LEUPROLIDE ACETATE DEPOT

Leuprolide acetate is a synthetic nonapeptide analog of naturally occurring gonadotropin-releasing hormone (GnRH). 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: Where: n=1 or 2 Leuprolide acetate has a molecular weight of 1209.41 as free base”. Leuprolide is freely soluble in water. LEUPROLIDE ACETATE FOR DEPOT SUSPENSION 22.5 mg for 3-month administration is available in a vial containing white to off white sterile lyophilized microspheres together with the corresponding sterile reconstitution diluent in a pre-filled syringe. When LEUPROLIDE ACETATE FOR DEPOT SUSPENSION and the diluent are mixed together they become a suspension intended as an intramuscular injection to be given ONCE EVERY 12 WEEKS as a single dose. Each vial of LEUPROLIDE ACETATE FOR DEPOT SUSPENSION 22.5 mg for 3-month administration delivers leuprolide acetate (22.5 mg), polylactic acid (188.4 mg), triethylcitrate (10.4 mg), polysorbate 80 (3.8 mg), mannitol (88.4 mg) and carmellose sodium (25 mg). The prefilled syringe containing the clear reconstitution diluent (2 mL) contains mannitol (16 mg), water for injections, and sodium hydroxide and hydrochloric acid to control pH. Leuprolide acetate for depot suspension is an extended release sterile, single dose injection in suspension form for intramuscular administration. fig 11

LEUPROLIDE ACETATE FOR DEPOT SUSPENSION 22.5 mg for 3-month administration (leuprolide acetate) is indicated for treatment of advanced prostate cancer. LEUPROLIDE ACETATE FOR DEPOT SUSPENSION is a gonadotropin-releasing hormone (GnRH) agonist indicated for: Treatment of advanced prostate cancer. ( 1 )

Due to different release characteristics, the dosage strengths are not additive and must be selected based upon the desired dosing schedule ( 2 ). LEUPROLIDE ACETATE FOR DEPOT SUSPENSION 22.5 mg for 3 months administration, given as a single intramuscular injection every 12 weeks. ( 2.1 ) 2.1 LEUPROLIDE ACETATE FOR DEPOT SUSPENSION 22.5 mg for 3-Month Administration LEUPROLIDE ACETATE FOR DEPOT SUSPENSION must be administered under the supervision of a physician. In patients treated with GnRH analogues for prostate cancer, treatment is usually continued upon development of metastatic castration-resistant prostate cancer. Table 1. LEUPROLIDE ACETATE FOR DEPOT SUSPENSION Recommended Dosing Dosage 22.5 mg for 3-Month Administration Recommended Dose 1 injection every 12 weeks The recommended dose of LEUPROLIDE ACETATE FOR DEPOT SUSPENSION 22.5 mg for 3-month administration is one injection every 12 weeks. Do not use concurrently a fractional dose, or a combination of doses of this or any depot formulation due to different release characteristics. Incorporated in a depot formulation, the lyophilized microspheres must be reconstituted and administered every 12 weeks as a single intramuscular injection. 2.2 Reconstitution Instructions for LEUPROLIDE ACETATE FOR DEPOT SUSPENSION Reconstitute and administer the lyophilized microspheres as a single intramuscular injection. The suspension should be administered immediately after reconstitution. As with other drugs administered by intramuscular injection, the injection site should be alternated periodically. Visually inspect LEUPROLIDE ACETATE FOR DEPOT SUSPENSION powder (white to off-white powder). DO NOT USE the vial if clumping or caking is evident. A thin layer of powder on the wall of the vial is considered normal prior to mixing with the diluent. The diluent contained in the prefilled syringe should appear clear and colorless. Use ONLY the provided diluent for reconstitution of LEUPROLIDE ACETATE FOR DEPOT SUSPENSION. DO NOT use other diluents. The reconstituted product is a suspension of milky, white color appearance. LEUPROLIDE ACETATE FOR DEPOT SUSPENSION is packaged in a commercial kit. Each kit contains: One vial containing 22.5 mg of leuprolide acetate as lyophilized microspheres. One prefilled syringe containing 2 mL of mannitol for injection. One MIXJECT transfer device including one needle. Please read the instructions completely before you begin. MIXJECT Preparation Wash your hands with soap and hot water and put on gloves 1 immediately prior to preparing the injection. Place the tray on a clean, flat surface that is covered with a sterile pad or cloth. Remove the MIXJECT device, the backstop, the prefilled syringe containing the solvent for reconstitution and the LEUPROLIDE ACETATE FOR DEPOT SUSPENSION vial. Remove the Flip-Off button from the top of the vial, revealing the rubber stopper. Place the vial in a standing upright position on the prepared surface. Disinfect the rubber stopper with the alcohol wipe. Discard the alcohol wipe and allow the stopper to dry. Insert the backstop to the flange of the syringe until you feel it snap in place . Proceed to MIXJECT Activation. MIXJECT Activation Peel the cover away from the blister pack containing the vial adapter (MIXJECT). Do not remove the vial adapter from the blister pack. Place the blister pack containing the vial adapter firmly on the vial top, piercing the vial. Push down gently until you feel it snap in place. Remove the cap from the syringe barrel and then, remove the blister pack from the vial adapter . Connect the syringe to the vial adapter by screwing it clockwise into the opening on the side of the vial adapter. Be sure to gently twist the syringe until it stops turning to ensure a tight connection. While holding the vial, place your thumb on the plunger rod and push the plunger rod in all the way to transfer the diluent from the pre-filled syringe into the vial. Do not release the plunger rod. Keeping the plunger rod depressed, gently swirl the vial for approximately one minute until a uniform milky-white suspension is obtained . This will ensure complete mixing of LEUPROLIDE ACETATE FOR DEPOT SUSPENSION and the sterile mannitol solution diluent. The suspension will now have a milky appearance. In order to avoid separation of the suspension, proceed to the next steps without delay. Invert the MIXJECT system so that the vial is at the top. Grasp the MIXJECT system firmly by the syringe and pull back the plunger rod slowly to draw the reconstituted LEUPROLIDE ACETATE FOR DEPOT SUSPENSION into the syringe. Return the vial to its upright position, and disconnect the vial adapter from the MIXJECT syringe assembly by grabbing firmly the syringe and turning the plastic cap of the vial adapter clockwise. Grasp only the plastic cap when removing . Keep the syringe UPRIGHT. With the opposite hand pull the needle cap upward. Advance the plunger to expel the air from the syringe. The syringe containing LEUPROLIDE ACETATE FOR DEPOT SUSPENSION is now ready for administration. The suspension should be administered immediately after reconstitution. After cleaning the injection site with an alcohol swab, administer the intramuscular injection by inserting the needle at a 90 degree angle into the gluteal area, anterior thigh, or deltoid; injection sites should be alternated (see Figure). NOTE: If a blood vessel is accidentally penetrated, aspirated blood will be visible just below the luer lock. If blood is present, remove the needle immediately. Do not inject the medication. Inject the entire contents of the syringe intramuscularly. Withdraw the needle. Once the syringe has been withdrawn, immediately discard the needle into a suitable sharps container. Dispose the syringe according to local regulations/procedures. fig 1.jpg fig 2.jpg Fig 3.jpg fig 4.jpg fig 5.jpg ifig 6.jpg fig 7.jpg fig 8.jpg fig 9.jpg fig 10.jpg

LEUPROLIDE ACETATE FOR DEPOT SUSPENSION is contraindicated in: Hypersensitivity LEUPROLIDE ACETATE FOR DEPOT SUSPENSION is contraindicated in individuals with known hypersensitivity to GnRH agonists or any of the excipients in LEUPROLIDE ACETATE FOR DEPOT SUSPENSION. 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 LEUPROLIDE ACETATE FOR DEPOT SUSPENSION. ( 4 ) .

The following is discussed in more detail in other sections of the labeling: Tumor Flare [ see Warnings and Precautions (5.1) ] Metabolic Syndrome [ see Warnings and Precautions (5.2) ] Cardiovascular Disease [ see Warnings and Precautions (5.3) ] Effect on QT/QTc Interval [ see Warnings and Precautions (5.4) ] Convulsions [see Warnings and Precautions (5.5) ] Most common adverse reactions (incidence > 10%) are hot flushes, upper respiratory infection, fatigue, diarrhea, pollakiuria, arthralgia, and injection site pain ( 6 ). As with other GnRH agonist, other adverse reactions, including decreased bone density and rare cases of pituitary apoplexy may occur. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Cipla at 1-866-604-3268 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 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. LEUPROLIDE ACETATE FOR DEPOT SUSPENSION 22.5 mg for 3-Month Administration In a clinical trial of LEUPROLIDE ACETATE FOR DEPOT SUSPENSION 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 LEUPROLIDE ACETATE FOR DEPOT SUSPENSION. Grade 3-4 adverse reactions reported as treatment-emergent in 13% of patients and treatment-related 4% of patients. CCTCAE 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 LEUPROLIDE ACETATE FOR DEPOT SUSPENSION 22.5 mg for 3-Month Administration N = 163 (%) Grade 1-4 Treatment-Emergent Treatment-Related Hot Flush/Flushing 1 128 (79) 127 (78) Upper Respiratory Infection 2 28 (17) 0 Fatigue/Asthenia 24 (15) 22 (13) Diarrhea 21 (13) 2 (1) Pollakiuria 20 (12) 3 (2) Arthralgia/Arthritis 18 (11) 2 (1) Injection Site Pain/Discomfort 18 (11) 15 (9) Constipation 15 (9) 1 (0.6) Extremity Pain 14 (9) 0 Nausea 14 (9) 4 (2) Nocturia 14 (9) 3 (2) Abdominal Pain/Discomfort 13 (8) 1 (0.6) Urinary Tract Pain 13 (8) 2 (1) Dizziness 12 (7) 2 (1) Headache/Sinus Headache 12 (7) 1 (0.6) Urinary Tract Infection 12 (7) 0 Bone Pain 11 (7) 4 (2) Back Pain 10 (6) 1 (0.6) Hypertension/Blood Pressure Increased 10 (6) 0 Pruritus/Generalized Pruritus 9 (6) 3 (2) In the same study, erectile dysfunction and testicular atrophy were reported in patients on LEUPROLIDE ACETATE FOR DEPOT SUSPENSION 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. 6.2 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 LEUPROLIDE ACETATE FOR DEPOT SUSPENSION. 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 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

No pharmacokinetic-based drug-drug interaction studies have been conducted with LEUPROLIDE ACETATE FOR DEPOT SUSPENSION. 7.1 Drug/Laboratory Test Interactions Administration of LEUPROLIDE ACETATE FOR DEPOT SUSPENSION 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 LEUPROLIDE ACETATE FOR DEPOT SUSPENSION, diagnostic tests of pituitary gonadotropic and gonadal functions conducted during treatment and up to three months after discontinuation of LEUPROLIDE ACETATE FOR DEPOT SUSPENSION may be affected.