TRELSTAR

TRELSTAR is a white to slightly yellow lyophilized cake. When reconstituted, TRELSTAR has a milky appearance. It contains a pamoate salt of triptorelin, a synthetic decapeptide agonist analog of gonadotropin releasing hormone (GnRH). The chemical name of triptorelin pamoate is 5-oxo-L-prolyl-L-histidyl-L-tryptophyl-L-seryl-L-tyrosyl-D-tryptophyl-L-leucyl-L-arginyl-L-prolylglycine amide (pamoate salt). The empirical formula is C 64 H 82 N 18 O 13 · C 23 H 16 O 6 and the molecular weight is 1699.9. The structural formula is: Structural formula for TRELSTAR (triptorelin pamoate). The TRELSTAR products are sterile, lyophilized biodegradable microgranule formulations supplied as single dose vials. Refer to Table 5 for the composition of each TRELSTAR product. Table 5. TRELSTAR Composition Ingredients TRELSTAR 3.75 mg TRELSTAR 11.25 mg TRELSTAR 22.5 mg triptorelin pamoate (base units) 3.75 mg 11.25 mg 22.5 mg poly- d,l -lactide-co-glycolide 138 mg 120 mg 183 mg mannitol, USP 71 mg 74 mg 74 mg carboxymethylcellulose sodium, USP 25 mg 26 mg 26 mg polysorbate 80, NF 1.7 mg 1.7 mg 1.7 mg When 2 mL sterile water is added to the vial containing TRELSTAR and mixed, a suspension is formed which is intended as an intramuscular injection. TRELSTAR is available in a vial plus a vial adapter, and a separate pre-filled syringe that contains sterile water for injection, USP, 2 mL.

TRELSTAR is indicated for the treatment of advanced prostate cancer [ see Clinical Studies (14) ]. TRELSTAR is a gonadotropin releasing hormone (GnRH) agonist indicated for the treatment of advanced prostate cancer. ( 1 )

TRELSTAR is administered as a single intramuscular injection in either buttock. Due to different release characteristics, the dosage strengths are not additive and must be selected based upon the desired dosing schedule. ( 2.1 ) 3.75 mg every 4 weeks. ( 2.1 ) 11.25 mg every 12 weeks. ( 2.1 ) 22.5 mg every 24 weeks. ( 2.1 ) Trelstar injection kit 2.1 Dosing Information TRELSTAR must be administered under the supervision of a physician. TRELSTAR is administered by a single intramuscular injection in either buttock. Dosing schedule depends on the product strength selected (Table 1). The lyophilized microgranules are to be reconstituted in sterile water . No other diluent should be used. Table 1. TRELSTAR Recommended Dosing Dosage 3.75 mg 11.25 mg 22.5 mg Recommended dose 1 injection every 4 weeks 1 injection every 12 weeks 1 injection every 24 weeks Due to different release characteristics, the dosage strengths are not additive and must be selected based upon the desired dosing schedule. The suspension should be administered within 2 minutes after reconstitution. As with other drugs administered by intramuscular injection, the injection site should be alternated periodically. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. 2.2 Reconstitution Instructions for TRELSTAR Important: Please read the instructions completely and prepare the patient before you begin the injection kit activation and drug administration procedure. *The strength indicated on the vial in the figure above is for representative purposes only. All three strengths of the Trelstar vial have their individual strengths indicated on the label. Users will see either 3.75 mg, 11.25 mg or 22.5 mg, with the corresponding duration of treatment (4, 12 or 24 weeks respectively). Preparation and Activation Check that you are using the prescribed strength/dose (3.75 mg, 11.25 mg, or 22.5 mg) and that the expiry date has not passed, before preparation and activation. Wash your hands with soap and hot water and put on gloves immediately prior to preparing the injection. Place the sealed tray on a clean, flat surface that is covered with a sterile pad or cloth. Peel the cover away from the tray and remove the injection kit components and TRELSTAR vial. General Instructions and Recommendations The product is a suspension of microgranules that can settle in the diluent. The final product to be administered is a suspension of microgranules with a milky, homogeneous appearance. If the product settles in the vial, shake it again to resuspend the microgranules. If the microgranules settle in the syringe, this will block the needle during administration. It is very important to inject the product within 2 minutes following reconstitution in the vial. If the product settles in the syringe, draw some air back into the syringe, shake it again, and expel the air (without priming the needle) before administering it. STEP 1 – PREPARE VIAL Remove the flip-off button cap from 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. STEP 2 – APPLY VIAL ADAPTER Peel the cover away from the blister pack containing the vial adapter. Do not remove the vial adapter from the blister pack . On a level surface, place the blister pack containing the vial adapter firmly on the vial top. Ensure the spike is centered and vertical when piercing the vial . Push down gently until you feel it snap into place. Remove the blister pack from the vial adapter. STEP 3 – PREPARE SYRINGE AND CONNECT TO VIAL ADAPTER (a) Grasp the plastic ‘spin lock’ collar on the syringe barrel with index finger and thumb. Unscrew and discard the gray rubber cap from the syringe barrel. (b) Maintaining your grip on the spin lock, attach the syringe to the vial adapter by screwing the spin lock clockwise onto the vial adapter luer lock. Gently twist the spin lock until it stops turning to ensure a tight connection. Note: Overtightening can result in a poor connection and leakage. STEP 4 – TRANSFER DILUENT TO VIAL Holding the vial and adapter with one hand, slowly push the plunger rod with the other hand and transfer all of the diluent into the vial. STEP 5 – MIX TRELSTAR SUSPENSION Gripping the vial and vial adapter firmly, shake vigorously for 30 seconds to mix the contents thoroughly . This will ensure complete mixing of TRELSTAR and the sterile water diluent. Check the appearance of the suspension through the bottom of the vial. The suspension should appear homogeneous and milky. In order to avoid separation of the suspension, proceed to the next steps without delay. The product must be injected within less than 2 minutes from reconstitution. Note: If there is sedimentation in the vial, shake again. STEP 6 – LOAD THE SYRINGE WITH TRELSTAR (a) Immediately invert the system so that the vial is at the top and the syringe is at the bottom. Pull back the plunger rod slowly to draw the reconstituted TRELSTAR into the syringe while maintaining pressure on the plunger rod to ensure it does not pull back too far. (b) Remove air bubbles by expelling air into the vial but do not propel the suspension beyond the luer lock. Note : If the product settles in the syringe, draw some air back into the syringe, shake it again, and expel the air (without priming the needle) before administering it. STEP 7 – DISCONNECT VIAL ADAPTER AND CONNECT NEEDLE (a) Hold the barrel and spin lock firmly. Hold the syringe barrel and spin lock with one hand and with the other hand turn the adapter counter-clockwise to disconnect the vial adapter and vial from the syringe. (b) Holding the syringe by the spin lock, attach the injection needle STEP 8 – PREPARE FOR INJECTION Make sure that the patient is ready for the administration. Lift up the safety cover and remove the clear plastic needle shield by pulling it from the assembly. The safety cover should be perpendicular to the needle, with the needle facing away from you. Do not prime the needle. The syringe containing the TRELSTAR suspension is now ready for administration. The suspension should be administered immediately (less than 2 minutes) after reconstitution to avoid excessive thickening of the suspension. STEP 9 – ADMINISTRATION Administer the injection by inserting the needle at a 90-degree angle into the large gluteal muscle. Ensure that the full amount of the product is injected within 10 seconds without interruption. Injection sites should be alternated. STEP 10 – SAFETY LOCK AFTER INJECTION After administering the injection, immediately activate the safety mechanism by centering your thumb or forefinger on the textured finger pad area of the safety cover and pushing it forward over the needle until you hear or feel it lock in place. Use the one-handed technique and activate the mechanism away from yourself and others. Immediately discard the syringe into a sharps container after a single use.

Known hypersensitivity to triptorelin or any other component of the product, or other GnRH agonists or GnRH. ( 4 ) 4.1 Hypersensitivity TRELSTAR is contraindicated in individuals with a known hypersensitivity to triptorelin or any other component of the product, or other GnRH agonists or GnRH [ see Warnings and Precautions (5.1) ].

The following is discussed in more detail in other sections of the labeling: Hypersensitivity Reactions [ see Warnings and Precautions ( 5.1 ) ] Tumor Flare [ see Warnings and Precautions ( 5.2 ) ]. Metabolic Syndrome [ see Warnings and Precautions ( 5.3 ) ] Cardiovascular Diseases [ see Warnings and Precautions ( 5.4 ) ]. Convulsions [ see Warnings and Precautions ( 5.5 ) ]. Severe Cutaneous Adverse Reactions [ see Warnings and Precautions ( 5.6 ) ]. Effect of QT/QTc Interval [ see Warnings and Precautions ( 5.7 ) ]. 3.75 mg: The most common adverse reactions (≥ 5%) during TRELSTAR 3.75 mg therapy included hot flushes, skeletal pain, impotence, and headache. ( 6.1 ) 11.25 mg: The most common adverse reactions (≥ 5%) during TRELSTAR 11.25 mg therapy included hot flushes, skeletal pain, headache, edema in legs, and leg pain. ( 6.1 ) 22.5 mg: The most common adverse reactions (≥ 5%) during TRELSTAR 22.5 mg therapy included hot flushes, erectile dysfunction, and testicular atrophy. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Verity Pharma at 1-844-837-4891 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 with rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of the three TRELSTAR formulations was evaluated in clinical trials involving patients with advanced prostate cancer. Mean testosterone levels increased above baseline during the first week following the initial injection, declining thereafter to baseline levels or below by the end of the second week of treatment. The transient increase in testosterone levels may be associated with temporary worsening of disease signs and symptoms, including bone pain, neuropathy, hematuria, and urethral or bladder outlet obstruction. Spinal cord compression with weakness or paralysis of the lower extremities have occurred [ see Warnings and Precautions (5.2) ]. Adverse reactions reported for each of the three TRELSTAR formulations in the clinical trials, are presented in Table 2, Table 3, and Table 4. The majority of adverse reactions related to TRELSTAR are a result of its pharmacological action, i.e., the induced variation in serum testosterone levels, either an increase in testosterone at the initiation of treatment, or a decrease in testosterone once castration is achieved. Local reactions at the injection site or allergic reactions may occur. The following adverse reactions were reported to have a possible or probable relationship to therapy as described by the treating physician in at least 1% of patients receiving TRELSTAR 3.75 mg. Table 2. TRELSTAR 3.75 mg: Treatment-Related Adverse Reactions Reported by 1% or More of Patients During Treatment Adverse Reaction s * TRELSTAR 3.75 mg N = 140 N % Application Site Disorders Injection site pain 5 3.6 Body as a Whole Hot flush 82 58.6 Pain 3 2.1 Leg pain 3 2.1 Fatigue 3 2.1 Cardiovascular Disorders Hypertension 5 3.6 Central and Peripheral Nervous System Disorders Headache 7 5.0 Dizziness 2 1.4 Gastrointestinal Disorders Diarrhea 2 1.4 Vomiting 3 2.1 Musculoskeletal System Disorders Skeletal pain 17 12.1 Psychiatric Disorders Insomnia 3 2.1 Impotence 10 7.1 Emotional lability 2 1.4 Red Blood Cell Disorders Anemia 2 1.4 Skin and Appendages Disorders Pruritus 2 1.4 Urinary System Disorders Urinary tract infection 2 1.4 Urinary retention 2 1.4 * Adverse reactions for TRELSTAR 3.75 mg are coded using the WHO Adverse Reactions Terminology (WHOART) The following adverse reactions were reported to have a possible or probable relationship to therapy as described by the treating physician in at least 1% of patients receiving TRELSTAR 11.25 mg. Table 3. TRELSTAR 11.25 mg: Treatment-Related Adverse Reactions Reported by 1% or More of Patients During Treatment Adverse Reactions * TRELSTAR 11.25 mg N = 174 N % Application Site Injection site pain 7 4.0 Body as a Whole Hot flush 127 73.0 Leg pain 9 5.2 Pain 6 3.4 Back pain 5 2.9 Fatigue 4 2.3 Chest pain 3 1.7 Asthenia 2 1.1 Peripheral edema 2 1.1 Cardiovascular Disorders Hypertension 7 4.0 Dependent edema 4 2.3 Central and Peripheral Nervous System Disorders Headache 12 6.9 Dizziness 5 2.9 Leg cramps 3 1.7 Endocrine Breast pain 4 2.3 Gynecomastia 3 1.7 Gastrointestinal Disorders Nausea 5 2.9 Constipation 3 1.7 Dyspepsia 3 1.7 Diarrhea 2 1.1 Abdominal pain 2 1.1 Liver and Biliary System Abnormal hepatic function 2 1.1 Metabolic and Nutritional Disorders Edema in legs 11 6.3 Increased alkaline phosphatase 3 1.7 Musculoskeletal System Disorders Skeletal pain 23 13.2 Arthralgia 4 2.3 Myalgia 2 1.1 Psychiatric Disorders Decreased libido 4 2.3 Impotence 4 2.3 Insomnia 3 1.7 Anorexia 3 1.7 Respiratory System Disorders Coughing 3 1.7 Dyspnea 2 1.1 Pharyngitis 2 1.1 Skin and Appendages Rash 3 1.7 Urinary System Disorders Dysuria 8 4.6 Urinary retention 2 1.1 Vision Disorders Eye pain 2 1.1 Conjunctivitis 2 1.1 * Adverse reactions for TRELSTAR 11.25 mg are coded using the WHO Adverse Reactions Terminology (WHOART) The following adverse reactions occurred in at least 5% of patients receiving TRELSTAR 22.5 mg. The table includes all reactions whether or not they were ascribed to TRELSTAR by the treating physician. The table also includes the incidence of these adverse reactions that were considered by the treating physician to have a reasonable causal relationship or for which the relationship could not be assessed. Table 4. TRELSTAR 22.5 mg: Adverse Reactions Reported by 5% or More of Patients During Treatment Adverse Reactions * TRELSTAR 22.5 mg N = 120 Treatment-Emergent Treatment-Related N % N % General Disorders and Administration Site Conditions Edema peripheral 6 5.0 0 0 Infections and Infestations Influenza 19 15.8 0 0 Bronchitis 6 5.0 0 0 Endocrine Diabetes Mellitus/Hyperglycemia 6 5.0 0 0 Musculoskeletal and Connective Tissue Disorders Back pain 13 10.8 1 0.8 Arthralgia 9 7.5 1 0.8 Pain in extremity 9 7.5 1 0.8 Nervous System Disorders Headache 9 7.5 2 1.7 Psychiatric Disorders Insomnia 6 5.0 1 0.8 Renal and Urinary Disorders Urinary tract infection 14 11.6 0 0 Urinary retention 6 5.0 0 0 Reproductive System and Breast Disorders Erectile dysfunction 12 10.0 12 10.0 Testicular atrophy 9 7.5 9 7.5 Vascular Disorders Hot flush 87 72.5 86 71.7 Hypertension 17 14.2 1 0.8 * Adverse reactions for TRELSTAR 22.5 mg are coded using the Medical Dictionary for Regulatory Activities (MedDRA) Changes in Laboratory Values During Treatment The following abnormalities in laboratory values not present at baseline were observed in 10% or more of patients: TRELSTAR 3.75 mg : There were no clinically meaningful changes in laboratory values detected during therapy. TRELSTAR 11.25 mg : Decreased hemoglobin and RBC count and increased glucose, BUN, SGOT, SGPT, and alkaline phosphatase at the Day 253 visit. TRELSTAR 22.5 mg : Decreased hemoglobin and increased glucose and hepatic transaminases were detected during the study. The majority of the changes were mild to moderate. 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. 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 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. Cardiovascular System – cerebrovascular accident, myocardial infarction, pulmonary emboli, thromboembolic events (including deep venous thrombosis, transient ischemic attack, and thrombophlebitis) Central/Peripheral Nervous System – convulsions Hepatobiliary Disorder – non-alcoholic fatty liver disease Respiratory, Thoracic, and Mediastinal Disorder – interstitial lung disease Skin and Subcutaneous Tissue Disorders – SJS/TEN, DRESS, AGEP, dermatitis exfoliative, bullous dermatitis, and erythema multiforme.

No drug-drug interaction studies involving TRELSTAR have been conducted. Human pharmacokinetic data with triptorelin suggest that C-terminal fragments produced by tissue degradation are either degraded completely within tissues, are rapidly degraded further in plasma, or cleared by the kidneys. Therefore, hepatic microsomal enzymes are unlikely to be involved in triptorelin metabolism. However, in the absence of relevant data and as a precaution, hyperprolactinemic drugs should not be used concomitantly with TRELSTAR since hyperprolactinemia reduces the number of pituitary GnRH receptors.