TRIPTODUR

TRIPTODUR contains the pamoate salt of triptorelin, a synthetic decapeptide analog of naturally occurring gonadotropin-releasing hormone (GnRH or LHRH). 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 molecular weight is 1699.9 and the structural formula is: TRIPTODUR for extended release injectable suspension for intramuscular use is provided as a sterile, lyophilized, biodegradable microgranule formulation in a single-dose vial, co-packaged with a syringe containing 2 mL Sterile Water for Injection for reconstitution of the lyophilisate. The triptorelin formulation is comprised of 22.5 mg triptorelin (equivalent to 31 mg triptorelin pamoate), carboxymethylcellulose sodium (26 mg), mannitol (74 mg), poly- d,l- lactide-co-glycolide (183 mg), and polysorbate 80 (1.7 mg). When 2 mL Sterile Water for Injection is added to the vial containing TRIPTODUR and mixed, a suspension is formed which is intended as a single intramuscular injection. triptodur-spl-11

TRIPTODUR is indicated for the treatment of pediatric patients 2 years of age and older with central precocious puberty (CPP). TRIPTODUR is a gonadotropin releasing hormone (GnRH) agonist indicated for the treatment of pediatric patients 2 years and older with central precocious puberty. ( 1 )

Must only be administered by a healthcare provider. ( 2.1 ) Administer TRIPTODUR as a single intramuscular injection of 22.5 mg once every 24 weeks. ( 2.1 ) Monitor response with LH levels after a GnRH or GnRH agonist stimulation test, basal LH, or serum concentration of sex steroid levels beginning 1 to 2 months following initiation of therapy, during therapy as necessary to confirm maintenance of efficacy, and with each subsequent dose. ( 2.2 ) Measure height every 3-6 months and monitor bone age periodically. ( 2.2 ) See FPI for complete reconstitution and administration instructions. ( 2.3 ) Once TRIPTODUR is mixed, proceed to the next steps and administer without delay. ( 2.3 ) The injection of the suspension should be performed rapidly and in a steady and uninterrupted manner in order to avoid any potential blockage of the needle. ( 2.3 ) 2.1 Dosing Information TRIPTODUR must only be administered by a healthcare provider. The dosage of TRIPTODUR is 22.5 mg reconstituted with accompanying diluent (Sterile Water) 2 mL, and administered as a single intramuscular injection once every 24 weeks. TRIPTODUR treatment should be discontinued at the appropriate age of onset of puberty at the discretion of the physician. 2.2 Monitoring Monitor response to TRIPTODUR with LH levels after a GnRH or GnRH agonist stimulation test, basal LH, or serum concentration of sex steroid levels beginning 1 to 2 months following initiation of therapy, during therapy as necessary to confirm maintenance of efficacy, and with each subsequent dose. Measure height (for calculation of growth rate) every 3-6 months and monitor bone age periodically. Noncompliance with drug regimen or inadequate dosing may result in inadequate control of the pubertal process with gonadotropins and/or sex steroids increasing above prepubertal levels. If the dose of TRIPTODUR is not adequate switching to an alternative GnRH agonist for the treatment of CPP with the ability for dose adjustment may be necessary. 2.3 Reconstitution and Administration Instructions Read these instructions completely before you begin. • Triptodur suspension will sediment very quickly and should be injected immediately after reconstitution in accordance with the detailed instructions below. • If the sequence of steps to prepare the suspension is interrupted and/or the vial is put aside, the suspension will start to separate into diluent and microgranules. • To minimize the risk of needle blockage during the injection, ensure that the preparation of the injection is not interrupted and/or the mixed suspension syringe is not put aside because the suspension will sediment quickly. 1. Use appropriate aseptic technique for preparation and administration. 2. Screw the plunger rod into the barrel end of the prefilled sterile water diluent syringe. 3. To remove the cap, twist counterclockwise to separate from the Luer lock on the syringe barrel. 4. Firmly attach one of the 21-gauge sterile safety needles onto the prefilled sterile water diluent syringe with a push and clockwise twist. This 21-gauge needle will only be used for reconstitution of the product. a. Remove the plastic Flip-off from the vial. Disinfect the visible part of the stopper b. Pull back on the safety cover towards the syringe and away from the 21-gauge needle. Then pull the clear needle shield off. 5. Insert the 21-gauge needle through the stopper. Inject the Sterile Water diluent into the vial, ensuring the diluent rinses the sides of the vial. Do not release the plunger rod. 6. If the syringe plunger is not maintained in position, it will naturally withdraw product into the syringe. Thoroughly mix the vial with agitation for 30 to 60 seconds, ensuring the diluent rinses the sides of the vial. 7. Before moving on to the next step, check visually that the suspension appears milky and homogeneous without any visible aggregates or precipitates. a. If the suspension DOES NOT appear milky and homogeneous without any visible aggregates or precipitates, continue with the agitation. An up and down agitation can also be used to help eliminate aggregates or precipitates. The complete and homogeneous (milky) suspension of the product may require up to 60 seconds of agitation. Important: Once mixed, proceed to the next steps and administer without delay. 8. The suspension will sediment very quickly so it is imperative to withdraw the suspension into the syringe directly after suspending the product in the vial. 9. Invert the vial and move back the syringe in order to position the end of the 21-gauge needle very near the level of the stopper, making sure the needle lumen is still completely in the vial. 10. Pull back the plunger rod slowly to withdraw the reconstituted product into the syringe, withdrawing as much of the reconstituted product into the syringe as possible. Move the tip of the needle at the level of the stopper so as to be able to withdraw a maximum amount of suspension. 11. Withdraw the needle from the vial and push the safety cover forward toward the needle until you hear and/or feel it lock. Then remove the first 21-gauge needle by grasping the needle hub to disconnect the needle from the syringe and discard it. This (first) 21-gauge needle will no longer be used. 12. Firmly attach the second sterile needle onto the syringe with a push and clockwise twist and pull back the safety cover towards the syringe. This 21-gauge needle will be used for administration. Triptodur must only be administered with a thin-wall 21 -gauge needle. 13. Do not prime the needle. Inspect the suspension visually for particulate matter and discoloration. a. If the suspension does not appear milky and homogeneous, continue with an up and down agitation. b. If the suspension appears milky and homogeneous without visible aggregates or precipitates, administer the suspension immediately. 14. Inject the patient intramuscularly, preferably in either buttock or thigh using the entire contents of the syringe. The injection of the suspension should be performed rapidly and in a steady and uninterrupted manner in order to avoid any potential blockage of the needle. 15. After administering the injection, immediately activate the safety cover: a. Center your thumb or forefinger on the textured finger pad area of the safety cover and push it forward over the needle until you hear or feel it lock. b. Use the one-handed technique and activate the mechanism away from yourself and others. c. Immediately discard the syringe assembly into a suitable sharps container. triptodur-spl-1 triptodur-spl-2 triptodur-spl-3 triptodur-spl-4 triptodur-spl-5 triptodur-spl-6 triptodur-spl-7 triptodur-spl-8 triptodur-spl-9 triptodur-spl-10

Hypersensitivity: TRIPTODUR is contraindicated in individuals with a known hypersensitivity to triptorelin, any other component of the product, or other GnRH agonists or GnRH [see Adverse Reactions (6.2) ] . Pregnancy: TRIPTODUR may cause fetal harm [see Use in Specific Populations (8.1) ] . Hypersensitivity reactions ( 4 ) Pregnancy ( 4 , 8.1 )

The following serious adverse reactions are described here and elsewhere in the label: Initial Rise of Gonadotropins and Sex Steroid Levels [ see Warnings and Precautions ( 5.1 ) ] Psychiatric Events [ see Warnings and Precautions ( 5.2 ) ] Convulsions [ see Warnings and Precautions ( 5.3 ) ] Severe Cutaneous Adverse Reactions [ see Warnings and Precautions ( 5.4 ) ] Pseudotumor Cerebri (Idiopathic Intracranial Hypertension) [ see Warnings and Precautions ( 5.5 ) ] In clinical trials for TRIPTODUR, the most common adverse reactions (≥4.5%) are injection site reactions, menstrual (vaginal) bleeding, hot flush, headache, cough, and infections (bronchitis, gastroenteritis, influenza, nasopharyngitis, otitis externa, pharyngitis, sinusitis, and upper respiratory tract infection). ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Azurity Pharmaceuticals, Inc. at 1-800-461-7449 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. The safety of TRIPTODUR was evaluated in one uncontrolled, open-label single-arm clinical trial in which 44 children with central precocious puberty received two doses of TRIPTODUR and were observed for 12 months. The median age of the study population was 8 years (range 2-9 years) at treatment start; 88.6% of subjects were female, 59.1% were White, 27.3% were Black and 4.5% were Asian. Table 1 shows all the adverse reactions that occurred in at least 2 patients (≥4.5%) during the open-label single-arm trial. Table 1: Adverse Reactions1 Occurring in ≥ 2 Patients Treated with TRIPTODUR in an Open-Label Single-Arm Trial Adverse Reactions Number of Patients Reporting Event (%) (Total N=44) Infections & Infestations Bronchitis 2 (4.5) Gastroenteritis 3 (6.8) Influenza 2 (4.5) Nasopharyngitis 6 (13.6) Otitis externa 2 (4.5) Pharyngitis 2 (4.5) Sinusitis 2 (4.5) Upper respiratory tract infection 4 (9.1) Nervous System Disorders Headache 6 (13.6) Reproductive System & Breast Disorders Menstrual (Vaginal bleeding) 2 3 (7.7) Respiratory, Thoracic & Mediastinal Disorder Cough 3 (6.8) Vascular Disorders Hot flush 2 (4.5) 1 Injection site reactions are presented separately 2 Includes % of patients with vaginal bleeding or menstrual disorder (“menstrual cycle returned”) in 39 females out of N=44. Other Selected Adverse Reactions: Injection Site Reactions Injection site reactions occurring in patients immediately and/or 2 hours after injection include pain (45%), redness (14%), pruritus (2.3%) and swelling (2.3%). Psychiatric Disorders Anxiety (2.3%) and mood altered (2.3%) 6.2 Post-marketing Experience The following adverse reactions have been identified during post-approval use of triptorelin or GnRH 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. Hypersensitivity Reactions: Anaphylactic shock, anaphylactoid reaction, angioedema, urticaria. Cardiovascular: Hypertension. Psychiatric: Emotional lability, such as crying, irritability, impatience, anger, and aggression . Depression, including rare reports of suicidal ideation and attempt. Many, but not all, of these patients had a history of psychiatric illness or other comorbidities with an increased risk of depression. Nervous System: Convulsions , pseudotumor cerebri (idiopathic intracranial hypertension) Vision Disorders: Visual impairment, visual disturbance Skin Reactions: erythema multiforme, bullous dermatitis, dermatitis exfoliative, drug reaction with eosinophilia and systemic symptoms, Stevens-Johnson syndrome and toxic epidermal necrolysis, and acute generalized exanthematous pustulosis

7.1 Drug-Drug Interactions Results of in vitro studies show that drug-drug interactions with triptorelin are unlikely [see Clinical Pharmacology (12.3)] . However, in the absence of relevant data and as a precaution, hyperprolactinemic drugs should not be used concomitantly with triptorelin since hyperprolactinemia reduces the number of pituitary GnRH receptors. 7.2 Drug-Laboratory Test Interactions Administration of TRIPTODUR results in suppression of the pituitary-gonadal system. The effect of TRIPTODUR on pituitary and gonadal function is expected to disappear within six to twelve months after treatment discontinuation. Therefore, diagnostic tests of pituitary gonadotropic and gonadal functions conducted during treatment or after discontinuation of treatment may be affected.