ENBREL (Page 5 of 16)

8.2 Lactation

Risk Summary

Limited data from published literature show that etanercept is present in low levels in human milk and minimally absorbed by a breastfed infant. No data are available on the effects of etanercept on the breastfed child or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Enbrel and any potential adverse effects on the breastfed child from the drug or from the underlying maternal condition.

8.4 Pediatric Use

Enbrel has been studied in 69 children with moderately to severely active polyarticular JIA aged 2 to 17 years.

Enbrel has been studied in 211 pediatric patients with moderate to severe PsO aged 4 to 17 years.

Enbrel has not been studied in children < 2 years of age with JIA and < 4 years of age with PsO. For pediatric specific safety information concerning malignancies and inflammatory bowel disease [see Warnings and Precautions (5.3) and Adverse Reactions (6.2)].

The clinical significance of infant exposure to Enbrel in utero is unknown. The safety of administering live or live-attenuated vaccines in exposed infants is unknown. Risks and benefits should be considered prior to administering live or live-attenuated vaccines to exposed infants. For pediatric specific safety information concerning vaccinations [see Warnings and Precautions (5.8) and Drug Interactions (7.1)].

8.5 Geriatric Use

A total of 480 RA patients ages 65 years or older have been studied in clinical trials. In PsO randomized clinical trials, a total of 138 out of 1965 patients treated with Enbrel or placebo were age 65 or older. No overall differences in safety or effectiveness were observed between these patients and younger patients, but the number of geriatric PsO patients is too small to determine whether they respond differently from younger patients. Because there is a higher incidence of infections in the elderly population in general, caution should be used in treating the elderly.

8.6 Use in Diabetics

There have been reports of hypoglycemia following initiation of Enbrel therapy in patients receiving medication for diabetes, necessitating a reduction in anti-diabetic medication in some of these patients.

10 OVERDOSAGE

No dose-limiting toxicities have been observed during clinical trials of Enbrel. Single IV doses up to 60 mg/m2 (approximately twice the recommended dose) have been administered to healthy volunteers in an endotoxemia study without evidence of dose-limiting toxicities.

11 DESCRIPTION

Etanercept, a tumor necrosis factor (TNF) blocker, is a dimeric fusion protein consisting of the extracellular ligand-binding portion of the human 75 kilodalton (p75) tumor necrosis factor receptor (TNFR) linked to the Fc portion of human IgG1. The Fc component of etanercept contains the CH 2 domain, the CH 3 domain and hinge region, but not the CH 1 domain of IgG1. Etanercept is produced by recombinant DNA technology in a Chinese hamster ovary (CHO) mammalian cell expression system. It consists of 934 amino acids and has an apparent molecular weight of approximately 150 kilodaltons.

Enbrel (etanercept) Injection in the single-dose prefilled syringe, the single-dose prefilled SureClick autoinjector and the single-dose vial is clear and colorless, sterile, preservative-free solution, and is formulated at pH 6.3 ± 0.2.

Enbrel (etanercept) for Injection is supplied in a multiple-dose vial as a sterile, white, preservative-free, lyophilized powder. Reconstitution with 1 mL of the supplied Sterile Bacteriostatic Water for Injection, USP (containing 0.9% benzyl alcohol) yields a multiple-dose, clear, and colorless solution 1 mL containing 25 mg of Enbrel, with a pH of 7.4 ± 0.3.

Enbrel (etanercept) Injection in the Enbrel Mini single-dose prefilled cartridge for use with the AutoTouch reusable autoinjector is clear and colorless, sterile, preservative-free solution, and is formulated at pH 6.3 ± 0.2.

Table 5. Contents of Enbrel
Presentation Active Ingredient Content Inactive Ingredients Content
Enbrel 50 mg prefilled syringe and SureClick autoinjector 50 mg etanercept in 1 mL 25 mM L-arginine hydrochloride120 mM sodium chloride1% sucrose
Enbrel 25 mg prefilled syringe 25 mg etanercept in 0.5 mL 25 mM L-arginine hydrochloride120 mM sodium chloride1% sucrose
Enbrel 25 mg single-dose vial 25 mg etanercept in 0.5 mL 25 mM L-arginine hydrochloride120 mM sodium chloride1% sucrose
Enbrel 25 mg multiple-dose vial After reconstitution, 25 mg etanercept in 1 mL 40 mg mannitol10 mg sucrose1.2 mg tromethamine
Enbrel 50 mg Enbrel Mini single-dose prefilled cartridge for use with the AutoTouch reusable autoinjector only 50 mg etanercept in 1 mL 25 mM L-arginine hydrochloride120 mM sodium chloride1% sucrose

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

TNF is a naturally occurring cytokine that is involved in normal inflammatory and immune responses. It plays an important role in the inflammatory processes of RA, polyarticular JIA, PsA, and AS and the resulting joint pathology. In addition, TNF plays a role in the inflammatory process of PsO. Elevated levels of TNF are found in involved tissues and fluids of patients with RA, JIA, PsA, AS, and PsO.

Two distinct receptors for TNF (TNFRs), a 55 kilodalton protein (p55) and a 75 kilodalton protein (p75), exist naturally as monomeric molecules on cell surfaces and in soluble forms. Biological activity of TNF is dependent upon binding to either cell surface TNFR.

Etanercept is a dimeric soluble form of the p75 TNF receptor that can bind TNF molecules. Etanercept inhibits binding of TNF-α and TNF-β (lymphotoxin alpha [LT-α]) to cell surface TNFRs, rendering TNF biologically inactive. In in vitro studies, large complexes of etanercept with TNF-α were not detected and cells expressing transmembrane TNF (that binds Enbrel) are not lysed in the presence or absence of complement.

12.2 Pharmacodynamics

Etanercept can modulate biological responses that are induced or regulated by TNF, including expression of adhesion molecules responsible for leukocyte migration (e.g. E-selectin, and to a lesser extent, intercellular adhesion molecule-1 [ICAM-1]), serum levels of cytokines (e.g. IL-6), and serum levels of matrix metalloproteinase-3 (MMP-3 or stromelysin). Etanercept has been shown to affect several animal models of inflammation, including murine collagen-induced arthritis.

12.3 Pharmacokinetics

After administration of 25 mg of Enbrel by a single SC injection to 25 patients with RA, a mean ± standard deviation half-life of 102 ± 30 hours was observed with a clearance of 160 ± 80 mL/hr. A maximum serum concentration (Cmax ) of 1.1 ± 0.6 mcg/mL and time to Cmax of 69 ± 34 hours was observed in these patients following a single 25 mg dose. After 6 months of twice weekly 25 mg doses in these same RA patients, the mean Cmax was 2.4 ± 1.0 mcg/mL (N = 23). Patients exhibited a 2- to 7-fold increase in peak serum concentrations and approximately 4-fold increase in AUC0-72 hr (range 1- to 17-fold) with repeated dosing. Serum concentrations in patients with RA have not been measured for periods of dosing that exceed 6 months.

In another study, serum concentration profiles at steady-state were comparable among patients with RA treated with 50 mg Enbrel once weekly and those treated with 25 mg Enbrel twice weekly. The mean (± standard deviation) Cmax , Cmin , and partial AUC were 2.4 ± 1.5 mcg/mL, 1.2 ± 0.7 mcg/mL, and 297 ± 166 mcg•h/mL, respectively, for patients treated with 50 mg Enbrel once weekly (N = 21); and 2.6 ± 1.2 mcg/mL, 1.4 ± 0.7 mcg/mL, and 316 ± 135 mcg•h/mL for patients treated with 25 mg Enbrel twice weekly (N = 16).

Patients with JIA (ages 4 to 17 years) were administered 0.4 mg/kg of Enbrel twice weekly (up to a maximum dose of 50 mg per week) for up to 18 weeks. The mean serum concentration after repeated SC dosing was 2.1 mcg/mL, with a range of 0.7 to 4.3 mcg/mL. Limited data suggest that the clearance of etanercept is reduced slightly in children ages 4 to 8 years. Population pharmacokinetic analyses predict that the pharmacokinetic differences between the regimens of 0.4 mg/kg twice weekly and 0.8 mg/kg once weekly in JIA patients are of the same magnitude as the differences observed between twice weekly and weekly regimens in adult RA patients.

The mean (± SD) serum steady-state trough concentrations for the 50 mg QW dosing in adult PsO subjects were 1.5 ± 0.7 mcg/mL. Pediatric PsO patients (age 4 to 17 years) were administered 0.8 mg/kg of Enbrel once weekly (up to a maximum dose of 50 mg per week) for up to 48 weeks. The mean (± SD) serum steady-state trough concentrations ranged from 1.6 ± 0.8 to 2.1 ± 1.3 mcg/mL at weeks 12, 24, and 48.

In clinical studies with Enbrel, pharmacokinetic parameters were not different between men and women and did not vary with age in adult patients. The pharmacokinetics of etanercept were unaltered by concomitant MTX in RA patients. No formal pharmacokinetic studies have been conducted to examine the effects of renal or hepatic impairment on etanercept disposition.

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