Trelstar

1 INDICATIONS AND USAGE 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 )

2 DOSAGE AND ADMINISTRATION 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…

5 WARNINGS AND PRECAUTIONS Hypersensitivity: Anaphylactic shock, hypersensitivity, and angioedema have been reported. In the event of a reaction, discontinue TRELSTAR and initiate appropriate medical management. ( 5.1 ) Tumor Flare: Transient increase in serum testosterone levels can occur within the first few weeks of treatment. This may worsen prostate cancer and result in spinal cord compression and urinary tract obstruction. Monitor patients at risk and manage as appropriate. ( 5.2 ) Metabolic Syndrome: The use of GnRH agonists may lead to an increased risk of metabolic changes such as hyperglycemia, diabetes, hyperlipidemia, and non-alcoholic fatty liver disease. Monitor for signs and symptoms of metabolic syndrome including lipids, blood glucose level and/or HbA1c and manage according to institutional guidelines. ( 5.3 ) Cardiovascular Diseases: Increased risk of myocardial infarction, sudden cardiac death and stroke has been reported in men. Monitor for cardiovascular disease and manage according toto institutional guidelines. ( 5.4 ) Convulsions: Convulsions have occurred in patients treated with GnRH analogs (including TRELSTAR) with or without a history of predisposing factors. Manage patients who experience convulsions according to institutional guidelines. ( 5.5 ) Severe Cutaneous Adverse Reactions (SCARs): SCARs have been reported in patients receiving GnRH agonists, including triptorelin products. Interrupt TRELSTAR if signs or symptoms of SCARs develop. Permanently discontinue TRELSTAR if a SCAR is confirmed. ( 5.6 ) Effect on QT/QTc Interval: Androgen deprivation therapy may prolong the QT interval. Consider risks and benefits. ( 5.7 ) Embryo-Fetal Toxicity: TRELSTAR may cause fetal harm. ( 5.10 , 8.1 ) 5.1 Hypersensitivity Reactions Anaphylactic shock, hypersensitivity, and angioedema related to TRELSTAR administration have been reported. In the event of a hypersensitivity reaction, discontinue TRELSTAR immediately and administer the appropriate supportive and symptomatic care. 5.2 Tumor Flare Initially, triptorelin (TRELSTAR), like other GnRH agonists, causes a transient increase in serum testosterone levels [ see Clinical Pharmacology (12.2) ]. As a result, worsening signs and symptoms of prostate cancer during the first weeks of treatment have been reported with GnRH agonists. Patients may experience worsening of symptoms or onset of new symptoms, including bone pain, neuropathy, hematuria, or urethral or bladder outlet obstruction. Closely monitor patients with metastatic vertebral lesions and/or with urinary tract obstruction during the first few weeks of therapy. 5.3 Metabolic Syndrome The use of GnRH agonists (including TRELSTAR) may lead to metabolic changes such as hyperglycemia, diabetes mellitus, and hyperlipidemia. Non-alcoholic fatty liver disease, including cirrhosis, occurred in the post-marketing setting. Hyperglycemia may represent new-onset of diabetes mellitus or worsening of glycemic control in patients with pre-existing diabetes. Monitor for changes in serum lipids, blood glucose and/or glycosylated hemoglobin (HbA1c) periodically in patients receiving TRELSTAR and manage according to institutional guidelines. 5.4 Cardiovascular Diseases Increased risk of developing myocardial infarction, sudden cardiac death and stroke has been reported in association with the use of GnRH agonists (including TRELSTAR) in men. The risk appears low based on the reported odds ratios and should be evaluated carefully along with cardiovascular risk factors when determining a treatment for patients with prostate cancer. Monitor patients receiving TRELSTAR for symptoms and signs suggestive of development of cardiovascular disease and manage according to current institutional guidelines. 5.5 Convulsions Convulsions have occurred in patients treated with GnRH analog (including TRELSTAR). These events included patients with risk factors for seizures such as a history of epilepsy, intracranial tumors or co-medicatio…

4 CONTRAINDICATIONS 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) ].

7 DRUG INTERACTIONS 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.

8.1 Pregnancy Risk Summary Based on findings in animal studies and mechanism of action, TRELSTAR can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1) ] . Expected hormonal changes that occur with TRELSTAR treatment increase the risk for pregnancy loss. In animal developmental and reproductive toxicology studies, daily administration of triptorelin to pregnant rats during the period of organogenesis caused maternal toxicity and embryo-fetal toxicities, including loss of pregnancy, at doses as low as 0.2, 0.8, and 8 times the estimated human daily dose based on body surface area. Advise pregnant patients and females of reproductive potential of the potential risk to the fetus. Data Animal Data Studies in pregnant rats administered triptorelin at doses of 2, 10, and 100 mcg/kg/day (approximately equivalent to 0.2, 0.8, and 8 times the estimated human daily dose based on body surface area) during the period of organogenesis demonstrated maternal toxicity and embryo-fetal toxicities. Embryo-fetal toxicities consisted of pre-implantation loss, increased resorption, and reduced mean number of viable fetuses at the high dose. Teratogenic effects were not observed in viable fetuses in rats or mice. Doses administered to mice were 2, 20, and 200 mcg/kg/day (approximately equivalent to 0.1, 0.7, and 7 times the estimated human daily dose based on body surface area).

6 ADVERSE REACTIONS 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 Reac…