Leuprolide

Lupron, Lupron Depot, Lupron Depot-Ped, Eligard

Lupron doses vary according to the brand, how often you receive treatment, and your condition.

Lupron doses range from 3.75 milligrams (mg) every month to 45 mg every six months.

Your health care provider injects the drug into the subcutaneous tissue or muscle of your upper thigh or shoulder.

Although doctors prescribe Eligard in similar doses and frequency as Lupron, Eligard is only to be injected subcutaneously, that is, just beneath the top layer of skin.

Store Lupron in the refrigerator between 36-46 degrees Fahrenheit. Never put Lupron in the freezer.

Lupron Overdose

If you suspect a Lupron overdose, contact an emergency room at 911 or a poison control center (800) 222-1222 right away.

Missed Dose of Lupron

If you miss a dose of Lupron, contact your doctor right away for direction.

Leuprolide is a prescription hormone medication used for several conditions, including the treatment of the symptoms of advanced prostate cancer, endometriosis, anemia caused by uterine fibroids, and early puberty.

Leuprolide belongs to a group of drugs called GnRH agonists, which work by decreasing the amount of certain hormones in the body.

Leuprolide injection comes as a long-acting suspension that is injected into a muscle (IM) by a healthcare provider in a medical office or clinic and is usually given once a month or every 3, 4, or 6 months. Leuprolide injection also comes as a long-acting suspension that is injected just under the skin by a healthcare provider in a medical office or clinic and is usually given every 1, 3, 4, or 6 months.

Common side effects include hot flashes, generalized pain, and irritation or pain at the site of injection.

Serious side effects have been reported. See the “Drug Precautions” section.

Common side effects include:

• hot flashes
• headache
• generalized pain
• irritation or pain at the site of injection
• mood changes
• fatigue
• acne
• rash
• swelling
• vaginal bleeding or discharge, dryness, and itching
• weight gain

This is not a complete list of leuprolide side effects. Ask your doctor or pharmacist for more information.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

Serious side effects have been reported with leuprolide including:

• signs of puberty
• seizures
• urinary blockage
• increased risk for heart attack or stroke
• increased risk for osteoporosis or fractures
• increased risk for diabetes or raised blood glucose (sugar) levels
• impotence
• worsening of depression

Do not take leuprolide if you:

• are allergic to any of its ingredients
• have vaginal bleeding
• are pregnant or planning to become pregnant
• are breastfeeding

Call your doctor for instructions if you miss a dose.

Get emergency medical help if you have signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat.

Call your doctor at once if you have:

• bone pain, loss of movement in any part of your body;

• swelling, rapid weight gain;

• a seizure;

• unusual changes in mood or behavior (crying spells, anger, feeling irritable);

• sudden chest pain or discomfort, wheezing, dry cough or hack;

• painful or difficult urination; or

• high blood sugar--increased thirst, increased urination, hunger, dry mouth, fruity breath odor.

Rare but serious side effects may occur. Call your doctor if you have:

• pain or unusual sensations in your back, numbness, weakness, or tingly feeling in your legs or feet;

• muscle weakness or loss of use, loss of bowel or bladder control;

• heart attack symptoms--chest pain or pressure, pain spreading to your jaw or shoulder, nausea, sweating;

• signs of a stroke--sudden numbness or weakness (especially on one side of the body), sudden severe headache, slurred speech; or

• severe skin reaction--fever, sore throat, swelling in your face or tongue, burning in your eyes, skin pain followed by a red or purple skin rash that spreads (especially in the face or upper body) and causes blistering and peeling.

Common side effects may include:

• hot flashes, sweating, acne, rash, itching;

• mood changes;

• headache, general pain;

• vaginal swelling, itching, or discharge;

• breakthrough bleeding;

• weight gain;

• decreased testicle size; or

• redness, pain, swelling, or oozing where the shot was given.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Clinical Trials

In the majority of patients testosterone levels increased above baseline during the first week, declining thereafter to baseline levels or below by the end of the second week of treatment. This transient increase was occasionally associated with a temporary worsening of signs and symptoms, usually manifested by an increase in bone pain (see WARNINGS section). In a few cases a temporary worsening of existing hematuria and urinary tract obstruction occurred during the first week. Temporary weakness and paresthesia of the lower limbs have been reported in a few cases.

Potential exacerbations of signs and symptoms during the first few weeks of treatment is a concern in patients with vertebral metastases and/or urinary obstruction which, if aggravated, may lead to neurological problems or increase the obstruction.

In a comparative trial of Leuprolide acetate versus DES, in 5% or more of the patients receiving either drug, the following adverse reactions were reported to have a possible or probable relationship to drug as ascribed by the treating physician. Often, causality is difficult to assess in patients with metastatic prostate cancer. Reactions considered not drug related are excluded.

In this same study, the following adverse reactions were reported in less than 5% of the patients on Leuprolide acetate injection.

Cardiovascular System - Angina, Cardiac arrhythmias, Myocardial infarction, Pulmonary emboli; Gastrointestinal System - Diarrhea, Dysphagia, Gastrointestinal bleeding, Gastrointestinal disturbance, Peptic ulcer, Rectal polyps; Endocrine System - Libido decrease, Thyroid enlargement; Musculoskeletal System - Joint pain; Central/Peripheral Nervous System - Anxiety, Blurred vision, Lethargy, Memory disorder, Mood swings, Nervousness, Numbness, Paresthesia, Peripheral neuropathy, Syncope/blackouts, Taste disorders; Respiratory System - Cough, Pleural rub, Pneumonia, Pulmonary fibrosis; Integumentary System - Carcinoma of skin/ear, Dry skin, Ecchymosis, Hair loss, Itching, Local skin reactions, Pigmentation, Skin lesions; Urogenital System - Bladder spasms, Dysuria, Incontinence, Testicular pain, Urinary obstruction; Miscellaneous - Depression, Diabetes, Fatigue, Fever/chills, Hypoglycemia, Increased BUN, Increased calcium, Increased creatinine, Infection/inflammation, Ophthalmologic disorders, Swelling (temporal bone).

In an additional clinical trial and from long-term observation of both studies, the following additional adverse events (excluding those considered not drug related) were reported for patients receiving Leuprolide acetate injection.

Cardiovascular System - Bradycardia, Carotid bruit, Extrasystole, Palpitations, Perivascular cuffing (eyes), Ruptured aortic aneurysm, Stroke, Tachycardia, Transient ischemic attack; Gastrointestinal System - Flatus, Dryness of mouth and throat, Hepatitis, Hepatomegaly, Occult blood (rectal exam), Rectal fistula/erythema; Endocrine System - Libido increase, Thyroid nodule; Musculoskeletal System - Ankylosing spondylosis, Arthritis, Blurred disc margins, Bone fracture, Muscle stiffness, Muscle tenderness, Pelvic fibrosis, Spasms/cramps; Central/Peripheral Nervous System - Auditory hallucinations/tinnitus, Decreased hearing, Decreased reflexes, Euphoria, Hyperreflexia, Loss of smell, Motor deficiency; Respiratory System - Chest tightness, Decreased breathing sounds, Hemoptysis, Pleuritic chest pain, Pulmonary infiltrate, Rales/rhonchi, Rhinitis, Strep throat, Wheezing/bronchitis; Integumentary System - Boil (pubic), Bruises, Hives, Keratosis, Mole, Shingles, Spiders; Urogenital System - Blisters on penis, Inguinal hernia, Penile swelling, Post void residual, Prostatic pain, Pyuria; Miscellaneous - Abdominal distention, Facial swelling/edema, Feet burning, Flu, Eyelid growth, Hypoproteinemia, Accidental injury, Knee effusion, Mass, Pallid, Sallow, Weakness.

Postmarketing

During postmarketing surveillance which includes other dosage forms and other patient populations, the following adverse events were reported.

Symptoms consistent with an anaphylactoid or asthmatic process have been rarely (incidence rate of about 0.002%) reported. Rash, urticaria, and photosensitivity reactions have also been reported.

Localized reactions including induration and abscess have been reported at the site of injection.

Symptoms consistent with fibromyalgia (e.g., joint and muscle pain, headaches, sleep disorders, gastrointestinal distress, and shortness of breath) have been reported individually and collectively.

Cardiovascular System - Hypotension, Myocardial infarction; Endocrine System – Diabetes; Gastrointestinal System - Hepatic dysfunction; Hemic and Lymphatic System - Decreased WBC; Integumentary System - Hair growth; Central/Peripheral Nervous System - Convulsion, Spinal fracture/paralysis, Hearing disorder; Miscellaneous - Hard nodule in throat, Weight gain, Increased uric acid; MusculoskeletalSystem - Tenosynovitis-like symptoms; Respiratory System - Respiratory disorders.

Changes in Bone Density: Decreased bone density has been reported in the medical literature in men who have had orchiectomy or who have been treated with an LH-RH agonist analog. In a clinical trial, 25 men with prostate cancer, 12 of whom had been treated previously with Leuprolide acetate for at least six months, underwent bone density studies as a result of pain. The Leuprolide-treated group had lower bone density scores than the nontreated control group. It can be anticipated that long periods of medical castration in men will have effects on bone density.

Pituitary apoplexy: During postmarketing surveillance, rare cases of pituitary apoplexy (a clinical syndrome secondary to infarction of the pituitary gland) have been reported after the administration of gonadotropin-releasing hormone agonists. In a majority of these cases, a pituitary adenoma was diagnosed, with a majority of pituitary apoplexy cases occurring within 2 weeks of the first dose, and some within the first hour. In these cases, pituitary apoplexy has presented as sudden headache, vomiting, visual changes, ophthalmoplegia, altered mental status, and sometimes cardiovascular collapse. Immediate medical attention has been required.

See other LUPRON DEPOT* and Leuprolide acetate injection package inserts for other events reported in the same and different patient populations.

Leuprolide, is an agonist of gonadotropin releasing hormone (GnRH) receptors. Acting as a potent inhibitor of gonadotropin secretion, leuprolide produces an initial increase in luteinizing hormone (LH) and follicle stimulating hormone (FSH), which leads to a transient increase (5 to 12 days [Cook 2000]) in testosterone and dihydrotestosterone (in males) and estrone and estradione (in premenopausal females). Continuous leuprolide administration then results in suppression of ovarian and testicular steroidogenesis due to decreased levels of LH and FSH with subsequent decrease in testosterone (male) and estrogen (female) levels. In males, testosterone levels are reduced to below castrate levels. Leuprolide may also have a direct inhibitory effect on the testes, and act by a different mechanism not directly related to reduction in serum testosterone.

Distribution

Males: Vd: 27 L

Metabolism

Major metabolite, pentapeptide (M-1)

Excretion

Urine (<5% as parent and major metabolite)

Prostate cancer, advanced: Note: Treatment is usually continued after development of metastatic (castration-resistant) disease.

IM:

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

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

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

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

SubQ:

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

Leuprolide acetate 5 mg/mL solution: 1 mg daily

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

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

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

Uterine leiomyomata (fibroids): IM (in combination with iron):

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

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

Breast cancer, premenopausal ovarian supression (off-label use): IM:

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

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

Treatment of paraphilia/hypersexuality (off-label use; Guay 2009; Reilly 2000): Males: IM:

Note: Additional trials may be necessary to further define the role of leuprolide in this condition. May cause an initial increase in androgen concentrations which may be treated with an antiandrogen (eg, flutamide, cyproterone) for 1 to 2 months (Guay 2009). Avoid use in patients with osteoporosis or active pituitary pathology.

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

Depot IM: 3.75 to 7.5 mg monthly

Antidiabetic Agents: Hyperglycemia-Associated Agents may diminish the therapeutic effect of Antidiabetic Agents. Monitor therapy

Choline C 11: Luteinizing Hormone-Releasing Hormone Analogs may diminish the therapeutic effect of Choline C 11. Monitor therapy

Corifollitropin Alfa: Luteinizing Hormone-Releasing Hormone Analogs may enhance the therapeutic effect of Corifollitropin Alfa. Avoid combination

Highest Risk QTc-Prolonging Agents: Moderate Risk QTc-Prolonging Agents may enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Avoid combination

Hydroxychloroquine: May enhance the QTc-prolonging effect of Moderate Risk QTc-Prolonging Agents. Avoid combination

Indium 111 Capromab Pendetide: Luteinizing Hormone-Releasing Hormone Analogs may diminish the diagnostic effect of Indium 111 Capromab Pendetide. Avoid combination

MiFEPRIStone: May enhance the QTc-prolonging effect of Moderate Risk QTc-Prolonging Agents. Avoid combination

Moderate Risk QTc-Prolonging Agents: May enhance the QTc-prolonging effect of other Moderate Risk QTc-Prolonging Agents. Management: Avoid such combinations when possible. Use should be accompanied by close monitoring for evidence of QT prolongation or other alterations of cardiac rhythm. Consider therapy modification

Probucol: May enhance the QTc-prolonging effect of Moderate Risk QTc-Prolonging Agents. Avoid combination

Promazine: May enhance the QTc-prolonging effect of Moderate Risk QTc-Prolonging Agents. Avoid combination

QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying): May enhance the QTc-prolonging effect of Moderate Risk QTc-Prolonging Agents. Monitor therapy

Vinflunine: May enhance the QTc-prolonging effect of Moderate Risk QTc-Prolonging Agents. Avoid combination

Xipamide: May enhance the QTc-prolonging effect of Moderate Risk QTc-Prolonging Agents. Monitor therapy

3.75 mg IM once a month for up to 6 months or 11.25 mg depot every 3 months

Comments:
-In women receiving leuprorelin for endometriosis, hormone replacement therapy is recommended to reduce bone mineral density loss and vasomotor symptoms. The risks and benefits of each therapy should be considered.

Uses: Management of endometriosis (including pain relief and reduction of endometriotic lesions), preoperative hematologic improvement of patients with anemia caused by uterine leiomyomata