Data from FDA - Curated by Toby Galbraith - Last updated 10 October 2017

Indication(s)

INDICATIONS AND USAGE Leuprolide acetate injection is indicated in the palliative treatment of advanced prostatic cancer.

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Advisory information

contraindications
CONTRAINDICATIONS 1.Leuprolide acetate injection is contraindicated in patients known to be hypersensitive to GnRH, GnRH agonist analogs, or any of the excipients in leuprolide acetate injection: Reports of anaphylactic reactions to GnRH agonist analogs have been reported in the medical literature. 2.Leuprolide acetate is contraindicated in women who are or may become pregnant while receiving the drug. Leuprolide acetate may cause fetal harm when administered to a pregnant woman. Therefore, the possibility exists that spontaneous abortion may occur if the drug is administered during pregnancy. If this drug is administered during pregnancy or if the patient becomes pregnant while taking any formulation of leuprolide acetate, the patient should be apprised of the potential hazard to the fetus.
Special warnings and precautions
PRECAUTIONS Patients with metastatic vertebral lesions and/or with urinary tract obstruction should be closely observed during the first few weeks of therapy (see WARNINGS and ADVERSE REACTIONS sections). Patients with known allergies to benzyl alcohol, an ingredient of the drug’s vehicle, may present symptoms of hypersensitivity, usually local, in the form of erythema and induration at the injection site. Hyperglycemia and an increased risk of developing diabetes have been reported in men receiving GnRH agonists. Hyperglycemia may represent development of diabetes mellitus or worsening of glycemic control in patients with diabetes. Monitor blood glucose and/or glycosylated hemoglobin (HbA1c) periodically in patients receiving a GnRH agonist and manage with current practice for treatment of hyperglycemia or diabetes. Increased risk of developing myocardial infarction, sudden cardiac death and stroke has been reported in association with use of GnRH agonists in men. The risk appears low based on the reported odds ratios, and should be evaluated carefully along with cardiovascular risk factors when determining a treatment for patients with prostate cancer. Patients receiving a GnRH agonist should be monitored for symptoms and signs suggestive of development of cardiovascular disease and be managed according to current clinical practice. Effect on QT/QTc Interval Androgen deprivation therapy may prolong the QT/QTc interval. Providers should consider whether the benefits of androgen deprivation therapy outweigh the potential risks in patients with congenital long QT syndrome, congestive heart failure, frequent electrolyte abnormalities, and in patients taking drugs known to prolong the QT interval. Electrolyte abnormalities should be corrected. Consider periodic monitoring of electrocardiograms and electrolytes. Information for Patients See INFORMATION FOR PATIENTS which appears after the REFERENCE section. Laboratory Tests Response to leuprolide acetate should be monitored by measuring serum levels of testosterone and prostate-specific antigen (PSA). 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. Castrate levels were reached within two to four weeks and once attained were maintained for as long as drug administration continued. Drug Interactions See CLINICAL PHARMACOLOGY. Pharmacokinetics section. Drug/Laboratory Test Interactions Administration of leuprolide acetate in therapeutic doses results in suppression of the pituitary-gonadal system. Normal function is usually restored within 4 to 12 weeks after treatment is discontinued. Carcinogenesis, Mutagenesis, Impairment of Fertility Two-year carcinogenicity studies were conducted in rats and mice. In rats, a dose-related increase of benign pituitary hyperplasia and benign pituitary adenomas was noted at 24 months when the drug was administered subcutaneously at high daily doses (0.6 to 4 mg/kg). There was a significant but not dose-related increase of pancreatic islet-cell adenomas in females and of testicular interstitial cell adenomas in males (highest incidence in the low dose group). In mice no pituitary abnormalities were observed at a dose as high as 60 mg/kg for two years. Patients have been treated with leuprolide acetate for up to three years with doses as high as 10 mg/day and for two years with doses as high as 20 mg/day without demonstrable pituitary abnormalities. Mutagenicity studies have been performed with leuprolide acetate using bacterial and mammalian systems. These studies provided no evidence of a mutagenic potential. Clinical and pharmacologic studies in adults (≥18 years) with leuprolide acetate and similar analogs have shown full reversibility of fertility suppression when the drug is discontinued after continuous administration for periods of up to 24 weeks. However, no clinical studies have been conducted with leuprolide acetate to assess the reversibility of fertility suppression. Pregnancy Teratogenic Effects Pregnancy Category X (See CONTRAINDICATIONS and WARNINGS sections.) When administered on day 6 of pregnancy at test dosages of 0.00024, 0.0024, and 0.024 mg/kg (1/600 to 1/6 the human dose) to rabbits, leuprolide acetate produced a dose-related increase in major fetal abnormalities. Similar studies in rats failed to demonstrate an increase in major fetal malformations throughout gestation. There was increased fetal mortality and decreased fetal weights with the two higher doses of leuprolide acetate in rabbits and with the highest dose in rats. The effects on fetal mortality are expected consequences of the alterations in hormonal levels brought about by this drug. Nursing Mothers It is not known whether leuprolide acetate is excreted in human milk. Leuprolide acetate should not be used by nursing mothers. Geriatric Use In the clinical trials for leuprolide acetate injection, the majority (69%) of subjects studied were at least 65 years of age. Therefore, the labeling reflects the pharmacokinetics, efficacy, and safety of leuprolide acetate in this population.
Adverse reactions
ADVERSE REACTIONS 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 injection 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. Leuprolide Acetate (N=98) DES (N=101) Number of Reports Cardiovascular System Congestive heart failure 1 5 ECG changes/ischemia 19 22 High blood pressure 8 5 Murmur 3 8 Peripheral edema 12 30 Phlebitis/thrombosis 2 10 Gastrointestinal System Anorexia 6 5 Constipation 7 9 Nausea/vomiting 5 17 Endocrine System Decreased testicular sizePhysiologic effect of decreased testosterone 7 11 Gynecomastia/breast tenderness or pain 7 63 Hot flashes 55 12 Impotence 4 12 Hemic and Lymphatic System Anemia 5 5 Musculoskeletal System Bone pain 5 2 Myalgia 3 9 Central/Peripheral Nervous System Dizziness/lightheadedness 5 7 General pain 13 13 Headache 7 4 Insomnia/sleep disorders 7 5 Respiratory System Dyspnea 2 8 Sinus congestion 5 6 Integumentary System Dermatitis 5 8 Urogenital System Frequency/urgency 6 8 Hematuria 6 4 Urinary tract infection 3 7 Miscellaneous Asthenia 10 10 In this same study, the following adverse reactions were reported in less than 5% of the patients on leuprolide acetate. 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. 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 Musculoskeletal System – 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 post-marketing 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 leuprolide acetate for depot suspension and leuprolide acetate injection package inserts for other events reported in the same and different patient populations.

Usage information

Dosing and administration
DOSAGE AND ADMINISTRATION The recommended dose is 1 mg (0.2 mL or 20 unit mark) administered as a single daily subcutaneous injection. As with other drugs administered chronically by subcutaneous injection, the injection site should be varied periodically. Each 0.2 mL contains 1 mg of leuprolide acetate, sodium chloride for tonicity adjustment, 1.8 mg of benzyl alcohol as preservative and water for injection. The pH may have been adjusted with sodium hydroxide and/or acetic acid. Follow the pictorial directions on the Administering the Injection Insert. NOTE: As with all parenteral products, inspect the solution for discoloration and particulate matter before each use.
Pregnancy and lactation
Nursing Mothers It is not known whether leuprolide acetate is excreted in human milk. Leuprolide acetate should not be used by nursing mothers.

Interactions

Drug Interactions See CLINICAL PHARMACOLOGY. Pharmacokinetics section. Drug/Laboratory Test Interactions Administration of leuprolide acetate in therapeutic doses results in suppression of the pituitary-gonadal system. Normal function is usually restored within 4 to 12 weeks after treatment is discontinued.

More information

Category Value
Authorisation number ANDA074728
Orphan designation No
Product NDC 0781-4003
Date Last Revised 31-08-2017
Type HUMAN PRESCRIPTION DRUG
RXCUI 797544
Marketing authorisation holder Sandoz Inc