as chronic alcohol use (more than 3 units per day), tobacco smoking, strong family history of osteoporosis, or chronic use of drugs that can decrease BMD such as anticonvulsants or corticosteroids.[51299] [42683] Gonadotropin Releasing Hormone (GnRH) analog therapy increases the risk of reduced BMD and may have particular relevance for people 65 years and older.[51299] [42683] [66721] [43800] [45097] [41676] [68727] The duration of therapy for the treatment of endometriosis and fibroids should not exceed 12 months due to the risk of loss of BMD. The addition of hormone replacement therapy (norethindrone acetate) to leuprolide therapy for endometriosis or uterine fibroids may be effective in reducing bone mineral loss in women. Once norethindrone is added, do not retreat with leuprolide without combination norethindrone; assess BMD prior to retreatment with leuprolide/norethindrone.[51299] [42683] It can be anticipated that long periods of medical castration in men with prostate cancer will also have effects on bone density.[66721] [43800] [45097] [68727] Additionally, reduced BMD has been reported in published literature and postmarketing reports in pediatric patients with central precocious puberty. Published studies have indicated that after discontinuation of leuprolide therapy, subsequent bone mass accrual is preserved and peak bone mass in late adolescence does not seem to be affected.[41676]

Carefully evaluate cardiovascular risk factors when determining a treatment plan for individuals with prostate cancer that are treated with leuprolide. An increased risk of developing myocardial infarction, sudden cardiac death, and stroke has been reported in association with the use of Gonadotropin Releasing Hormone (GnRH) agonists in men; the risk appears to be low based on the reported odds ratios. Monitor patients for signs and symptoms suggestive of cardiac disease; if cardiovascular disease develops, manage according to current clinical practice.[66721] [43800] [45097] [66709] [68727] At this time, there are no known comparable studies evaluating the risk of cardiovascular disease in other individuals taking GnRH agonists for other indications.[42122]

Use leuprolide with caution in patients with diabetes mellitus or a history of hyperlipidemia. Metabolic changes including hyperglycemia, diabetes mellitus, and hyperlipidemia have been reported in men receiving Gonadotropin Releasing Hormone (GnRH) agonists; diabetes has also been reported in postmarketing experience in pediatric studies with leuprolide. Non-alcoholic fatty liver disease including cirrhosis has been reported in postmarketing experience in adults treated with leuprolide.[66709] [45097] [66721] [43800] [65368] [41676] [68727] Hyperglycemia may represent the development of diabetes or worsening of glycemic control in patients with pre-existing diabetes. Monitor for changes in serum lipids, blood glucose, and/or glycosylated hemoglobin (HbA1c) periodically in men receiving leuprolide therapy; manage according to current clinical practice.[66709] [45097] [66721] [43800] [68727] There are no known comparable epidemiologic studies evaluating the risk of diabetes in women taking GnRH agonists.[40127]

Androgen deprivation therapy (e.g., leuprolide) may prolong the QT interval. Consider whether the benefits of leuprolide therapy outweigh the potential risk for QT prolongation in patients with congenital long QT syndrome, electrolyte imbalance (e.g., hypokalemia, hypomagnesemia, hypocalcemia), congestive heart failure, or in patients receiving medications known to prolong the QT interval. Correct any electrolyte abnormalities and consider periodic monitoring of electrocardiograms and electrolytes. Also, use leuprolide with caution in patients with conditions that may increase the risk of QT prolongation including bradycardia, AV block, heart failure, stress-related cardiomyopathy, myocardial infarction, stroke, hypomagnesemia, hypokalemia, hypocalcemia, or in patients receiving medications known to cause electrolyte imbalances. Female patients, people 65 years and older, patients with sleep deprivation, pheochromocytoma, sickle cell disease, hypothyroidism, hyperparathyroidism, hypothermia, systemic inflammation (e.g., human immunodeficiency virus (HIV) infection, fever, and some autoimmune diseases including rheumatoid arthritis, systemic lupus erythematosus (SLE), and celiac disease) and patients undergoing apheresis procedures (e.g., plasmapheresis [plasma exchange], cytapheresis) may also be at increased risk for QT prolongation.[28432] [28457] [43800] [56592] [65180] [66721] [45097] [66709] [68727]

Use leuprolide with caution in patients with a pre-existing 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. Manage patients receiving leuprolide who experience convulsions according to current clinical practice.[41676] [43800] [51299] [66709] [42683] [65368] [45097] [66721] [68727] [45097]

Use leuprolide with caution in patients with depression and emotional instability; monitor patients for worsening of psychiatric symptoms during treatment with leuprolide. Refer patients with new or worsening depression to a mental health professional, as appropriate. 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.[41676] [65368] [51299] [42683]

Use leuprolide with caution in geriatric patients. First, geriatric patients may be at increased risk for QT prolongation when receiving leuprolide. Second, GnRH analog therapy increases the risk of reduced bone mineral density, which may be particularly relevant for geriatric patients who may be more likely to have osteopenia or osteoporosis.[28432] [28457] [43800] [56592] [65180] [66721] [42683] [51299] [66709] [45097] [68727]

Gonadotropin releasing hormone (GnRH) agonists, including leuprolide, have been associated with cases of pseudotumor cerebri (idiopathic intracranial hypertension) in pediatric patients. Monitor for signs and symptoms including headache, papilledema, blurred vision, diplopia, loss of vision, pain behind the eye or pain with eye movement, tinnitus, dizziness, and nausea.[41676] [65368]

Based on findings in animal studies and mechanism of action, leuprolide can cause fetal harm, including early pregnancy loss, when administered to a pregnant woman. Formulations of leuprolide acetate used for indications that may involve treatment of individuals capable of becoming pregnant (i.e., Fensolvi, Lupron Depot-Ped, Lupron Depot 3.75 mg, and Lupron Depot 11.25 mg) are contraindicated for use during pregnancy. In animal developmental and reproductive toxicology studies, administration of a monthly formulation of leuprolide on day 6 of pregnancy (sustained exposure was expected throughout the period of organogenesis) caused adverse embryo-fetal toxicity in animals at doses less than the human dose based on body surface area (BSA) using an estimated daily dose. A similar rat study also showed increased fetal mortality and decreased fetal weights but no major fetal abnormalities at doses less than the recommended human dose based on BSA using an estimated daily dose. Advise pregnant individuals and females of reproductive potential of the potential risk to the fetus.[28432] [28457] [42683] [43800] [45097] [51299] [56592] [65180] [65368] [41676] [66709] [66721] [68727]

Serious rash and skin disease, including toxic epidermal necrolysis (TEN), Stevens Johnson syndrome (SJS), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP) occurred in patients treated with leuprolide; some cases also had visceral involvement and/or required skin grafts. Monitor patients for severe cutaneous adverse reactions (SCARs) and educate patients about the signs and symptoms (e.g., a prodrome of fever, flu-like symptoms, mucosal lesions, progressive skin rash, or lymphadenopathy). If a SCAR is suspected, interrupt therapy until the etiology has been determined; a dermatology consult is recommended. Permanently discontinue leuprolide for grade 4 skin reactions or confirmed SCARs.[43800]

Counsel patients about the reproductive risk and contraception requirements during leuprolide treatment. Leuprolide can cause fetal harm or early pregnancy loss if used during pregnancy. Exclude pregnancy (e.g., perform pregnancy testing) prior to initiating leuprolide treatment if clinically indicated. When used at the recommended dose and dosing interval, leuprolide usually reduces fertility; however, contraception is not ensured by taking leuprolide. Individuals capable of becoming pregnant should use effective non-hormonal contraception during leuprolide treatment. Based on its pharmacodynamic effects of decreasing secretion of gonadal steroids, reduced fertility or infertility is expected while on treatment with leuprolide. Clinical and pharmacologic studies in adults with leuprolide acetate and similar analogs have shown reversibility of fertility suppression when the drug is discontinued after continuous administration for periods of up to 24 weeks.[66709] [45097] [43800] [41676] [65368] [51299] [42683] [66721] [68727]

There are no data regarding the presence of leuprolide in human milk, the effects on a breast-fed infant, or the effects on milk production. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition when treating lactating individuals with Lupron Depot 3.25 mg, Lupron Depot 11.25 mg, Lupron Depot-Ped, or Fensolvi.[51299] [42683] [41676] [65368] Although leuprolide products used for prostate cancer treatment (e.g., Lupron, Lupron Depot, Eligard, and Camcevi) are not usually indicated in individuals that would be breast-feeding, advise such individuals to discontinue breast-feeding if they are receiving treatment with these products.[66721] [43800] [45097] [66709] [68727]