DailyMed Label: Leuprolide Acetate

DailyMed Label: leuprolide acetate

2008

DailyMed Prescription

leuprolide acetate

leuprolide acetate

TAP Pharmaceutical Products Inc.

NDC: 0300-3612

NDC: 0300-3612

Leuprolide acetate is a synthetic nonapeptide analog of naturally occurring gonadotropin releasing hormone (GnRH or LH-RH). The analog possesses greater potency than the natural hormone. The chemical name is 5-oxo-L-prolyl-L-histidyl-L-tryptophyl-L-seryl-L-tyrosyl-D-leucyl-L-leucyl-L-arginyl-N-ethyl-L-prolinamide acetate (salt) with the following structural formula: LUPRON INJECTION is a sterile, aqueous solution intended for subcutaneous injection. It is available in a 2.8 mL multiple-dose vial containing leuprolide acetate (5 mg/mL), sodium chloride, USP (6.3 mg/mL) for tonicity adjustment, benzyl alcohol, NF as a preservative (9 mg/mL), and water for injection, USP. The pH may have been adjusted with sodium hydroxide, NF and/or acetic acid, NF.

LUPRON INJECTION (leuprolide acetate) is indicated in the palliative treatment of advanced prostatic cancer.

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 reverse side of this package insert for administration. NOTE: As with all parenteral products, inspect the solution for discoloration and particulate matter before each use.

LUPRON INJECTION is contraindicated in patients known to be hypersensitive to GnRH, GnRH agonist analogs or any of the excipients in LUPRON INJECTION: Reports of anaphylactic reactions to GnRH agonist analogs have been reported in the medical literature. 1,2 LUPRON is contraindicated in women who are or may become pregnant while receiving the drug. LUPRON 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 LUPRON, the patient should be apprised of the potential hazard to the fetus.

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. See INFORMATION FOR PATIENTS which appears after the REFERENCE section. 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. See CLINICAL PHARMACOLOGY, Pharmacokinetics section. 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. 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. (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, LUPRON 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 LUPRON 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. It is not known whether leuprolide acetate is excreted in human milk. LUPRON should not be used by nursing mothers. See labeling for LUPRON INJECTION for Pediatric Use for the safety and effectiveness in children with central precocious puberty. In the clinical trials for LUPRON INJECTION, the majority (69%) of subjects studied were at least 65 years of age. Therefore, the labeling reflects the pharmacokinetics, efficacy and safety of LUPRON in this population.

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

See CLINICAL PHARMACOLOGY, Pharmacokinetics section.

LUPRON INJECTION (leuprolide acetate) is a sterile solution supplied in a 2.8 mL multiple-dose vial. The vial is packaged as follows: 14 Day Patient Administration Kit with 14 disposable syringes and 28 alcohol swabs, NDC 0300-3612-28 and six-vial carton, NDC 0300-3612-24. Store below 77°F (25°C). Do not freeze. Protect from light; store vial in carton until use. U.S. Patent Nos. 4,005,063 and 4,005,194.

Leuprolide acetate, an LH-RH agonist, acts as a potent inhibitor of gonadotropin secretion when given continuously and in therapeutic doses. Animal and human studies indicate that following an initial stimulation of gonadotropins, chronic administration of leuprolide acetate results in suppression of ovarian and testicular steroidogenesis. This effect is reversible upon discontinuation of drug therapy. Administration of leuprolide acetate has resulted in inhibition of the growth of certain hormone dependent tumors (prostatic tumors in Noble and Dunning male rats and DMBA-induced mammary tumors in female rats) as well as atrophy of the reproductive organs. In humans, subcutaneous administration of single daily doses of leuprolide acetate results in an initial increase in circulating levels of luteinizing hormone (LH) and follicle stimulating hormone (FSH), leading to a transient increase in levels of the gonadal steroids (testosterone and dihydrotestosterone in males, and estrone and estradiol in pre-menopausal females). However, continuous daily administration of leuprolide acetate results in decreased levels of LH and FSH. In males, testosterone is reduced to castrate levels. In pre-menopausal females, estrogens are reduced to post-menopausal levels. These decreases occur within two to four weeks after initiation of treatment, and castrate levels of testosterone in prostatic cancer patients have been demonstrated for periods of up to five years. Leuprolide acetate is not active when given orally. Bioavailability by subcutaneous administration is comparable to that by intravenous administration. The mean steady-state volume of distribution of leuprolide following intravenous bolus administration to healthy male volunteers was 27 L. In vitro binding to human plasma proteins ranged from 43% to 49%. In healthy male volunteers, a 1 mg bolus of leuprolide administered intravenously revealed that the mean systemic clearance was 7.6 L/h, with a terminal elimination half-life of approximately 3 hours based on a two compartment model. In rats and dogs, administration of 14 C-labeled leuprolide was shown to be metabolized to smaller inactive peptides, a pentapeptide (Metabolite I), tripeptides (Metabolites II and III) and a dipeptide (Metabolite IV). These fragments may be further catabolized. The major metabolite (M-I) plasma concentrations measured in 5 prostate cancer patients reached maximum concentration 2 to 6 hours after dosing and were approximately 6% of the peak parent drug concentration. One week after dosing, mean plasma M-I concentrations were approximately 20% of mean leuprolide concentrations. Following administration of LUPRON DEPOT 3.75 mg to 3 patients, less than 5% of the dose was recovered as parent and M-I metabolite in the urine. The pharmacokinetics of the drug in hepatically and renally impaired patients has not been determined. No pharmacokinetic-based drug-drug interaction studies have been conducted with leuprolide acetate. However, because leuprolide acetate is a peptide that is primarily degraded by peptidase and not by cytochrome P-450 enzymes as noted in specific studies, and the drug is only about 46% bound to plasma proteins, drug interactions would not be expected to occur.

In a controlled study comparing LUPRON 1 mg/day given subcutaneously to DES (diethylstilbestrol), 3 mg/day, the survival rate for the two groups was comparable after two years of treatment. The objective response to treatment was also similar for the two groups.

Be sure to consult your physician with any questions you may have or for information about LUPRON INJECTION (leuprolide acetate) and its use. WHAT IS LUPRON? LUPRON INJECTION (leuprolide acetate) is chemically similar to gonadotropin releasing hormone (GnRH or LH-RH) a hormone which occurs naturally in your body. Normally, your body releases small amounts of LH-RH and this leads to events which stimulate the production of sex hormones. However, when you inject LUPRON INJECTION (leuprolide acetate), the normal events that lead to sex hormone production are interrupted and testosterone is no longer produced by the testes. LUPRON must be injected because, like insulin which is injected by diabetics, LUPRON is inactive when taken by mouth. If you were to discontinue the drug for any reason, your body would begin making testosterone again. DIRECTIONS FOR USING LUPRON Wash hands thoroughly with soap and water. If using a new bottle for the first time, flip off the plastic cover to expose the grey rubber stopper. Wipe metal ring and rubber stopper with an alcohol wipe each time you use LUPRON. Check the liquid in the container. If it is not clear or has particles in it, DO NOT USE IT. Exchange it at your pharmacy for another container. Remove outer wrapping from one syringe. Pull plunger back until the tip of the plunger is at the 0.2 mL or 20 unit mark. Take cover off needle. Push the needle through the center of the rubber stopper on the LUPRON bottle. Push the plunger all the way in to inject air into the bottle. Keep the needle in the bottle and turn the bottle upside down. Check to make sure the tip of the needle is in the liquid. Slowly pull back on the plunger, until the syringe fills to the 0.2 mL or 20 unit mark. Toward the end of a two-week period, the amount of LUPRON left in the bottle will be small. Take special care to hold the bottle straight and to keep the needle tip in liquid while pulling back on the plunger. Keeping the needle in the bottle and the bottle upside down, check for air bubbles in the syringe. If you see any, push the plunger slowly in to push the air bubble back into the bottle. Keep the tip of the needle in the liquid and pull the plunger back again to fill to the 0.2 mL or 20 unit mark. Do this again if necessary to eliminate air bubbles. To protect your skin, inject each daily dose at a different body spot. Choose an injection spot. Cleanse the injection spot with another alcohol wipe. Hold the syringe in one hand. Hold the skin taut, or pull up a little flesh with the other hand, as you were instructed. Holding the syringe as you would a pencil, thrust the needle all the way into the skin at a 90° angle. Push the plunger to administer the injection. Hold an alcohol wipe down on your skin where the needle is inserted and withdraw the needle at the same angle it was inserted. Use the disposable syringe only once and dispose of it properly as you were instructed. Needles thrown into a garbage bag could accidentally stick someone. NEVER LEAVE SYRINGES, NEEDLES OR DRUGS WHERE CHILDREN CAN REACH THEM. SOME SPECIAL ADVICE You may experience hot flashes when using LUPRON INJECTION (leuprolide acetate). During the first few weeks of treatment you may experience increased bone pain, increased difficulty in urinating, and less commonly but most importantly, you may experience the onset or aggravation of nerve symptoms. In any of these events, discuss the symptoms with your doctor. Like other treatment options, LUPRON may cause impotence. Notify your doctor if you develop new or worsened symptoms after beginning LUPRON treatment. You may experience some irritation at the injection site, such as burning, itching or swelling. These reactions are usually mild and go away. If they do not, tell your doctor. If you have experienced an allergic reaction to other drugs like LUPRON, you should not use this drug. Do not stop taking your injections because you feel better. You need an injection every day to make sure LUPRON keeps working for you. If you need to use an alternate to the syringe supplied with LUPRON, low-dose insulin syringes should be utilized. When the drug level gets low, take special care to hold the bottle straight up and down and to keep the needle tip in liquid while pulling back on the plunger. Do not try to get every last drop out of the bottle. This will increase the possibility of drawing air into the syringe and getting an incomplete dose. Some extra drug has been provided so that you can withdraw the recommended number of doses. Tell your pharmacist when you will need LUPRON so it will be at the pharmacy when you need it. Store below 77°F (25°C). Do not store near a radiator or other very warm place. Do not freeze. Protect from light; store vial in carton until use. Do not leave your drug or hypodermic syringes where anyone can pick them up. Keep this and all other medications out of reach of children.