EGRIFTA SV

1 INDICATIONS AND USAGE EGRIFTA SV is indicated for the reduction of excess abdominal fat in HIV-infected adult patients with lipodystrophy. Limitations of Use: Long-term cardiovascular safety of EGRIFTA SV has not been established. Consider risk/benefit of continuation of treatment in patients who have not had a reduction in visceral adipose tissue. EGRIFTA SV is not indicated for weight loss management as it has a weight neutral effect. There are no data to support improved compliance with anti-retroviral therapies in HIV-positive patients taking EGRIFTA SV. EGRIFTA SV is a growth hormone-releasing factor (GHRF) analog indicated for the reduction of excess abdominal fat in HIV-infected adult patients with lipodystrophy. ( 1 ) Limitations of use: Long-term cardiovascular safety of EGRIFTA SV has not been established. ( 1 ) Not indicated for weight loss management. ( 1 ) There are no data to support improved compliance with anti-retroviral therapies in HIV-positive patients taking EGRIFTA SV. ( 1 )

2 DOSAGE AND ADMINISTRATION The recommendations in this prescribing information only apply to EGRIFTA SV (tesamorelin) for injection 2 mg per vial formulation. For recommendations for tesamorelin for injection 1 mg per vial formulation, see the EGRIFTA prescribing information. These two formulations and strengths have differences in the dosage, the number of vials required to prepare a dose, reconstitution instructions, and storage requirements. ( 2.1 ). The dose of EGRIFTA SV is 1.4 mg (0.35 mL of the reconstituted solution) injected subcutaneously once daily. ( 2.1 ) Inject EGRIFTA SV into the abdomen, rotating injection sites. ( 2.1 , 5.6 ) Use only the diluent provided, Sterile Water for Injection, to reconstitute EGRIFTA SV. ( 2.2 ) Reconstitute one vial of lyophilized powder with 0.5 mL of diluent. Mix by rolling the vial gently in your hands for 30 seconds. Do not shake. ( 2.2 ) Inspect the reconstituted vial visually for particulate matter and discoloration. Use only if the solution is clear, colorless and without particulate matter. ( 2.2 ) Administer 0.35 mL of EGRIFTA SV immediately following reconstitution and throw away any unused solution and diluent. ( 2.2 ) 2.1 Dosage and Administration • The dosage and administration recommendations in this prescribing information only apply to EGRIFTA SV (tesamorelin) for injection 2 mg per vial formulation. For dosage and administration recommendations for tesamorelin for injection 1 mg per vial formulation, see the EGRIFTA prescribing information. These two formulations and strengths have differences in the dosage, the number of vials required to prepare a dose, reconstitution instructions, and storage requirements. • The dose of EGRIFTA SV is 1.4 mg, 0.35 mL of the reconstituted solution [see Dosage and Administration ( 2.2 )] , injected subcutaneously once daily. • Inject EGRIFTA SV into the abdomen. Rotate injection sites to different areas of the abdomen [see Warnings and Precautions ( 5.5 )] . Do not inject into scar tissue, bruises or the navel. 2.2 Reconstitution Procedure • Instruct patients to read the Instructions for Use enclosed in the EGRIFTA SV Medication Box. • Use only the diluent provided, Sterile Water for Injection, to reconstitute EGRIFTA SV. • Reconstitute 1 vial of EGRIFTA SV lyophilized powder with 0.5 mL of diluent (2 mg per 0.5 mL). Mix by rolling the vial gently in your hands for 30 seconds. Do not shake. • Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Use only if the solution is clear, colorless and without particulate matter. • Administer 0.35 mL of EGRIFTA SV immediately following reconstitution and throw away any unused solution and diluent. If not used immediately, discard the reconstituted solution. Do not freeze or refrigerate the reconstituted solution.

4 CONTRAINDICATIONS EGRIFTA SV is contraindicated in: Patients with disruption of the hypothalamic-pituitary axis ( 4 ) Patients with active malignancy ( 4 ) Patients with known hypersensitivity to tesamorelin or excipients in EGRIFTA SV ( 4 ) Pregnancy ( 4 ) EGRIFTA SV is contraindicated in: Patients with disruption of the hypothalamic-pituitary axis due to hypophysectomy, hypopituitarism, pituitary tumor/surgery, head irradiation or head trauma. Patients with active malignancy. Any preexisting malignancy should be inactive and its treatment complete prior to instituting therapy [see Warnings and Precautions ( 5.1 )] . Patients with known hypersensitivity to tesamorelin or the excipients in EGRIFTA SV [see Warnings and Precautions ( 5.5 )]. Pregnant women because modifying visceral adipose tissue offers no benefit in a pregnant woman and could result in fetal harm [see Use in Specific Populations ( 8.1 )].

5 WARNINGS AND PRECAUTIONS Increased risk of neoplasms: Preexisting malignancy should be inactive and its treatment complete prior to starting EGRIFTA SV . Discontinue EGRIFTA SV if there is any evidence of recurrent malignancy. ( 5.1 ) Elevated IGF-1: EGRIFTA SV stimulates GH production and increases serum IGF-1, a growth factor. The effects of prolonged elevations in IGF-1 levels are unknown. Monitor IGF-1 levels during EGRIFTA SV therapy. Consider discontinuing in patients with persistent elevations. ( 5.2 ) Fluid retention: May occur with EGRIFTA SV and may include edema, arthralgia, and carpal tunnel syndrome. ( 5.3 ) Glucose intolerance or diabetes mellitus: May develop with EGRIFTA SV use. Evaluate glucose prior to and during therapy. ( 5.4 ) Hypersensitivity reactions: Have occurred in clinical trials. Advise patients to seek immediate medical attention and discontinue treatment if suspected. ( 5.5 ) Increased mortality in patients with acute critical illness: Consider discontinuation in critically ill patients . ( 5.7 ) 5.1 Increased Risk of Neoplasms New Malignancy Carefully consider the decision to start treatment with EGRIFTA SV based on the increased background risk of malignancies in HIV-positive patients. Active Malignancy EGRIFTA SV induces the release of endogenous growth hormone (GH), a known growth factor. Do not treat patients with active malignancy with EGRIFTA SV [see Contraindications ( 4 )] . History of Malignancy For patients with a history of non-malignant neoplasms, initiate EGRIFTA SV therapy after careful evaluation of the potential benefit of treatment. For patients with a history of treated and stable malignancies, initiate EGRIFTA SV therapy only after careful evaluation of the potential benefit of treatment relative to the risk of re-activation of the underlying malignancy. Discontinue EGRIFTA SV if there is any evidence of recurrent malignancy. 5.2 Elevated IGF-1 Levels EGRIFTA SV stimulates GH production and increases serum IGF-1, a growth factor. The effects of prolonged elevations in IGF-1 levels are unknown. Monitor IGF-1 levels during EGRIFTA SV therapy. Consider discontinuing EGRIFTA SV in patients with persistent elevations of IGF-1 levels (e.g., >3 SDS), particularly if the efficacy response is not robust. Among patients who received EGRIFTA for 26 weeks, 47% had IGF-1 levels greater than 2 standard deviation scores (SDS), and 36% had SDS >3, with this effect seen as early as 13 weeks of treatment. Among those patients who remained on EGRIFTA for a total of 52 weeks, at the end of treatment, 34% had IGF-1 SDS >2 and 23% had IGF-1 SDS >3. 5.3 Fluid Retention Fluid retention may occur during EGRIFTA SV therapy and is thought to be related to the induction of GH secretion. This manifests as increased tissue turgor and musculoskeletal discomfort resulting in adverse reactions (e.g. edema, arthralgia, and carpal tunnel syndrome) which are either transient or resolve with discontinuation of treatment. 5.4 Glucose Intolerance or Diabetes Mellitus EGRIFTA SV treatment can result in glucose intolerance. During clinical trials, the percentages of patients with elevated HbA 1c (≥ 6.5%) from baseline to Week 26 were 5% and 1% in the EGRIFTA and placebo groups, respectively. An increased risk of developing diabetes with EGRIFTA (HbA 1c level ≥ 6.5%) relative to placebo was observed [intent-to-treat hazard odds ratio of 3.3 (CI 1.4, 9.6)]. Evaluate glucose status prior to initiating EGRIFTA SV. Monitor all patients treated with EGRIFTA SV periodically to diagnose those who develop impaired glucose tolerance or diabetes. If patients treated with EGRIFTA SV develop glucose intolerance or diabetes, consider discontinuing EGRIFTA SV in patients who do not show a clear efficacy response. EGRIFTA SV increases IGF-1, monitor patients with diabetes who are receiving treatment with EGRIFTA SV at regular intervals for potential development or worsening of retinopathy. 5.5 Hypersensitivity Reactions Hypersensitivity reactions occurred in 4% of patients treated with EGRIFTA in clinical trials. Reactions included pruritus, erythema, flushing, urticaria, and rash. In cases of suspected hypersensitivity reactions, advise patients to seek prompt medical attention and immediately discontinue treatment with EGRIFTA SV. 5.6 Injection Site Reactions EGRIFTA SV treatment may cause injection site reactions, including injection site erythema, pruritus, pain, irritation, and bruising. The incidence of injection site reactions was 25% in EGRIFTA treated patients and 14% in placebo-treated patients during the first 26 weeks of treatment in clinical trials. Rotate injection sites to different areas of the abdomen to decrease injection site reactions [see Dosage and Administration ( 2.1 )]. 5.7 Increased Mortality in Patients with Acute Critical Illness Increased mortality in patients with acute critical illness due to complications following open heart surgery, abdominal surgery or multiple accidental trauma, or those with acute respiratory failure has been reported after treatment with pharmacologic amounts of growth hormone. EGRIFTA SV is a growth hormone-releasing hormone (GHRH) and since it stimulates growth hormone production, consider discontinuing EGRIFTA SV in critically ill patients.

7 DRUG INTERACTIONS Cytochrome P450-metabolized drugs : Monitor patients for potential interactions when administering with EGRIFTA SV . ( 7.1 ) Glucocorticoids : Patients receiving glucocorticoid replacement for previously diagnosed hypoadrenalism may require an increase in maintenance or stress doses following initiation of EGRIFTA SV. ( 7.2 ) 7.1 Cytochrome P450-Metabolized Drugs Co-administration of tesamorelin with simvastatin, a CYP3A substrate had no significant impact on the pharmacokinetics profiles of simvastatin in healthy subjects [see Clinical Pharmacology ( 12.3 )] . EGRIFTA SV stimulates GH production. Published data indicate that GH may modulate cytochrome P450 (CYP450) mediated antipyrine clearance. These data suggest that GH may alter the clearance of compounds known to be metabolized by CYP450 liver enzymes (e.g., corticosteroids, sex steroids, anticonvulsants, and cyclosporine). Monitor patients for potential interactions when administering EGRIFTA SV in combination with other drugs known to be metabolized by CYP450 liver enzymes. 7.2 Glucocorticoids GH inhibits 11β-hydroxysteroid dehydrogenase type 1 (11βHSD-1), a microsomal enzyme required for conversion of cortisone to its active metabolite, cortisol, in hepatic and adipose tissue. EGRIFTA SV stimulates GH production; therefore, patients receiving glucocorticoid replacement for previously diagnosed hypoadrenalism may require an increase in maintenance or stress doses following initiation of EGRIFTA SV. Patients treated with cortisone acetate and prednisone may be affected more than others because conversion of these drugs to their biologically active metabolites is dependent on the activity of 11βHSD-1.

6 ADVERSE REACTIONS The following important adverse reactions are also described elsewhere in the labeling: Increased risk of neoplasms [see Warnings and Precautions ( 5.1 )] Elevated IGF-1 levels [see Warnings and Precautions ( 5.2 )] Fluid retention [see Warnings and Precautions ( 5.3 )] Glucose intolerance or diabetes mellitus [see Warnings and Precautions ( 5.4 )] Hypersensitivity reactions [see Warnings and Precautions ( 5.5 )] Injection site reactions [see Warnings and Precautions ( 5.6 )] Most commonly reported adverse reactions (>5%): Arthralgia, injection site erythema, injection site pruritus, pain in extremity, peripheral edema, and myalgia. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact THERA patient support ® toll free at 1-833-23THERA (1-833-238-4372) 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 EGRIFTA SV (2 mg/vial formulation) has been established based on clinical trials conducted with EGRIFTA (1 mg/vial formulation). Adverse reactions for the 1.4 mg dose (2 mg/vial formulation) of EGRIFTA SV are expected to be similar to those observed with the 2 mg dose (1 mg/vial formulation) of EGRIFTA [see Clinical Pharmacology ( 12.3 )]. Seven hundred and forty (740) HIV-infected patients with lipodystrophy and excess abdominal fat were treated with EGRIFTA in clinical trials; of these, 543 received EGRIFTA during the initial 26-week placebo-controlled phase. The most commonly reported adverse reactions were hypersensitivity reactions (e.g., rash, urticaria), edema-related reactions (e.g., arthralgia, extremity pain, peripheral edema, and carpal tunnel syndrome), hyperglycemia, and injection site reactions (injection site erythema, pruritus, pain, urticaria, irritation, swelling, and hemorrhage). Adverse reactions that occurred more frequently with EGRIFTA relative to placebo and had an incidence ≥1% during the first 26 weeks across all studies are presented in Table 1 . Table 1. Adverse Reactions Reported in ≥ 1% and More Frequent in EGRIFTA –treated than Placebo Patients during the 26-Week Phase (Combined Studies) * Injection site reaction includes: Injection site erythema, Injection site pruritus, Injection site rash, Injection site urticaria, Injection site pain, Injection site swelling, Injection site irritation, Injection site hemorrhage. Preferred Term Placebo (N=263) EGRIFTA (N=543) Injection site reaction* Arthralgia Pain in extremity Myalgia Edema peripheral Paresthesia Hypoesthesia Rash Dyspepsia Musculoskeletal pain Pain Pruritus Vomiting Musculoskeletal stiffness Blood creatine phosphokinase increased Carpal tunnel syndrome Joint swelling Muscle strain Night sweats Palpitations 6 11 5 2 2 2 2 2 1 1 1 1 0 0 0 0 0 0 0 0 17 13 6 6 6 5 4 4 2 2 2 2 3 2 1 1 1 1 1 1 In the EGRIFTA clinical trials, mean baseline HbA 1c was 5.3% among patients in both the EGRIFTA and placebo groups. Patients receiving EGRIFTA had an increased risk of developing diabetes (HbA 1c level ≥ 6.5%) compared with placebo (5% vs. 1%), with a hazard ratio of 3.3 (CI 1.4, 9.6).

8.1 Pregnancy Risk Summary EGRIFTA SV is contraindicated in pregnant women because modifying visceral adipose tissue offers no benefit in pregnant women and could result in fetal harm [see Clinical Considerations and Contraindications ( 4 )] . Administration of tesamorelin acetate to rats during organogenesis resulted in hydrocephaly in offspring at a dose of approximately two and four times the clinical dose, based on measured drug exposure (AUC). If EGRIFTA SV is used during pregnancy, or if the patient becomes pregnant while taking it, discontinue EGRIFTA SV. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Disease-associated maternal and/or embryo/fetal risk During pregnancy, visceral adipose tissue increases due to normal metabolic and hormonal changes. Modifying pregnancy-associated physiologic changes in visceral adipose tissue with EGRIFTA SV offers no known benefit and could result in fetal harm. Data Animal Data Tesamorelin acetate administration to rats during organogenesis and lactation resulted in hydrocephaly in offspring at a dose of approximately two and four times the clinical dose, respectively, based on measured drug exposure (AUC). Actual animal dose was 1.2 mg/kg. During organogenesis, lower doses approximately 0.1 to 1-times the clinical dose caused delayed skull ossification in rats. Actual animal doses were 0.1 to 0.6 mg/kg. No adverse developmental effects occurred in rabbits using doses up to approximately 500 times the clinical dose.