Lutrate Drug Information

22.5 mg for 3-month administration (leuprolide acetate) is indicated for treatment of advanced prostate cancer. LUTRATE DEPOT is a gonadotropin-releasing hormone (GnRH) agonist indicated for: Treatment of advanced prostate cancer.

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. LUTRATE DEPOT 22.5 mg for 3-Month Administration In a clinical trial of LUTRATE DEPOT 22.5 mg for 3-month administration, patients were treated for 24 weeks with 157/163 receiving two injections. The table includes adverse reactions were reported in 5% or more of the patients during the treatment period as well as the incidence of these adverse reaction that were considered, by the treating physician, to be at least possibly related to LUTRATE DEPOT. Grade 3-4 adverse reactions reported as treatment-emergent in 13% of patients and treatment-related 4% of patients.

CTCAE v.3 1 Includes cold sweat, flushing, hot flush, hyperhidrosis, and night sweats 2 Includes influenza, influenza-like illness, nasal congestion, nasopharyngitis, rhinorrhea, upper respiratory tract infection and congestion Table 2. Adverse Reactions Reported in ≥ 5% of Patients LUTRATE DEPOT 22.5 mg for 3-Month Administration N = 163 (%) Grade 1-4 Treatment-Emergent Treatment-Related Hot Flush/Flushing 1 128 127 Upper Respiratory Infection 2 28 0 Fatigue/Asthenia 24 22 Diarrhea 21 2 Pollakiuria 20 3 Arthralgia/Arthritis 18 2 Injection Site Pain/Discomfort 18 15 Constipation 15 1 Extremity Pain 14 0 Nausea 14 4 Nocturia 14 3 Abdominal Pain/Discomfort 13 1 Urinary Tract Pain 13 2 Dizziness 12 2 Headache/Sinus Headache 12 1 Urinary Tract Infection 12 0 Bone Pain 11 4 Back Pain 10 1 Hypertension/Blood Pressure Increased 10 0 Pruritus/Generalized Pruritus 9 3 In the same study, erectile dysfunction and testicular atrophy were reported in patients on LUTRATE DEPOT 22.5 mg. Laboratory abnormalities During the treatment period, at least a one grade change in laboratory values was seen (>10%) in the following: anemia, increased triglyceride, hyperglycemia, increased cholesterol, increased creatine kinase, leukopenia, increased AST, increased creatinine, and increased ALT.

Post-marketing Experience

The following adverse reactions have been identified during post approval use of gonadotropin-releasing hormone agonists. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Mood swings, including depression, have been reported.

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 LUTRATE DEPOT. 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. 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. 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. 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 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 six months, underwent bone density studies as a result of pain.

The leuprolide acetate-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. Immune Disorders: Anaphylaxis Psychiatric Disorders: Depression Cardiovascular System - hypotension, myocardial infarction, pulmonary embolism Respiratory, Thoracic and Mediastinal disorder - Pneumonitis, interstitial lung disease Hepato-biliary disorder - serious drug-induced liver injury, non-alcoholic fatty liver disease Skin reactions – rash, urticaria, photosensitivity, erythema multiforme, bullous dermatitis, exfoliative dermatitis, DRESS, SJS/TEN, and AGEP Blood and Lymphatic System - decreased WBC Central/Peripheral Nervous System - convulsion, peripheral neuropathy, spinal fracture/paralysis Endocrine System - diabetes mellitus Musculoskeletal System - tenosynovitis-like symptoms Urogenital System - prostate pain

Drug/Laboratory Test Interactions

Administration of LUTRATE DEPOT in therapeutic doses results in suppression of the pituitary-gonadal system. Normal function is usually restored within three months after treatment is discontinued. Due to the suppression of the pituitary-gonadal system by LUTRATE DEPOT, diagnostic tests of pituitary gonadotropic and gonadal functions conducted during treatment and up to three months after discontinuation of LUTRATE DEPOT may be affected.

Pregnancy Risk summary Based on findings in animal studies and mechanism of action, LUTRATE DEPOT may cause fetal harm when administered to a pregnant woman . There are no available data in pregnant women to inform the drug-associated risk. In animal developmental and reproductive toxicology studies, administration of a monthly formulation of leuprolide acetate 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 using an estimated daily dose (see data). Advise pregnant patients and females of reproductive potential of the potential risk to the fetus. Animal Data Major fetal malformations were observed in developmental and reproductive toxicology studies in rabbits after a single administration of the monthly formulation of leuprolide acetate on day 6 of pregnancy at doses of 0.00024, 0.0024, and 0.024 mg/kg (approximately 1/1600 to 1/16 the human dose based on body surface area using an estimated daily dose in animals and humans). Since a depot formulation was utilized in the study, a sustained exposure to leuprolide acetate was expected throughout the period of organogenesis and to the end of gestation.

Similar studies in rats did not demonstrate an increase in fetal malformations, however, there was increased fetal mortality and decreased fetal weights with the two higher doses of the monthly formulation of leuprolide acetate in rabbits and with the highest dose (0.024 mg/kg) in rats.

Pediatric Use The safety and effectiveness of LUTRATE DEPOT in pediatric patients have not been established.

is contraindicated in: Hypersensitivity LUTRATE DEPOT is contraindicated in individuals with known hypersensitivity to GnRH agonists or any of the excipients in LUTRATE DEPOT. Reports of anaphylactic reactions to GnRH agonists have been reported in the medical literature. Hypersensitivity to GnRH, GnRH agonist or any of the excipients in LUTRATE DEPOT..

There is no experience of overdosage in clinical trials. In rats, a single subcutaneous dose of 100 mg/kg (approximately 4,000 times the estimated daily human dose based on body surface area), resulted in dyspnea, decreased activity, and excessive scratching. In early clinical trials with daily subcutaneous leuprolide acetate, doses as high as 20 mg/day for up two years caused no adverse effects differing from those observed with the 1 mg/day dose.