Egrifta Wr Drug Information

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. Do not inject into scar tissue, bruises or the navel.

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.

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. Seven hundred and forty 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).

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 . 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.

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.

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 . 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.

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.

is contraindicated in: Patients with disruption of the hypothalamic-pituitary axis Patients with active malignancy Patients with known hypersensitivity to tesamorelin or excipients in EGRIFTA WR Pregnancy 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 . Patients with known hypersensitivity to tesamorelin or the excipients in EGRIFTA WR. Pregnant women because modifying visceral adipose tissue offers no benefit in a pregnant woman and could result in fetal harm.