AZMIRO

AZMIRO (testosterone cypionate) injection for intramuscular injection, contains testosterone cypionate which is the oil-soluble 17 (beta)-cyclopentylpropionate ester of the androgenic hormone testosterone. Testosterone cypionate is a white or creamy white crystalline powder, odorless or nearly so and stable in air. It is insoluble in water, freely soluble in alcohol, chloroform, dioxane, ether, and soluble in vegetable oils. The chemical name for testosterone cypionate is androst-4-en-3-one, 17-(3-cyclopentyl-1-oxopropoxy)-, (17ß)-. Its molecular formula is C 27 H 40 O 3 , and the molecular weight 412.61. The structural formula is shown in the following figure: AZMIRO (testosterone cypionate) injection is provided as sterile, clear colorless to pale yellow solution containing 200 mg/mL testosterone cypionate in vials and prefilled syringes. Each mL of solution contains: Testosterone cypionate………………………………………..200 mg Benzyl alcohol………………………………………………….20 mg Benzyl benzoate……………………………………………….0.2 mL Cottonseed oil…………………………………………………542 mg Testosteron structure

INDICATIONS & USAGE AZMIRO is indicated for testosterone replacement therapy in males in conditions associated with a deficiency or absence of endogenous testosterone: • Primary hypogonadism (congenital or acquired): testicular failure due to conditions such as cryptorchidism, bilateral torsion, orchitis, vanishing testis syndrome; or orchiectomy, Klinefelter’s syndrome, or toxic damage from alcohol or heavy metals, chemotherapy, or toxic damage from alcohol or heavy metals. These men usually have low serum testosterone concentrations and gonadotropins (follicle stimulating hormone (FSH), luteinizing hormone (LH)) above the normal range [ see Dosage and Administration ( 2.2 ) ]. • Hypogonadotropic hypogonadism (congenital or acquired): gonadotropin or luteinizing hormone-releasing hormone (LHRH) deficiency, or pituitary-hypothalamic injury from tumors, trauma, or radiation. These men have low testosterone serum concentrations but have gonadotropins in the normal or low range [ see Dosage and Administration (2.2) ]. Limitations of Use • Safety and efficacy of AZMIRO in men with “age- related hypogonadism” (also referred to as “late-onset hypogonadism”) have not been established. • Safety and efficacy of AZMIRO in pediatric patients below the age of 12 years have not been established [ see Use in Specific Populations ( 8.4 ) ]. AZMIRO is an androgen indicated for testosterone replacement therapy in males for conditions associated with a deficiency or absence of endogenous testosterone ( 1 ): Limitations of Use: • Safety and efficacy of AZMIRO in men with “age-related hypogonadism” (also referred to as “late-onset hypogonadism”) have not been established ( 1 ). • Safety and effectiveness in pediatric patients below the age of 12 years have not been established ( 8.4 ).

• Injectable testosterone products may have different doses, strengths, or administration instructions and they are not substitutable on a milligram-per-milligram basis. Administer AZMIRO by deep gluteal intramuscular injection only ( 2.1 ). • Prior to initiating AZMIRO, confirm the diagnosis of hypogonadism by ensuring that serum testosterone concentrations have been measured in the morning on at least two separate days and that these serum concentrations are below the normal range ( 2.2 ). • Recommended dosage is 50 mg to 400 mg administered every two to four weeks as a deep intramuscular injection in the gluteal muscle. Individualize the dose and schedule based on the patient’s age, diagnosis, response to treatment, and the appearance of adverse reactions ( 2.3 ). • The prefilled syringe should be administered as an intramuscular injection by a healthcare professional only. 2.1 Important Dosage Information • Injectable testosterone products may have different doses, strengths, or administration instructions and they are not substitutable on a milligram-per-milligram basis. • Administer AZMIRO by deep gluteal intramuscular injection only. 2.2 Confirmation of Hypogonadism before Initiation of AZMIRO Prior to initiating AZMIRO, confirm the diagnosis of hypogonadism by ensuring that serum testosterone concentrations have been measured in the morning on at least two separate days and that these serum testosterone concentrations are below the normal range. 2.3 Recommended Dosage The recommended dosage of AZMIRO is 50 mg to 400 mg administered every two to four weeks as a deep intramuscular injection in the gluteal muscle. Individualize the dose and schedule of AZMIRO based on the patient’s age, diagnosis, response to treatment, and the appearance of adverse reactions. 2.4 Administration Instructions for AZMIRO Single-dose Vial • Visually inspect parenteral drug products for particulate matter and discoloration prior to administration, whenever solution and container permit. • Discard any unused portions of drug remaining in the single-dose vial. 2.5 Important Administration Information and Administration Instructions for AZMIRO Prefilled Syringe Important Administration Information • The prefilled syringe should be administered as an intramuscular injection by a healthcare professional only. • The prefilled syringe should only be used to administer doses of 200 mg. For administration of doses other than 200 mg, use the AZMIRO single-dose vial. • AZMIRO 200 mg/mL is supplied as single-dose prefilled syringe with luer lock connector. • The prefilled syringe carton does not contain a needle. Obtain suitable needle separately. • Do not use if the packaging appears to be damaged. • Do not use the prefilled syringe if it appears to be damaged or the syringe cap is detached from the Luer lock. Administration Instructions Hold the syringe upright while gripping the ribbed part of the luer lock. Then with the other hand unscrew the syringe cap in a counter-clockwise direction (Figure A). Once the syringe cap is removed, avoid any hand contact with the tip of the glass syringe, to maintain the sterility. • Screw the needle onto the luer lock end of the syringe in a clockwise direction until it is firmly attached (Figure B). • Remove the needle cap by pulling it straight off. • Check syringe for air bubbles. If there are air bubbles: Gently tap the syringe with your fingers until the bubbles rise to the top of the syringe. Then press the plunger up to slowly expel the air. • Clean the injection site for injection into the gluteal muscle with an alcohol swab and allow the skin to dry. • Insert the needle straight into the skin at a 90° angle (Figure C). Push the plunger down to inject the entire contents (1 mL) of the prefilled syringe (Figure D). • After administration of the injection, discard the syringe into a sharps disposal container or in accordance with local requirements (Figure E). Figure-A Figure-B Figure-C Figure-D Figure-E

AZMIRO is contraindicated in: • Known hypersensitivity to AZMIRO or to any of its components [see Description ( 11 )]. Hypersensitivity, including skin manifestations and anaphylactoid reactions have been reported [ see Adverse Reactions ( 6.2 ) ]. • Men with carcinoma of the breast or known or suspected carcinoma of the prostate gland [ see Warnings and Precautions ( 5.3 ) ]. • Women who are pregnant. Testosterone can cause virilization of the female fetus when administered to a pregnant woman [ see Use in Specific Populations ( 8.1 ) ]. • Known hypersensitivity to AZMIRO or any of its components, skin manifestations and anaphylactoid reactions have been reported ( 4 ) • Men with carcinoma of the breast or known or suspected carcinoma of the prostate ( 4 ). • Women who are pregnant. Testosterone may cause fetal harm ( 4 ).

The following clinically significant adverse reactions are discussed elsewhere in the labeling: • Polycythemia [ see Warnings and Precautions ( 5.1 ) ] • Venous Thromboembolism [ see Warnings and Precautions ( 5.2 )] • Worsening of Benign Prostatic Hyperplasia (BPH) and Potential Risk of Prostate Cancer [ see Warnings and Precautions ( 5.3 ) ] • Blood Pressure Increases [ see Warnings and Precautions ( 5.4 ) ] • Hepatic Adverse Effects [ see Warnings and Precautions ( 5.8 ) ] • Edema [ see Warnings and Precautions ( 5.9 ) ] • Sleep Apnea [ see Warnings and Precautions ( 5.10 ) ] • Gynecomastia [ see Warnings and Precautions ( 5.11 ) ] • Lipid Changes [ see Warnings and Precautions ( 5.12 ) ] • Hypercalcemia [ see Warnings and Precautions ( 5.13 ) ] • Decreased Thyroxine-binding Globulin [ see Warnings and Precautions ( 5.14 ) ] • Increases in Prolactin [ see Warnings and Precautions ( 5.15 ) ] • Adverse Effects on Bone Maturation [ see Warnings and Precautions ( 5.16 ) ] Common adverse reactions (incidence ≥4%) are injection site erythema and injection site reaction ( 6.1 ). Other adverse reactions include: polycythemia, gynecomastia, headache, and depression ( 6.2 ). 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 Trial 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 AZMIRO was evaluated, in Study 1, a randomized, single-dose, open-label study conducted in 27 adult males with hypogonadism. Patients were 18 to 65 years of age with a body mass index of 18 to 35 kg/m 2 . Patients received a single intramuscular dose AZMIRO 200 mg or comparator intramuscular testosterone replacement therapy product and were observed for adverse reactions and injection site reactions over 31 days. The most common adverse reactions in patients who received AZMIRO were injection site erythema (26%) and injection site reaction (4%). All cases of injection site erythema and injection site reaction were categorized as mild based on a pre-defined injection site assessment scale that defined injection site reactions as mild if they were slight or barely perceptible. Cardiovascular Outcomes TRAVERSE was a randomized, double-blind, cardiovascular outcomes study to assess the cardiovascular (CV) safety of topical testosterone gel compared to placebo in 5198 hypogonadal men aged 45 to 80 years with a history of CV disease or with multiple CV risk factors. The primary outcome was the incidence of the composite endpoint of major adverse cardiovascular events (MACE), consisting of CV death, non-fatal myocardial infarction (MI), and non-fatal stroke The mean duration of therapy was approximately 22 months. The mean duration of follow-up was 33 months. Approximately 61% of all patients discontinued topical testosterone gel or placebo therapy. The mean patient age (±SD) was 63.3 (7.9) years, with 2452 patients aged 65 years or more (47%); 2847 (about 55%) patients had pre-existing cardiovascular disease, whereas 2357 patients (about 45%) had an elevated cardiovascular risk at baseline, and mean BMI was 35 kg/m 2 . Approximately 80% of patients were White, 17% were Black, and 3% were of other races or ethnic groups. Approximately 69%, 84%, and 93% had diabetes mellitus, hyperlipidemia, and hypertension, respectively. The mean serum testosterone concentration at baseline in patients receiving topical testosterone gel was 220.4 ng/dL (n=2596). The mean serum testosterone concentrations at 12 months, 24 months, 36 months, and 48 months in patients receiving topical testosterone gel were 440.5 ng/dL (n=1683), 420.9 ng/dl (n=1125), 428.7 ng/dL (n=731), and 365.2 ng/dL (n=220), respectively. For patients treated with topical testosterone gel, the incidence of MACE was 7.0% (n=182 events) and for those receiving placebo, the incidence of MACE was 7.3% (n=190 events). The study demonstrated non-inferiority of topical testosterone gel versus placebo because the upper bound of 95% CI was less than the pre-specified risk margin, of 1.5 for MACE (Hazard Ratio 0.96 [95% CI: 0.78, 1.17]). Additional Adverse Reactions Reported in TRAVERSE Additional adverse reactions reported in TRAVERSE at an incidence rate >2% in either treatment group and greater in topical testosterone gel versus placebo included: nonfatal arrythmias warranting intervention (5.2% vs 3.3%), atrial fibrillation (3.5% vs 2.4%), acute kidney injury (2.3% vs 1.5%) and bone fracture (3.5% vs 2.5%). For the adverse reaction of bone fracture, each event was adjudicated by clinical review. 6.2 Other Adverse Reactions The following adverse reactions associated with the use of testosterone were identified in clinical studies or postmarketing reports. Because some of these reactions were 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. Administration site reactions : Inflammation and pain at the site of intramuscular injection. Allergic : Hypersensitivity, including skin manifestations and anaphylactoid reactions. Cardiovascular disorders : myocardial infarction, stroke. Endocrine and urogenital : Gynecomastia, premature closure of bony epiphyses with termination of growth, precocious puberty. Fluid and electrolyte disturbances : Retention of sodium, chloride, water, potassium, calcium, and inorganic phosphates. Gastrointestinal: Nausea, cholestatic jaundice, alterations in liver function tests, rarely hepatocellular neoplasms and peliosis hepatis. Hematologic : Suppression of clotting factors II, V, VII, and X, bleeding in patients on concomitant anticoagulant therapy, and polycythemia. Nervous system : Increased or decreased libido, headache, anxiety, depression, and generalized paresthesia. Reproductive system : Excessive frequency and duration of penile erections, oligospermia, and priapism Vascular disorders : Venous thromboembolism. Skin and appendages : Male pattern baldness, seborrhea, and acne. Special senses : Rare cases of central serous chorioretinopathy (CSCR).

• Insulin: In patients with diabetes, concomitant use with AZMIRO may decrease blood glucose and insulin requirements ( 7.1 ). • Oral Anticoagulants: Concomitant use with AZMIRO may cause changes in anticoagulant activity. Monitor International Normalized Ratio and prothrombin time frequently ( 7.2 ). • Corticosteroids: Concomitant use with AZMIRO may result in increased fluid retention. Use with caution, particularly in patients with cardiac, renal, or hepatic disease ( 7.3 ). 7.1 Insulin Changes in insulin sensitivity or glycemic control may occur in patients treated with androgens. In diabetic patients, the metabolic effects of androgens may decrease blood glucose and, therefore, insulin requirements. 7.2 Oral Anticoagulants Changes in anticoagulant activity may be seen with androgens. Frequent monitoring of INR and prothrombin time may be necessary in patients taking anticoagulants, especially at the initiation and termination of androgen therapy. 7.3 Corticosteroids The concurrent use of testosterone with corticosteroids may result in increased fluid retention and should be monitored cautiously, particularly in patients with cardiac, renal or hepatic disease.