Leuprolide Acetate Injection

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:

LEUPROLIDE ACETATE 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. The pH range is 4.0 to 6.0.

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.

In a controlled study comparing LEUPROLIDE ACETATE 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.

LEUPROLIDE ACETATE INJECTION is indicated in the palliative treatment of advanced prostatic cancer.

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 synthetic GnRH or GnRH agonist analogs have been reported in the medical literature.¹
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.

Initially, LEUPROLIDE ACETATE, like other LH-RH agonists, causes increases in serum levels of testosterone. Transient worsening of symptoms, or the occurrence of additional signs and symptoms of prostate cancer, may occasionally develop during the first few weeks of LEUPROLIDE ACETATE treatment. A small number of patients may experience a temporary increase in bone pain, which can be managed symptomatically. As with other LH-RH agonists, isolated cases of ureteral obstruction and spinal cord compression have been observed, which may contribute to paralysis with or without fatal complications. Safe use of leuprolide acetate in pregnancy has not been established clinically. Before starting treatment with LEUPROLIDE ACETATE, pregnancy must be excluded (see CONTRAINDICATIONS section). Periodic monitoring of serum testosterone and prostate-specific antigen (PSA) levels is recommended, especially if the anticipated clinical or biochemical response to treatment has not been achieved. It should be noted that results of testosterone determinations are dependent on assay methodology. It is advisable to be aware of the type and precision of the assay methodology to make appropriate clinical and therapeutic decisions.

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 PRECAUTIONS 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.

In rats subcutaneous administration of 250 to 500 times the recommended human dose, expressed on a per body weight basis, resulted in dyspnea, decreased activity, and local irritation at the injection site. There is no evidence at present that there is a clinical counterpart of this phenomenon. In early clinical trials with leuprolide acetate doses as high as 20 mg/day for up to two years caused no adverse effects differing from those observed with the 1 mg/day dose.

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.

LEUPROLIDE ACETATE INJECTION is a sterile solution supplied in a 2.8 mL multiple-dose vial. The vial is packaged as a 14 Day Patient Administration Kit with 14 disposable syringes and 28 alcohol swabs, NDC 0185-7400-85. Store below 77°F (25°C). Do not freeze. Protect from light; store vial in carton until use.

1. MacLeod TL, Eisen A, Sussman GL, et al: Anaphylactic reaction to synthetic luteinizing hormone-releasing hormone. Fertil Steril 1987 Sept; 48(3): 500-502.

Be sure to consult your physician with any questions you may have or for information about LEUPROLIDE ACETATE INJECTION and its use.

WHAT IS LEUPROLIDE ACETATE?

LEUPROLIDE ACETATE INJECTION 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 LEUPROLIDE ACETATE INJECTION, the normal events that lead to sex hormone production are interrupted and testosterone is no longer produced by the testes. LEUPROLIDE ACETATE must be injected because, like insulin which is injected by diabetics, LEUPROLIDE ACETATE 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 LEUPROLIDE ACETATE

1. Wash hands thoroughly with soap and water.
2. 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 LEUPROLIDE ACETATE. 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.
3. 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.
4. Take cover off needle. Push the needle through the center of the rubber stopper on the LEUPROLIDE ACETATE bottle.
5. Push the plunger all the way in to inject air into the bottle.
6. 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.
7. Toward the end of a two-week period, the amount of LEUPROLIDE ACETATE 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.
8. 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.
9. Do this again if necessary to eliminate air bubbles.
10. To protect your skin, inject each daily dose at a different body spot.
11. Choose an injection spot. Cleanse the injection spot with another alcohol wipe.
12. Hold the syringe in one hand. Hold the skin taut, or pull up a little flesh with the other hand, as you were instructed.
13. 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.
14. Hold an alcohol wipe down on your skin where the needle is inserted and withdraw the needle at the same angle it was inserted.
15. 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 LEUPROLIDE ACETATE INJECTION. 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, LEUPROLIDE ACETATE may cause impotence. Notify your doctor if you develop new or worsened symptoms after beginning LEUPROLIDE ACETATE 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 LEUPROLIDE ACETATE, 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 LEUPROLIDE ACETATE keeps working for you.
• If you need to use an alternate to the syringe supplied with LEUPROLIDE ACETATE INJECTION, 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 LEUPROLIDE ACETATE 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.

Manufactured by Ben Venue Laboratories, Inc., Bedford, OH 44146

Manufactured for Sandoz Inc., Princeton, NJ 08540 and Oakwood Laboratories, L.L.C. Oakwood Village, OH 44146

OS8247

Rev. 12/07

Leuprolide

Acetate Injection

For Subcutaneous

Injection

1 mg/0.2 mL

STERILE

SANDOZ