Certolizumab Pegol

1 INDICATIONS AND USAGE CIMZIA is a tumor necrosis factor (TNF) blocker indicated for: Reducing signs and symptoms of Crohn's disease and maintaining clinical response in adult patients with moderately to severely active disease who have had an inadequate response to conventional therapy ( 1.1 ) Treatment of adults with moderately to severely active rheumatoid arthritis ( 1.2 ) Treatment of active polyarticular juvenile idiopathic arthritis (pJIA) in patients 2 years of age and older ( 1.3 ) Treatment of adult patients with active psoriatic arthritis. ( 1.4 ) Treatment of adults with active ankylosing spondylitis ( 1.5 ) Treatment of adults with active non-radiographic axial spondyloarthritis with objective signs of inflammation ( 1.6 ) Treatment of adults with moderate-to-severe plaque psoriasis who are candidates for systemic therapy or phototherapy ( 1.7 ) 1.1 Crohn's Disease CIMZIA is indicated for reducing signs and symptoms of Crohn's disease and maintaining clinical response in adult patients with moderately to severely active disease who have had an inadequate response to conventional therapy. 1.2 Rheumatoid Arthritis CIMZIA is indicated for the treatment of adults with moderately to severely active rheumatoid arthritis (RA). 1.3 Polyarticular Juvenile Idiopathic Arthritis CIMZIA is indicated for the treatment of active polyarticular juvenile idiopathic arthritis (pJIA) in patients 2 years of age and older. 1.4 Psoriatic Arthritis CIMZIA is indicated for the treatment of adult patients with active psoriatic arthritis (PsA). 1.5 Ankylosing Spondylitis CIMZIA is indicated for the treatment of adults with active ankylosing spondylitis (AS). [see Clinical Studies (14.5) ] 1.6 Non-radiographic Axial Spondyloarthritis CIMZIA is indicated for the treatment of adults with active non-radiographic axial spondyloarthritis (nr-axSpA) with objective signs of inflammation [see Clinical Studies (14.6) ]. 1.7 Plaque Psoriasis CIMZIA is indicated for the treatment of adults with moderate-to-severe plaque psoriasis (PsO) who are candidates for systemic therapy or phototherapy [see Clinical Studies (14.7) ]

12.1 Mechanism of Action Certolizumab pegol binds to human TNFα with a KD of 90pM. TNFα is a key pro-inflammatory cytokine with a central role in inflammatory processes. Certolizumab pegol selectively neutralizes TNFα (IC 90 of 4 ng/mL for inhibition of human TNFα in the in vitro L929 murine fibrosarcoma cytotoxicity assay) but does not neutralize lymphotoxin α (TNFβ). Certolizumab pegol cross-reacts poorly with TNF from rodents and rabbits, therefore in vivo efficacy was evaluated using animal models in which human TNFα was the physiologically active molecule. Certolizumab pegol was shown to neutralize membrane-associated and soluble human TNFα in a dose-dependent manner. Incubation of monocytes with certolizumab pegol resulted in a dose-dependent inhibition of LPS-induced TNFα and IL-1β production in human monocytes. Certolizumab pegol does not contain a fragment crystallizable (Fc) region, which is normally present in a complete antibody, and therefore does not fix complement or cause antibody-dependent cell-mediated cytotoxicity in vitro . It does not induce apoptosis in vitro in human peripheral blood-derived monocytes or lymphocytes, nor does certolizumab pegol induce neutrophil degranulation. A tissue reactivity study was carried out ex vivo to evaluate potential cross-reactivity of certolizumab pegol with cryosections of normal human tissues. Certolizumab pegol showed no reactivity with a designated standard panel of normal human tissues.

2 DOSAGE AND ADMINISTRATION CIMZIA is administered by subcutaneous injection . Injection sites should be rotated and injections should not be given into areas where the skin is tender, bruised, red or hard. When a 400 mg dose is needed (given as two subcutaneous injections of 200 mg), injections should occur at separate sites in the thigh or abdomen. The solution should be carefully inspected visually for particulate matter and discoloration prior to administration. The solution should be a clear to opalescent, colorless to yellow liquid, essentially free from particulates and should not be used if cloudy or if foreign particulate matter is present. CIMZIA does not contain preservatives; therefore, unused portions of drug remaining in the syringe or vial should be discarded. CIMZIA is administered by subcutaneous injection ( 2 ). Crohn's Disease ( 2.1 ) 400 mg initially and at Weeks 2 and 4. If response occurs, follow with 400 mg every four weeks Rheumatoid Arthritis ( 2.2 ) 400 mg initially and at Weeks 2 and 4, followed by 200 mg every other week; for maintenance dosing, 400 mg every 4 weeks can be considered Polyarticular Juvenile Idiopathic Arthritis ( 2.3 ) 10 kg (22 lbs) to less than 20 kg (44 lbs): 100 mg initially and at Weeks 2 and 4, followed by 50 mg every other week 20 kg (44 lbs) to less than 40 kg (88 lbs): 200 mg initially and at Weeks 2 and 4, followed by 100 mg every other week Greater than or equal to 40 kg (88 lbs): 400 mg initially and at Weeks 2 and 4, followed by 200 mg every other week Psoriatic Arthritis ( 2.4 ) 400 mg initially and at week 2 and 4, followed by 200 mg every other week; for maintenance dosing, 400 mg every 4 weeks can be considered. Ankylosing Spondylitis ( 2.5 ) 400 mg (given as 2 subcutaneous injections of 200 mg each) initially and at weeks 2 and 4, followed by 200 mg every other week or 400 mg every 4 weeks. Non-radiographic Axial Spondyloarthritis ( 2.6 ) 400 mg (given as 2 subcutaneous injections of 200 mg each) initially and at weeks 2 and 4, followed by 200 mg every other week or 400 mg every 4 weeks. Plaque Psoriasis ( 2.7 , 14.7 ) 400 mg (given as 2 subcutaneous injections of 200 mg each) every other week. For some patients (with body weight less than or equal to 90 kg), a dose of 400 mg (given as 2 subcutaneous injections of 200 mg each) initially and at Weeks 2 and 4, followed by 200 mg every other week may be considered. 2.1 Crohn's Disease The recommended initial adult dose of CIMZIA is 400 mg (given as two subcutaneous injections of 200 mg) initially, and at Weeks 2 and 4. In patients who obtain a clinical response, the recommended maintenance regimen is 400 mg every four weeks. 2.2 Rheumatoid Arthritis The recommended dose of CIMZIA for adult patients with rheumatoid arthritis is 400 mg (given as two subcutaneous injections of 200 mg) initially and at Weeks 2 and 4, followed by 200 mg every other week. For maintenance dosing, CIMZIA 400 mg every 4 weeks can be considered [see Clinical Studies (14.2) ] . 2.3 Polyarticular Juvenile Idiopathic Arthritis The recommended dose of CIMZIA for patients 2 years of age and older with pJIA is based on weight as shown below. Weight range (2 years of age and older) Loading dose Maintenance dose (beginning at Week 6) 10 kg (22 lbs) to less than 20 kg (44 lbs) 100 mg at Week 0, 2 and 4 50 mg every 2 weeks 20 kg (44 lbs) to less than 40 kg (88 lbs) 200 mg at Week 0, 2 and 4 100 mg every 2 weeks Greater than or equal to 40 kg (88 lbs) 400 mg at Week 0, 2 and 4 200 mg every 2 weeks There is no dosage form for Cimzia that allows for patient self-administration for doses below 200 mg. Doses less than 200 mg require administration by a health care professional using the vial kit. 2.4 Psoriatic Arthritis The recommended dose of CIMZIA for adult patients with psoriatic arthritis is 400 mg (given as 2 subcutaneous injections of 200 mg each) initially and at week 2 and 4, followed by 200 mg every other week. For maintenance dosing, CIMZIA 400 mg e

6 ADVERSE REACTIONS The most serious adverse reactions were: Serious Infections [see Warnings and Precautions (5.1) ] Malignancies [see Warnings and Precautions (5.2) ] Heart Failure [see Warnings and Precautions (5.3) ] Hypersensitivity Reactions [see Warnings and Precautions (5.4) ] Hepatitis B Virus Reactivation [see Warnings and Precautions (5.5) ] Neurologic Reactions [see Warnings and Precautions (5.6) ] Hematologic Reactions [see Warnings and Precautions (5.7) ] Autoimmunity [see Warnings and Precautions (5.9) ] Immunosuppression [see Warnings and Precautions (5.11) ] Most common adverse reactions (≥7%): upper respiratory tract infection, rash, and urinary tract infection ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact UCB, Inc. at 1-866-822-0068 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical studies are conducted under widely varying and controlled conditions, adverse reaction rates observed in clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug, and may not predict the rates observed in a broader patient population in clinical practice. In premarketing controlled trials of all adult patient populations combined the most common adverse reactions (≥ 8%) were upper respiratory infections (18%), rash (9%) and urinary tract infections (8%). Adverse Reactions Most Commonly Leading to Discontinuation of Treatment in Premarketing Controlled Trials The proportion of patients with Crohn's disease who discontinued treatment due to adverse reactions in the controlled clinical studies was 8% for CIMZIA and 7% for placebo. The most common adverse reactions leading to the discontinuation of CIMZIA (for at least 2 patients and with a higher incidence than placebo) were abdominal pain (0.4% CIMZIA, 0.2% placebo), diarrhea (0.4% CIMZIA, 0% placebo), and intestinal obstruction (0.4% CIMZIA, 0% placebo). The proportion of patients with rheumatoid arthritis who discontinued treatment due to adverse reactions in the controlled clinical studies was 5% for CIMZIA and 2.5% for placebo. The most common adverse reactions leading to discontinuation of CIMZIA were tuberculosis infections (0.5%); and pyrexia, urticaria, pneumonia, and rash (0.3%). Controlled Studies with Crohn's Disease The data described below reflect exposure to CIMZIA at 400 mg subcutaneous dosing in studies of patients with Crohn's disease. In the safety population in controlled studies, a total of 620 patients with Crohn's disease received CIMZIA at a dose of 400 mg, and 614 subjects received placebo (including subjects randomized to placebo in Study CD2 following open-label dosing of CIMZIA at Weeks 0, 2, 4). In controlled and uncontrolled studies, 1,564 patients received CIMZIA at some dose level, of whom 1,350 patients received 400 mg CIMZIA. Approximately 55% of subjects were female, 45% were male, and 94% were Caucasian. The majority of patients in the active group were between the ages of 18 and 64. During controlled clinical studies, the proportion of patients with serious adverse reactions was 10% for CIMZIA and 9% for placebo. The most common adverse reactions (occurring in ≥ 5% of CIMZIA-treated patients, and with a higher incidence compared to placebo) in controlled clinical studies with CIMZIA were upper respiratory infections (e.g. nasopharyngitis, laryngitis, viral infection) in 20% of CIMZIA-treated patients and 13% of placebo-treated patients, urinary tract infections (e.g. bladder infection, bacteriuria, cystitis) in 7% of CIMZIA-treated patients and in 6% of placebo-treated patients, and arthralgia (6% CIMZIA, 4% placebo). Other Adverse Reactions The most commonly occurring adverse reactions in controlled trials of Crohn's disease were described above. Other serious or significant adverse reactions reported in controlled and uncontrolled studies in Crohn's disease and other diseases, occurring in patients receiving CIMZIA at doses of 400 mg or other

5 WARNINGS AND PRECAUTIONS Serious Infections : CIMZIA should not be initiated in patients with an active infection. Monitor for infection during and after treatment; discontinue if a serious infection develops. If invasive fungal infection develops in patients who reside or travel to regions where mycoses are endemic, consider empiric antifungal therapy. ( 5.1 ) Malignancies : Cases of lymphoma and other malignancies have been observed among patients receiving TNF blockers, including CIMZIA. ( 5.2 ) Heart Failure : Monitor patients for new onset or worsening congestive heart failure. ( 5.3 ) Hypersensitivity Reactions : Discontinue CIMZIA and institute appropriate therapy if anaphylaxis or other serious hypersensitivity reactions occur. ( 5.4 ) Hepatitis B Virus Reactivation : Test for HBV infection before starting CIMZIA. Monitor HBV carriers during and several months after therapy. If reactivation occurs, stop CIMZIA and begin anti-viral therapy ( 5.5 ) Neurologic Reactions : Exacerbation or new onset demyelinating disease may occur; use caution in patients with pre-existing or recent-onset demyelinating disorders. ( 5.6 ) Hematological Reactions (including leukopenia, pancytopenia and thrombocytopenia) : Use with caution in patients who have ongoing, or a history of, significant hematologic abnormalities. Advise patients to seek immediate medical attention if symptoms develop; consider discontinuing CIMZIA in patients with confirmed abnormalities. ( 5.7 ) Use with Anakinra, Abatacept, Rituximab and Natalizumab : Increased risk of serious infections; concomitant use is not recommended. ( 5.8 , 7.1 ) Autoimmunity : Discontinue CIMZIA if lupus-like syndrome develops. ( 5.9 ) Live vaccines : Avoid use with CIMZIA ( 5.10 , 7.2 ) 5.1 Risk of Serious Infections Patients treated with CIMZIA are at an increased risk for developing serious infections involving various organ systems and sites that may lead to hospitalization or death. Opportunistic infections due to bacterial, mycobacterial, invasive fungal, viral, parasitic, or other opportunistic pathogens including aspergillosis, blastomycosis, candidiasis, coccidioidomycosis, histoplasmosis, legionellosis, listeriosis, pneumocystosis and tuberculosis have been reported with TNF blockers. Patients have frequently presented with disseminated rather than localized disease. Treatment with CIMZIA should not be initiated in patients with an active infection, including clinically important localized infections. Patients greater than 65 years of age, patients with co-morbid conditions, and/or patients taking concomitant immunosuppressants (e.g. corticosteroids or methotrexate) may be at a greater risk of infection. The risks and benefits of treatment should be considered prior to initiating therapy in patients: with chronic or recurrent infection who have been exposed to tuberculosis with a history of an opportunistic infection who have resided or traveled in areas of endemic tuberculosis or endemic mycoses, such as histoplasmosis, coccidioidomycosis, or blastomycosis with underlying conditions that may predispose them to infection Tuberculosis Cases of reactivation of tuberculosis or new tuberculosis infections have been observed in patients receiving CIMZIA, including patients who have previously or concomitantly received treatment for latent or active tuberculosis. Reports included cases of pulmonary and extrapulmonary (i.e., disseminated) tuberculosis. Evaluate patients for tuberculosis risk factors and test for latent infection prior to initiating CIMZIA and periodically during therapy. Treatment of latent tuberculosis infection prior to therapy with TNF-blocking agents has been shown to reduce the risk of tuberculosis reactivation during therapy. Prior to initiating CIMZIA, assess if treatment for latent tuberculosis is needed; and consider an induration of 5 mm or greater a positive tuberculin skin test result, even for patients previously vaccinated with Bacille Calmette-Guerin (

4 CONTRAINDICATIONS CIMZIA is contraindicated in patients with a history of hypersensitivity reaction to certolizumab pegol or to any of the excipients. Reactions have included angioedema, anaphylaxis, serum sickness, and urticaria [see Warnings and Precautions (5.4) ] . Serious hypersensitivity reaction to certolizumab pegol or to any of the excipients. ( 4 )