Mora Hipoglicemiante

DN0735V7 CR22-05126 December 20, 2002 Page 1 of 16

HUMIRA™ (adalimumab) Rx only Tear at Perforation to Dispense Patient Information WARNING RISK OF INFECTIONS Cases of tuberculosis (frequently disseminated or extrapulmonary at clinical presentation) have been observed in patients receiving HUMIRA. Patients should be evaluated for latent tuberculosis infection with a tuberculin skin test.Treatment of latent tuberculosis infection should be initiated prior to therapy with HUMIRA.

DESCRIPTION HUMIRA (adalimumab) is a recombinant human IgG1 monoclonal antibody specific for human tumor necrosis factor (TNF). HUMIRA was created using phage display technology resulting in an antibody with human derived heavy and light chain variable regions and human IgG1:κ constant regions. HUMIRA isproduced by recombinant DNA technology in a mammalian cell expression system and is purified by a process that includes specific viral inactivation and removal steps. It consists of 1330 amino acids and has a molecular weight of approximately 148 kilodaltons. HUMIRA is supplied in single-use, 1 mL pre-filled glass syringes, and also 2 mL glass vials as a sterile, preservative-free solution forsubcutaneous administration. The solution of HUMIRA is clear and colorless, with a pH of about 5.2. Each syringe delivers 0.8 mL (40 mg) of drug product. Each vial contains approximately 0.9 mL of solution to deliver 0.8 mL (40 mg) of drug product. Each 0.8 mL HUMIRA contains 40 mg adalimumab, 4.93 mg sodium chloride, 0.69 mg monobasic sodium phosphate dihydrate, 1.22 mg dibasic sodium phosphatedihydrate, 0.24 mg sodium citrate, 1.04 mg citric aci d monohydrate, 9.6 mg mannitol, 0.8 mg polysorbate 80 and Water for Injection, USP. Sodium hydroxide added as necessary to adjust pH. CLINICAL PHARMACOLOGY General

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Adalimumab binds specifically to TNF-alpha and blocks its interaction with the p55 and p75 cell surface TNF receptors. Adalimumabalso lyses surface TNF expressing cells in vitro in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (TNF-beta). TNF is a naturally occurring cytokine that is involved in normal inflammatory and immune responses. Elevated levels of TNF are found in the synovial fluid of rheumatoid arthritis patients and play an important role in both the pathologic inflammation and thejoint destruction that are hallmarks of rheumatoid arthritis. Adalimumab also modulates biological responses that are induced or regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). Pharmacodynamics After treatment with HUMIRA, a rapid decrease in levels of acute phase reactants ofinflammation (C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR)) and serum cytokines (IL-6) was observed compared to baseline in patients with rheumatoid arthritis. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that produce tissue remodeling responsible for cartilage destruction were also decreased after HUMIRA administration. Pharmacokinetics The maximum serumconcentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 µg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of HUMIRA to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three studies following a single 40 mg subcutaneous dose was 64%. The pharmacokinetics of adalimumab were linear over thedose range of 0.5 to 10.0 mg/kg following a single intravenous dose. The single dose pharmacokinetics of adalimumab were determined i several studies with n intravenous doses ranging from 0.25 to 10 mg/kg. The distribution volume (V ) ranged ss from 4.7 to 6.0 L. The systemic clearance of adalimumab is approximately 12 mL/hr. The mean terminal half-life was approximately 2 weeks, ranging from 10...