Tesamorelin

EGRIFTA WR 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 WR has not been established. Consider risk/benefit of continuation of treatment in patients who have not had a reduction in visceral adipose tissue. EGRIFTA WR 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 WR. EGRIFTA WR 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 WR 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 WR. ( 1 )

The recommendations in this prescribing information only apply to EGRIFTA WR (tesamorelin) for injection 11.6 mg per vial formulation. For recommendations for tesamorelin for injection 2 mg per vial formulation, see the EGRIFTA SV 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. EGRIFTA WR and EGRIFTA SV are not substitutable. ( 2.1 ). The dose of EGRIFTA WR is 1.28 mg (0.16 mL of the reconstituted solution) injected subcutaneously once daily. ( 2.1 ) Inject EGRIFTA WR into the abdomen, rotating injection sites. ( 2.1 , 5.6 ) Use only the diluent provided, Bacteriostatic Water for Injection, USP, to reconstitute EGRIFTA WR. ( 2.2 ) Reconstitute one vial of lyophilized powder with 1.3 mL of diluent. Move the vial in a circle (swirl) to mix all the powder and liquid. 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 ) One reconstituted vial provides daily doses for 7 days. Discard unused solution of EGRIFTA WR vial 7 days after mixing. ( 2.2 )

2.1 Recommended Dosage and Administration Instructions There are two EGRIFTA formulations (EGRIFTA WR and EGRIFTA SV) with different recommended dosages. These two formulations and strengths have differences in the dosage, the number of vials required to prepare a dose, reconstitution instructions, and storage requirements. EGRIFTA WR and EGRIFTA SV are not substitutable. The dosage and administration recommendations in this prescribing information only apply to EGRIFTA WR (tesamorelin) for injection 11.6 mg per vial formulation. For dosage and administration recommendations for tesamorelin for injection 2 mg per vial formulation, see the EGRIFTA SV prescribing information. The recommended dosage of EGRIFTA WR is 1.28 mg subcutaneously once daily. Inject EGRIFTA WR into the abdomen. Rotate injection sites to different areas of the abdomen [see Warnings and Precautions ( 5.6 )]. 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 WR Injection Box. Use only the diluent provided, Bacteriostatic Water for Injection, to reconstitute EGRIFTA WR. Reconstitute 1 vial of EGRIFTA WR lyophilized powder with 1.3 mL of diluent (8 mg per mL). Move the vial in a circle (swirl) to mix all the powder and liquid. Do not shake. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. EGRIFTA WR is a clear, colorless solution. Do not use if solid particles appear or if the solution is cloudy or colored. One reconstituted EGRIFTA WR vial provides daily doses for 7 consecutive days. One dose of EGRIFTA WR is 1.28 mg in 0.16 mL of the reconstituted solution. Store reconstituted EGRIFTA WR at room temperature at 20°C to 25°C (68°F to 77°F). Discard unused solution of EGRIFTA WR 7 days after mixing. Do not freeze.

For injection: 11.6 mg of tesamorelin as a white to off-white lyophilized powder in a single-patient-use vial for reconstitution and a diluent of 30 mL of multiple-dose Bacteriostatic Water for Injection, USP. For injection: 11.6 mg of tesamorelin as a lyophilized powder in single-patient-use vial for reconstitution. ( 3 )

EGRIFTA WR 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 WR ( 4 ) Pregnancy ( 4 ) EGRIFTA WR 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 WR [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 )].

Cytochrome P450-metabolized drugs : Monitor patients for potential interactions when administering with EGRIFTA WR . ( 7.1 ) Glucocorticoids : Patients receiving glucocorticoid replacement for previously diagnosed hypoadrenalism may require an increase in maintenance or stress doses following initiation of EGRIFTA WR. ( 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 WR 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 WR 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 WR 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 WR. 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.

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 WR (11.6 mg/vial formulation) has been established based on clinical trials conducted with EGRIFTA (1 mg/vial formulation). Adverse reactions for the 1.28 mg dose (11.6 mg/vial formulation) of EGRIFTA WR 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 HbA1c was 5.3% among patients in both the EGRIFTA and placebo groups. Patients receiving EGRIFTA had an increased risk of developing diabetes (HbA1c level ≥ 6.5%) compared with placebo (5% vs. 1%), with a hazard ratio of 3.3 (CI 1.4, 9.6).

Lactation: HIV-1 infected mothers should not breastfeed to avoid potential postnatal transmission of HIV-1. ( 8.2 )

8.1 Pregnancy Risk Summary EGRIFTA WR 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 WR is used during pregnancy, or if the patient becomes pregnant while taking it, discontinue EGRIFTA WR. 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 WR 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.

8.2 Lactation Risk Summary The Centers for Disease Control and Prevention recommend that HIV-infected mothers in the United States not breastfeed their infants to avoid risking postnatal transmission of HIV-1 infection. There are no data on the presence of tesamorelin in human milk, the effects on the breastfed child, or the effects on milk production. Because of both the potential for (1) HIV-1 infection transmission (in HIV-negative infants), (2) developing viral resistance (in HIV-positive patients), and (3) any possible adverse effects of tesamorelin, mothers should not breastfeed if they receive EGRIFTA WR.

8.4 Pediatric Use The safety and effectiveness of EGRIFTA WR in pediatric patients have not been established. In pediatric patients with open epiphyses, treatment with EGRIFTA WR may result in linear growth acceleration and excessive growth. EGRIFTA WR is not indicated for use in pediatric patients with open or closed epiphyses.

8.5 Geriatric Use There is no information on the use of EGRIFTA WR in patients greater than 65 years of age.

Risk Summary EGRIFTA WR 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 WR is used during pregnancy, or if the patient becomes pregnant while taking it, discontinue EGRIFTA WR. 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 WR 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.

The safety and effectiveness of EGRIFTA WR in pediatric patients have not been established. In pediatric patients with open epiphyses, treatment with EGRIFTA WR may result in linear growth acceleration and excessive growth. EGRIFTA WR is not indicated for use in pediatric patients with open or closed epiphyses.

There is no information on the use of EGRIFTA WR in patients greater than 65 years of age.

Tesamorelin is a human growth hormone-releasing factor (GRF) analog produced synthetically. It is comprised of the 44 amino acid sequence of human GRF and a hexenoyl moiety, a C6 chain with a double bond at position 3, attached to the tyrosine residue at the N-terminal part of the molecule. Tesamorelin is prepared as an acetate salt. The molecular formula of tesamorelin acetate is C 221 H 366 N 72 O 67 S

• x C 2 H 4 O 2 (x ≈ 7) and its molecular weight (as free base equivalent) is 5135.9 Da. The structural formula of tesamorelin acetate is: EGRIFTA WR (tesamorelin) for injection is a sterile, white to off-white, preservative-free lyophilized powder for subcutaneous injection. Each single-patient-use vial of EGRIFTA WR contains tesamorelin 11.6 mg (equivalent to approximately 11.9 mg of tesamorelin acetate) and the following inactive ingredients: 145 mg hydroxypropyl betadex, 43.5 mg mannitol. Hydrochloric acid and/or sodium hydroxide may be used to adjust the pH. The pH of EGRIFTA WR is between 4.5 and 7.4. After reconstitution with 1.3 mL of Bacteriostatic Water for Injection, USP, resultant concentration is 8 mg/mL and the solution is clear and colorless. Bacteriostatic Water for Injection, USP contains benzyl alcohol as preservative. Structural Formula

In vitro, tesamorelin binds and stimulates human GRF receptors with similar potency as the endogenous GRF [see Clinical Pharmacology ( 12.2 )]. Growth hormone-releasing factor (GHRF), also known as growth hormone-releasing hormone (GHRH), is a hypothalamic peptide that acts on the pituitary somatotroph cells to stimulate the synthesis and pulsatile release of endogenous growth hormone (GH), which is both anabolic and lipolytic. GH exerts its effects by interacting with specific receptors on a variety of target cells, including chondrocytes, osteoblasts, myocytes, hepatocytes, and adipocytes, resulting in a host of pharmacodynamic effects. Some, but not all these effects, are primarily mediated by IGF-1 produced in the liver and in peripheral tissues.

Tesamorelin stimulates growth hormone secretion, and subsequently increases IGF-1 and IGFBP-3 levels. No clinically significant changes in the levels of other pituitary hormones, including thyroid-stimulating hormone (TSH), luteinizing hormone (LH), adrenocorticotropic hormone (ACTH) and prolactin, were observed in patients receiving EGRIFTA in clinical trials.

Absorption The absolute bioavailability of tesamorelin after subcutaneous administration of a 2 mg dose of EGRIFTA (1 mg/vial formulation) was determined to be less than 4% in healthy adult subjects. Single and multiple dose pharmacokinetics have been characterized in healthy subjects and HIV-infected patients without lipodystrophy using a 2 mg dose of EGRIFTA (1 mg/vial formulation). Tesamorelin mean extent of absorption (AUC) was 34% higher in HIV-infected patients than healthy subjects. Tesamorelin peak plasma concentration (C max ) was similar in HIV-infected patients and healthy subjects. The median peak plasma tesamorelin concentration (T max ) was 0.15 h in both populations. Following single dose of subcutaneous administration of 1.28 mg of EGRIFTA WR (11.6 mg/vial formulation) in healthy subjects, the mean [coefficient of variation (CV)] AUC 0-inf was 1172 (48%) pg.h/mL. The mean (CV) C max value was 3831 (40%) pg/mL and the median T max was 0.15 h. The systemic exposure (C max and AUC s ) of tesamorelin is similar between the 1.28 mg dose of EGRIFTA WR (11.6 mg/vial formulation) and the 2 mg dose of EGRIFTA (1 mg/vial formulation). Distribution The mean volume of distribution (±SD) of tesamorelin following a single subcutaneous administration of the 1.28 mg dose of EGRIFTA WR (11.6 mg/vial formulation) was 4.8 ± 1.9 L/kg in healthy subjects. Metabolism No formal metabolism studies have been performed in humans. Elimination Mean elimination half-life (t1/2) of tesamorelin was 11 minutes in healthy subjects after single dose subcutaneous administration of the 1.28 mg of EGRIFTA WR (11.6 mg/vial formulation). Specific Populations Pharmacokinetics of tesamorelin in patients with renal or hepatic impairment, in pediatric patients, or in elderly patients has not been established. Drug Interactions Simvastatin The effect of multiple dose administration of EGRIFTA on the pharmacokinetics of simvastatin and simvastatin acid was evaluated in healthy subjects. Co-administration with simvastatin (a CYP3A substrate) resulted in 8% decrease in extent of absorption (AUC inf ) and 5% increase in rate of absorption (C max ) of simvastatin. For simvastatin acid there was a 15% decrease in AUC inf and 1% decrease in C max [see Drug Interactions ( 7.1 )] . Ritonavir The effect of multiple dose administration of EGRIFTA on the pharmacokinetics of ritonavir was evaluated in healthy subjects. Co-administration with ritonavir resulted in 9% decrease in AUC inf and 11% decrease in C max of ritonavir [see Drug Interactions ( 7.1 )] .

, Mutagenesis, Impairment of Fertility Life-time carcinogenicity studies in rodents have not been conducted with tesamorelin acetate. No potential mutagenicity of tesamorelin acetate was revealed in a battery of tests including induction of gene mutations in bacteria (the Ames test), gene mutations in mammalian cells grown in vitro (hamster CHOK1 cells), and chromosomal damage in intact animals (bone marrow cells in mice). There was no effect on fertility in male or female rats following administration of tesamorelin acetate at doses up to 0.6 mg/kg (approximately equal to clinical exposure) for 28 days in males or 14 days in females.

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling ( Patient Information and Instructions for Use ). Increased Risk of Malignancy Inform patients about the increased background risk of malignancies in HIV-positive patients and for patients with a history of neoplasms, inform them about the risk of malignancy reoccurrence [see Warnings and Precautions ( 5.1 )]. Elevated IGF-1 Levels Inform patients that treatment with EGRIFTA WR increases IGF-1 levels and that they will need periodic monitoring of their IGF-1 levels [see Warnings and Precautions ( 5.2 )]. Fluid Retention Inform patients that treatment with EGRIFTA WR may cause fluid retention, resulting in adverse reactions including edema, arthralgia, and carpal tunnel syndrome [see Warnings and Precautions ( 5.3 )]. Glucose Intolerance or Diabetes Mellitus Inform patients that treatment with EGRIFTA WR may result in glucose intolerance or diabetes mellitus. Advise patients that they will need to be monitored to see if impaired glucose tolerance or diabetes mellitus develops, and that if they have pre-existing diabetes mellitus, they may need adjustments to their anti-diabetic medications [see Warnings and Precautions ( 5.4 )]. Hypersensitivity Reactions Inform patients that hypersensitivity reactions (e.g., rash, urticaria) may occur during treatment with EGRIFTA WR. Advise patients to seek prompt medical attention and to immediately discontinue treatment with EGRIFTA WR if a reaction occurs [see Warnings and Precautions ( 5.5 )]. Injection Site Reactions Inform patients that injection site reactions may occur with EGRIFTA WR, including injection site erythema, pruritus, pain, irritation, and bruising. Advise patients to rotate the site of injection to reduce the risk of injection site reactions [see Warnings and Precautions ( 5.6 )]. Pregnancy Advise women to discontinue EGRIFTA WR if pregnancy occurs, as the drug offers no known benefit to pregnant women and could result in fetal harm [see Contraindications ( 4 ) and Use in Specific Populations ( 8.1 )]. Lactation Because of both the potential for HIV-1 infection transmission and serious adverse reactions in nursing infants, mothers receiving EGRIFTA WR should be instructed not to breastfeed [see Use in Specific Populations ( 8.2 )] . Administration Counsel patients that they should never share an EGRIFTA WR syringe with another person, even if the needle is changed. Sharing of syringes or needles between patients may pose a risk of transmission of infection. EGRIFTA WR is a trademark of Theratechnologies Inc. Manufactured by Theratechnologies Inc., 2015 Peel Street, Suite 1100, Montréal, Québec, Canada H3A 1T8 US License No. 2091 for Theratechnologies Inc. Thera technologies