CIMZIA- certolizumab pegol

Certolizumab pegol binds to human TNFalpha with a KD of 90pM. TNFalpha is a key pro-inflammatory cytokine with a central role in inflammatory processes. Certolizumab pegol selectively neutralizes TNFalpha (IC 90 in vitro in vivo Certolizumab pegol was shown to neutralize membrane-associated and soluble human TNFalpha in a dose-dependent manner. Incubation of monocytes with certolizumab pegol resulted in a dose-dependent inhibition of LPS-induced TNFalpha and IL-1beta 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 in vitro A tissue reactivity study was carried out ex vivo Biological activities ascribed to TNFalpha include the upregulation of cellular adhesion molecules and chemokines, upregulation of major histocompatibility complex (MHC) class I and class II molecules, and direct leukocyte activation. TNFalpha stimulates the production of downstream inflammatory mediators, including interleukin-1, prostaglandins, platelet activating factor, and nitric oxide. Elevated levels of TNFalpha have been implicated in the pathology of Crohn's disease and rheumatoid arthritis. Certolizumab pegol binds to TNFalpha, inhibiting its role as a key mediator of inflammation. TNFalpha is strongly expressed in the bowel wall in areas involved by Crohn's disease and fecal concentrations of TNFalpha in patients with Crohn's disease have been shown to reflect clinical severity of the disease. After treatment with certolizumab pegol, patients with Crohn's disease demonstrated a decrease in the levels of C-reactive protein (CRP). Increased TNFalpha levels are found in the synovial fluid of rheumatoid arthritis patients and play an important role in the joint destruction that is a hallmark of this disease. Absorption A total of 126 healthy subjects received doses of up to 800 mg certolizumab pegol subcutaneously (sc) and up to 10 mg/kg intravenously (IV) in four pharmacokinetic studies. Data from these studies demonstrate that single intravenous and subcutaneous doses of certolizumab pegol have predictable dose-related plasma concentrations with a linear relationship between the dose administered and the maximum plasma concentration (C max max Certolizumab pegol plasma concentrations were broadly dose-proportional and pharmacokinetics observed in patients with rheumatoid arthritis, Crohn's disease, and plaque psoriasis were consistent with those seen in healthy subjects. Following subcutaneous administration, peak plasma concentrations of certolizumab pegol were attained between 54 and 171 hours post-injection. Certolizumab pegol has bioavailability (F) of approximately 80% (ranging from 76% to 88%) following subcutaneous administration compared to intravenous administration. In pediatric patients with JIA with active polyarthritis, mean peak plasma concentrations, measured 1 week following loading dose and maintenance dose were 58. 8 µg/ml and 41. 8 µg/ml, respectively. Similar peak plasma concentrations were observed across the different body weight groups (10 kg to less than 20 kg, 20 kg to less than 40 kg, and greater than or equal to 40 kg). Distribution The steady state volume of distribution (Vss) was estimated as 4. 7 to 8 L in the population pharmacokinetic analysis for adult patients with Crohn's disease, patients with rheumatoid arthritis, and adult patients with plaque psoriasis. The volume of distribution in pediatric patients with JIA with active polyarthritis was dependent on body size. Metabolism The metabolism of certolizumab pegol has not been studied in human subjects. Data from animals indicate that once cleaved from the Fab' fragment the PEG moiety is mainly excreted in urine without further metabolism. Elimination PEGylation, the covalent attachment of PEG polymers to peptides, delays the metabolism and elimination of these entities from the circulation by a variety of mechanisms, including decreased renal clearance, proteolysis, and immunogenicity. Accordingly, certolizumab pegol is an antibody Fab' fragment conjugated with PEG in order to extend the terminal plasma elimination half-life (t 1/2 1/2 In pediatric patients with JIA with active polyarthritis, clearance was body weight dependent, and t 1/2 Specific Populations Population pharmacokinetic analysis was conducted on data from adult patients with rheumatoid arthritis and patients with Crohn's disease, to evaluate the effect of age, race, gender, methotrexate use, concomitant medication, creatinine clearance and presence of anti-certolizumab antibodies on pharmacokinetics of certolizumab pegol. A population pharmacokinetic analysis was also conducted on data from patients with plaque psoriasis to evaluate the effect of age, gender, body weight, and presence of anti-certolizumab pegol antibodies. Only bodyweight and presence of anti-certolizumab antibodies significantly affected certolizumab pegol pharmacokinetics. Pharmacokinetic exposure was inversely related to body weight but pharmacodynamic exposure-response analysis showed that no additional therapeutic benefit would be expected from a weight-adjusted dose regimen. When assessed using the previous ELISA method, the presence of anti-certolizumab antibodies was associated with a >= 3 to 4 fold increase in clearance. Geriatric Patients: Pediatric Patients: In the JIA with active polyarthritis study (NCT01550003), the mean trough plasma concentrations at Week 12 (steady-state) were 31. 8 µg/mL, 27. 9 µg/mL, and 36. 8 µg/mL for patients weighing 10 to <20 kg, 20 to <40 kg, and >=40 kg, respectively. Population pharmacokinetic analyses showed that plasma concentrations in pediatric patients with JIA with active polyarthritis are in the same range as observed in adult patients with RA receiving a 200 mg Q2W maintenance dose. Similar to the adult indications, body weight and anti-certolizumab antibodies titers affected certolizumab pegol pharmacokinetics, where higher body weights and presence of anti-certolizumab antibodies was associated with lower exposures. There was no observed impact from the use of concomitant methotrexate on certolizumab pegol plasma concentrations. Racial or Ethnic Groups: Male and Female Patients: Patients with Renal Impairment: Drug Interaction Studies Methotrexate pharmacokinetics is not altered by concomitant administration with CIMZIA in patients with rheumatoid arthritis. The effect of methotrexate on CIMZIA pharmacokinetics was not studied. However, methotrexate-treated patients have lower incidence of antibodies to CIMZIA. Thus, therapeutic plasma levels are more likely to be sustained when CIMZIA is administered with methotrexate in patients with rheumatoid arthritis. Formal drug-drug interaction studies have not been conducted with CIMZIA upon concomitant administration with corticosteroids, nonsteroidal anti-inflammatory drugs, analgesics or immunosuppressants.

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. 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 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. CIMZIA is indicated for the treatment of adults with moderately to severely active rheumatoid arthritis (RA). CIMZIA is indicated for the treatment of active polyarticular juvenile idiopathic arthritis (pJIA) in patients 2 years of age and older. CIMZIA is indicated for the treatment of adult patients with active psoriatic arthritis (PsA). CIMZIA is indicated for the treatment of adults with active ankylosing spondylitis (AS). [see Clinical Studies (14. 5) 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) 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.

DOSAGE AND ADMINISTRATION
CIMZIA is administered by subcutaneous injection. 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 ) 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. 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. 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) The recommended dose of CIMZIA for patients 2 years of age and older with pJIA is based on weight as shown below. Weight range Loading dose Maintenance dose 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. 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. 4) The recommended dose of CIMZIA for adult patients with ankylosing spondylitis is 400 mg (given as 2 subcutaneous injections of 200 mg each) initially and at weeks 2 and 4, followed by 200 mg every 2 weeks or 400 mg every 4 weeks. The recommended dose of CIMZIA for adult patients with non-radiographic axial spondyloarthritis is 400 mg (given as 2 subcutaneous injections of 200 mg each) initially and at weeks 2 and 4, followed by 200 mg every 2 weeks or 400 mg every 4 weeks. The recommended dose of CIMZIA for adults with moderate-to-severe plaque psoriasis is 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), CIMZIA 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 can be considered [see Clinical Studies (14. 7) CIMZIA Lyophilized powder should be prepared and administered by a health care professional. CIMZIA is provided in a package that contains everything required to reconstitute and inject the drug [see How Supplied/Storage and Handling (16) Preparation and Storage If refrigerated, remove CIMZIA from the refrigerator and allow the vial(s) to sit at room temperature for 30 minutes before reconstituting. Do not warm the vial in any other way. Use appropriate aseptic technique when preparing and administering CIMZIA. Reconstitute the vial(s) of CIMZIA with 1 mL of Sterile Water for Injection, USP using the 20-gauge needle provided. The sterile water for injection should be directed at the vial wall rather than directly on CIMZIA. Gently swirl each vial of CIMZIA for about one minute without shaking, assuring that all of the powder comes in contact with the Sterile Water for Injection. The swirling should be as gentle as possible in order to avoid creating a foaming effect. Continue swirling every 5 minutes as long as non-dissolved particles are observed. Full reconstitution may take as long as 30 minutes. The final reconstituted solution contains 200 mg/mL and should be clear to opalescent, colorless to yellow liquid essentially free from particulates. Once reconstituted, CIMZIA can be stored in the vials for up to 24 hours between 2° to 8° C (36° to 46° F) prior to injection. Do not freeze. Administration Prior to injecting, reconstituted CIMZIA should be at room temperature but do not leave reconstituted CIMZIA at room temperature for more than two hours prior to administration. Withdraw the reconstituted solution into a separate syringe for each vial using a new 20-gauge needle for each vial so that each syringe contains the required volume of CIMZIA [see Dosage and Administration (2. 7)] Replace the 20-gauge needle(s) on the syringes with a 23-gauge(s) for administration. Inject the full contents of the syringe(s) subcutaneously After proper training in subcutaneous injection technique, a patient may self-inject with the CIMZIA Prefilled Syringe if a physician determines that it is appropriate. If refrigerated, remove the prefilled syringe from the carton and let it warm to room temperature. Inspect the liquid in the prefilled syringe. It should be clear to opalescent and colorless to yellow and free from particulates. Discard the syringe if cloudy, discolored or contains particulates. Suitable sites for injection include the thigh or abdomen at least 2 inches away from the navel. Inject at least 1 inch from the previous site. Do not inject into areas where the skin is tender, bruised, red or hard, or where there are scars or stretch marks. The needle shield inside the removable cap of the CIMZIA prefilled syringe contains a derivative of natural rubber latex which may cause allergic reactions and should be handled with caution by latex-sensitive individuals [see Warnings and Precautions (5. 4) Before initiation of therapy with CIMZIA, all patients must be evaluated for both active and inactive (latent) tuberculosis infection. The possibility of undetected latent tuberculosis should be considered in patients who have immigrated from or traveled to countries with a high prevalence of tuberculosis or had close contact with a person with active tuberculosis. Appropriate screening tests (e. tuberculin skin test and chest x-ray) should be performed in all patients. CIMZIA may be used as monotherapy or concomitantly with non-biological disease modifying anti-rheumatic drugs (DMARDs). The use of CIMZIA in combination with biological DMARDs or other tumor necrosis factor (TNF) blocker therapy is not recommended.
Instructions for Use
CIMZIA registered Read this Instructions for Use booklet that comes with CIMZIA before you start receiving it, and before each injection of CIMZIA. This Instructions for Use booklet does not take the place of talking with your healthcare provider about your medical condition or treatment. These instructions are for 1 injection only. You may need more than 1 injection at a time depending on your prescribed dose of CIMZIA. Do not share your CIMZIA Prefilled Syringe with needle attached with another person. You may give another person an infection or get an infection from them. Supplies you will need to give your CIMZIA injection: See Figure A Figure B 1 CIMZIA prefilled syringe with needle attached. You may need 2 CIMZIA prefilled syringes with needles attached to give higher doses. 1 or 2 alcohol swabs 1 or 2 clean cotton balls or gauze pads 1 puncture-resistant sharps disposal container. See " Disposal of your syringes with needles attached CIMZIA comes in a tray containing either 1 or 2 prefilled glass syringes. Use a new CIMZIA syringe for each injection. Storage information: Keep CIMZIA in the refrigerator between 36°F to 46°F (2°C to 8°C). Do not freeze. Do not shake. Protect CIMZIA from light. Store CIMZIA in the carton it came in. Do not use CIMZIA if the medicine is expired. Check the expiration date on the prefilled syringe or carton. If needed, CIMZIA syringes may be stored at room temperature up to 77°F (25°C) in the original carton to protect from light for a single period of up to 7 days. After your CIMZIA syringe has been stored at room temperature, do not place back in refrigerator. Write the date removed from the refrigerator in the space provided on the carton and throw away (discard) if not used within the 7-day period. Setting up for your CIMZIA injection: Step 1. See Figure C If the expiration date has passed, do not Step 2. Do not Step 5. Selecting and preparing your injection site: Step 7. See Figure D Choose a new injection site each time you use CIMZIA. Each new injection should be given at least 1 inch from the site you used before. If you choose your stomach, avoid the 2 inches around your belly button (navel). Do not inject into areas where your skin is tender, bruised, red or hard, or where you have scars or stretch marks. Change injection sites between your stomach and upper thighs to reduce the chance of having a skin reaction. You may want to write down the site you use for your injection to help you remember to use a different site each time you inject. Giving your CIMZIA injection: Step 9. See Figure E Do not Step 10. See Figure F Step 11. See Figure G Step 12. See Figure H Step 13. See Figure I Do not rub the injection site. Do not use an alcohol swab as it may cause stinging. If there is a little bleeding, cover the injection site with a small bandage. To avoid a needle-stick injury, do not try to recap the needle. Disposal of your syringes with needles attached: See Figure J Do not throw away (dispose of) loose syringes and needles in your household trash. If you do not have a FDA-cleared sharps disposal container, you may use a household container that is: made of a heavy-duty plastic can be closed with a tight-fitting, puncture-resistant lid, without sharps being able to come out upright and stable during use leak-resistant properly labeled to warn of hazardous waste inside the container When your sharps disposal container is almost full, you will need to follow your community guidelines for the right way to dispose of your sharps disposal container. There may be state or local laws about how you should throw away used needles and syringes. For more information about safe sharps disposal, and for specific information about sharps disposal in the state that you live in, go to the FDA''s website at: http://www. gov/safesharpsdisposal Do not dispose of your used sharps disposal container in your household trash unless your community guidelines permit this. Do not recycle your used sharps disposal container. This Instructions for Use has been approved by the U. Food and Drug Administration. Product manufactured by: Revised: 9/2024 Figure A and B Figure C Figure D Figure E Figure F Figure G Figure H Figure I Figure J.

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. gov/medwatch. 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. 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. nasopharyngitis, laryngitis, viral infection) in 20% of CIMZIA-treated patients and 13% of placebo-treated patients, urinary tract infections (e. 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 doses include: Blood and lymphatic system disorders: Cardiac disorders: Eye disorders: General disorders and administration site conditions: Hepatobiliary disorders Immune system disorders Psychiatric disorders: Renal and urinary disorders: Reproductive system and breast disorders: Skin and subcutaneous tissue disorders: Vascular disorders: Controlled Studies with Rheumatoid Arthritis CIMZIA was studied primarily in placebo-controlled trials and in long-term follow-up studies. The data described below reflect the exposure to CIMZIA in 2,367 RA patients, including 2,030 exposed for at least 6 months, 1,663 exposed for at least one year and 282 for at least 2 years; and 1,774 in adequate and well-controlled studies. In placebo-controlled studies, the population had a median age of 53 years at entry; approximately 80% were females, 93% were Caucasian and all patients were suffering from active rheumatoid arthritis, with a median disease duration of 6. Most patients received the recommended dose of CIMZIA or higher. Table 1 summarizes the reactions reported at a rate of at least 3% in patients treated with CIMZIA 200 mg every other week compared to placebo (saline formulation), given concomitantly with methotrexate. Table 1: Adverse Reactions Reported by >=3% of Patients Treated with CIMZIA Dosed Every Other Week during Placebo-Controlled Period of Rheumatoid Arthritis Studies, with Concomitant Methotrexate. Adverse Reaction Placebo+ MTX EOW = Every other Week, MTX = Methotrexate. CIMZIA 200 mg EOW + MTX(%) Upper respiratory tract infection 2 6 Headache 4 5 Hypertension 2 5 Nasopharyngitis 1 5 Back pain 1 4 Pyrexia 2 3 Pharyngitis 1 3 Rash 1 3 Acute bronchitis 1 3 Fatigue 2 3 Hypertensive adverse reactions were observed more frequently in patients receiving CIMZIA than in controls. These adverse reactions occurred more frequently among patients with a baseline history of hypertension and among patients receiving concomitant corticosteroids and non-steroidal anti-inflammatory drugs. Patients receiving CIMZIA 400 mg as monotherapy every 4 weeks in rheumatoid arthritis controlled clinical trials had similar adverse reactions to those patients receiving CIMZIA 200 mg every other week. Other Adverse Reactions Other infrequent adverse reactions (occurring in less than 3% of RA patients) were similar to those seen in Crohn's disease patients. Polyarticular Juvenile Idiopathic Arthritis Clinical Study CIMZIA has been studied in 193 patients with juvenile idiopathic arthritis (JIA) with active polyarthritis aged 2 years and older. In general, the safety profile for pediatric patients with JIA with active polyarthritis was similar to the safety profile seen in adult RA patients treated with CIMZIA. Psoriatic Arthritis Clinical Study CIMZIA has been studied in 409 patients with psoriatic arthritis (PsA) in a placebo-controlled trial. The safety profile for patients with PsA treated with CIMZIA was similar to the safety profile seen in patients with RA and previous experience with CIMZIA. Ankylosing Spondylitis Clinical Study CIMZIA has been studied in 325 patients with axial spondyloarthritis of whom the majority had ankylosing spondylitis (AS) in a placebo-controlled study (AS-1). The safety profile for patients in study AS-1 treated with CIMZIA was similar to the safety profile seen in patients with RA. Non-radiographic Axial Spondyloarthritis Clinical Study CIMZIA has been studied in 317 patients with non-radiographic axial spondyloarthritis (nr-axSpA-1). The safety profile for patients with nr-axSpA treated with CIMZIA was similar to the safety profile seen in patients with RA and previous experience with CIMZIA. Plaque Psoriasis Clinical Studies In clinical studies, a total of 1112 subjects with plaque psoriasis were treated with CIMZIA. Of these, 779 subjects were exposed for at least 12 months, 551 for 18 months, and 66 for 24 months. Data from three placebo-controlled studies (Studies PS-1, PS-2, and PS-3) in 1020 subjects (mean age 46 years, 66% males, 94% white) were pooled to evaluate the safety of CIMZIA [see Clinical Studies (14) Placebo-Controlled Period (Week 0-16) In the placebo-controlled period of Studies PS-1, PS-2 and PS-3 in the 400 mg group, adverse events occurred in 63. 5% of subjects in the CIMZIA group compared to 61. 8% of subjects in the placebo group. The rates of serious adverse events were 4. 7% in the CIMZIA group and 4. 5% in the placebo group. Table 2 summarizes the adverse reactions that occurred at a rate of at least 1% and at a higher rate in the CIMZIA group than in the placebo group. Table 2: Adverse Reactions Occurring in >=1% of Subjects in the CIMZIA Group and More Frequently than in the Placebo Group in the Plaque Psoriasis Studies PS-1, PS-2, and PS-3. Adverse Reactions Cimzia 400 mg every other week Cimzia 200 mg Subjects received 400 mg of CIMZIA at Weeks 0, 2, and 4, followed by 200 mg every other week. Placebo Upper respiratory tract infections Upper respiratory tract infection cluster includes upper respiratory tract infection, pharyngitis bacterial, pharyngitis streptococcal, upper respiratory tract infection bacterial, viral upper respiratory tract infection, viral pharyngitis, viral sinusitis, and nasopharyngitis. 0) Headache Headache includes headache and tension headache. 5) Injection site reactions Injection site reactions cluster includes injection site reaction, injection site erythema, injection site bruising, injection site discoloration, injection site pain, and injection site swelling. 6) Cough 11 (3. 9) Herpes infections Herpes infections cluster includes oral herpes, herpes dermatitis, herpes zoster, and herpes simplex. 3) Elevated Liver Enzymes Elevated liver enzymes were reported more frequently in the CIMZIA-treated subjects (4. 3% in the 200 mg group and 2. 3% in the 400 mg group) than in the placebo-treated subjects (2. Of CIMZIA-treated subjects who had elevation of liver enzymes, two subjects were discontinued from the trial. In controlled Phase 3 studies of CIMZIA in adults with PsO with a controlled period duration ranging from 0 to 16 weeks, AST and/or ALT elevations >=5 × ULN occurred in 0. 9% of CIMZIA 200 mg or CIMZIA 400 mg arms and none in placebo arm. Psoriasis-Related Adverse Events In controlled clinical studies in psoriasis, change of plaque psoriasis into a different psoriasis sub-types (including erythrodermic, pustular and guttate), was observed in <1% of Cimzia treated subjects. Adverse Reactions of Special Interest Across Indications Infections The incidence of infections in controlled studies in Crohn's disease was 38% for CIMZIA-treated patients and 30% for placebo-treated patients. The infections consisted primarily of upper respiratory infections (20% for CIMZIA, 13% for placebo). The incidence of serious infections during the controlled clinical studies was 3% per patient-year for CIMZIA-treated patients and 1% for placebo-treated patients. Serious infections observed included bacterial and viral infections, pneumonia, and pyelonephritis. The incidence of new cases of infections in controlled clinical studies in rheumatoid arthritis was 0. 91 per patient-year for all CIMZIA-treated patients and 0. 72 per patient-year for placebo-treated patients. The infections consisted primarily of upper respiratory tract infections, herpes infections, urinary tract infections, and lower respiratory tract infections. In the controlled rheumatoid arthritis studies, there were more new cases of serious infection adverse reactions in the CIMZIA treatment groups, compared to the placebo groups (0. 06 per patient-year for all CIMZIA doses vs. 02 per patient-year for placebo). Rates of serious infections in the 200 mg every other week dose group were 0. 06 per patient-year and in the 400 mg every 4 weeks dose group were 0. 04 per patient-year. Serious infections included tuberculosis, pneumonia, cellulitis, and pyelonephritis. In the placebo group, no serious infection occurred in more than one subject. There is no evidence of increased risk of infections with continued exposure over time [see Warnings and Precautions (5. 1) In controlled clinical studies in psoriasis, the incidence rates of infections were similar in the CIMZIA and placebo groups. The infections consisted primarily of upper respiratory tract infections and viral infections (including herpes infections). Serious adverse events of infection occurred in CIMZIA-treated patients during the placebo-controlled periods of the pivotal studies (pneumonia, abdominal abscess, and hematoma infection) and Phase 2 study (urinary tract infection, gastroenteritis, and disseminated tuberculosis). In an open-label clinical study of 193 pediatric patients with JIA with active polyarthritis, there were 26 serious infections; the most frequently reported serious infection was pneumonia. Tuberculosis and Opportunistic Infections In completed and ongoing global clinical studies in all indications including 5,118 CIMZIA-treated patients, the overall rate of tuberculosis is approximately 0. 61 per 100 patient-years across all indications. The majority of cases occurred in countries with high endemic rates of TB. Reports include cases of disseminated (miliary, lymphatic, and peritoneal) as well as pulmonary TB. The median time to onset of TB for all patients exposed to CIMZIA across all indications was 345 days. In the studies with CIMZIA in RA, there were 36 cases of TB among 2,367 exposed patients, including some fatal cases. Rare cases of opportunistic infections have also been reported in these clinical trials. In Phase 2 and Phase 3 studies with CIMZIA in plaque psoriasis, there were 2 cases of TB among 1112 exposed patients [see Warnings and Precautions (5. 1) In an open-label clinical study of 193 pediatric patients with JIA with active polyarthritis, opportunistic infections consisted of tuberculosis, liver tuberculosis, varicella, pneumonia fungal, and esophageal candidiasis. Two cases of disseminated tuberculosis (liver TB and disseminated TB) were fatal. Malignancies In clinical studies of CIMZIA, the overall incidence rate of malignancies was similar for CIMZIA-treated and control patients. For some TNF blockers, more cases of malignancies have been observed among patients receiving those TNF blockers compared to control patients [see Warnings and Precautions (5. 2) Heart Failure In placebo-controlled and open-label studies, cases of new or worsening heart failure have been reported for CIMZIA-treated patients. The majority of these cases were mild to moderate and occurred during the first year of exposure [see Warnings and Precautions (5. 3) Hypersensitivity Reactions The following symptoms that could be compatible with hypersensitivity reactions have been reported rarely following CIMZIA administration to patients: angioedema, allergic dermatitis, dizziness (postural), dyspnea, hot flush, hypotension, injection site reactions, malaise, pyrexia, rash, serum sickness, and (vasovagal) syncope [see Warnings and Precautions (5. 4) Autoantibodies In clinical studies in Crohn's disease, 4% of patients treated with CIMZIA and 2% of patients treated with placebo that had negative baseline ANA titers developed positive titers during the studies. One of the 1,564 Crohn's disease patients treated with CIMZIA developed symptoms of a lupus-like syndrome. In clinical trials of TNF blockers, including CIMZIA, in patients with RA, some patients have developed ANA. Four patients out of 2,367 patients treated with CIMZIA in RA clinical studies developed clinical signs suggestive of a lupus-like syndrome. The impact of long-term treatment with CIMZIA on the development of autoimmune diseases is unknown [see Warnings and Precautions (5. 9) In a clinical study in pediatric patients with JIA with active polyarthritis, 17. 1% of patients treated with CIMZIA that had negative baseline ANA titers developed positive titers during the study. 1% of the patients developed anti-dsDNA antibodies during the study; no patients developed symptoms of a lupus-like syndrome. The observed incidence of anti-drug antibodies is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies in the studies described below with the incidence of anti-drug antibodies in other studies, including those of certolizumab pegol or of other certolizumab products. Patients with Crohn's disease were tested at multiple time points for antibodies to certolizumab pegol during Studies CD1 and CD2. In patients continuously exposed to CIMZIA, the overall percentage of patients who were antibody positive to CIMZIA on at least one occasion was 8%; approximately 6% were neutralizing in vitro In two long-term (up to 7 years of exposure), open-label Crohn's disease studies, overall 23% (207/903) of patients developed antibodies against certolizumab pegol on at least one occasion. Of the 207 patients who were antibody positive, 152 (73%) had a persistent reduction of drug plasma concentration, which represents 17% (152/903) of the study population. The data from these two studies do not suggest an association between the development of antibodies and adverse events. The overall percentage of patients with antibodies to certolizumab pegol detectable on at least one occasion was 7% (105 of 1,509) in the rheumatoid arthritis placebo-controlled trials. Approximately one third (3%, 39 of 1,509) of these patients had antibodies with neutralizing activity in vitro Antibody formation was associated with lowered drug plasma concentration and reduced efficacy. In patients receiving the recommended CIMZIA dosage of 200 mg every other week with concomitant MTX, the ACR20 response was lower among antibody positive patients than among antibody-negative patients (Study RA-I, 48% versus 60%; Study RA-II 35% versus 59%, respectively). In Study RA-III, too few patients developed antibodies to allow for meaningful analysis of ACR20 response by antibody status. In Study RA-IV (monotherapy), the ACR20 response was 33% versus 56%, antibody-positive versus antibody-negative status, respectively [see Clinical Pharmacology (12. 3) Approximately 8 % (22/265) and 19% (54/281) of subjects with psoriasis who received CIMZIA 400 mg every 2 weeks and CIMZIA 200 mg every 2 weeks for 48 weeks, respectively, developed antibodies to certolizumab pegol. Of the subjects who developed antibodies to certolizumab pegol, 45% (27/60) had antibodies that were classified as neutralizing. Antibody formation was associated with lowered drug plasma concentration and reduced efficacy. A more sensitive and drug tolerant electrochemiluminesence (ECL)-based bridging assay was used for the first time in the nr-axSpA-1 study, resulting in a greater proportion of samples having measurable antibodies to certolizumab pegol and thus a greater incidence of patients being classed as antibody positive. In the placebo-controlled trial in patients with non-radiographic axial spondyloarthritis, after up to 52 weeks of treatment, the overall incidence of patients who were antibody positive to certolizumab pegol was 97% (248/255 patients). Of these antibody positive patients, higher titers were associated with reduced certolizumab pegol plasma levels. The data above reflect the percentage of patients whose test results were considered positive for antibodies to certolizumab pegol in an ELISA or ECL-based bridging assay, and are highly dependent on the sensitivity and specificity of the assay. In a clinical study of pediatric patients with JIA with active polyarthritis, immunogenicity was evaluated using an ECL-based assay. For the patients receiving the recommended CIMZIA dose, the incidence of treatment emergent-anti-certolizumab pegol antibody positivity was 92. 4% for the entire treatment period. The following adverse reactions have been identified during post-approval use of CIMZIA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to estimate reliably their frequency or establish a causal relationship to drug exposure. Vascular disorder Skin Immune System Disorders Neoplasms benign, malignant and unspecified (including cysts and polyps): [see Warnings and Precautions (5.

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.

Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to CIMZIA during pregnancy. For more information, healthcare providers or patients can contact: MotherToBaby Pregnancy Studies conducted by the Organization of Teratology Information Specialists (OTIS). The OTIS AutoImmune Diseases Study at 1-877-311-8972 or visit http://mothertobaby. org/pregnancy-studies/ Risk Summary Limited data from the ongoing pregnancy registry on use of CIMZIA in pregnant women are not sufficient to inform a risk of major birth defects or other adverse pregnancy outcomes. However, certolizumab pegol plasma concentrations obtained from two studies of CIMZIA use during the third trimester of pregnancy demonstrated that placental transfer of certolizumab pegol was negligible in most infants at birth, and low in other infants at birth (see Data in utero (see Clinical Considerations The estimated background risk of major birth defects and miscarriage for the indicated population(s) are unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. general population, the estimated background risks of major birth defects and miscarriage in clinically recognized pregnancies are 2 to 4% and 15 to 20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk Published data suggest that the risk of adverse pregnancy outcomes in women with rheumatoid arthritis or Crohn's disease is correlated with maternal disease activity and that active disease increases the risk of adverse pregnancy outcomes, including fetal loss, preterm delivery (before 37 weeks of gestation), low birth weight (less than 2500 g) and small for gestational age birth. Fetal/Neonatal Adverse Reactions Due to its inhibition of TNFalpha, CIMZIA administered during pregnancy could affect immune responses in the in utero in utero (see Data Data Human Data A limited number of pregnancies have been reported in the ongoing pregnancy exposure registry. Due to the small number of CIMZIA-exposed pregnancies with known outcomes (n=54), no meaningful comparisons between the exposed group and control groups may be conducted to determine an association with CIMZIA and major birth defects or adverse pregnancy outcomes. A multicenter clinical study was conducted in 16 women treated with CIMZIA at a maintenance dose of 200 mg every 2 weeks or 400 mg every 4 weeks during the third trimester of pregnancy for rheumatological diseases or Crohn's disease. The last dose of CIMZIA was given on average 11 days prior to delivery (range 1 to 27 days). Certolizumab pegol plasma concentrations were measured in samples from mothers and infants using an assay that can measure certolizumab pegol concentrations at or above 0. Certolizumab pegol plasma concentrations measured in the mothers at delivery (range: 4. 4 mcg/mL) were consistent with non-pregnant women's plasma concentrations in Study RA-I [see Clinical Studies (14. 2) In another clinical study conducted in 10 pregnant women with Crohn´s disease treated with CIMZIA (400 mg every 4 weeks for every mother), certolizumab pegol concentrations were measured in maternal blood as well as in cord and infant blood at the day of birth with an assay that can measure concentrations at or above 0. The last dose of CIMZIA was given on average 19 days prior to delivery (range 5 to 42 days). Plasma certolizumab pegol concentrations ranged from not measurable to 1. 66 mcg/mL in cord blood and 1. 58 mcg/mL in infant blood; and ranged from 1. 57 mcg/mL in maternal blood. Plasma certolizumab pegol concentrations were lower (by at least 75%) in the infants than in mothers suggesting low placental transfer of certolizumab pegol. In one infant, the plasma certolizumab pegol concentration declined from 1. 84 mcg/mL over 4 weeks suggesting that certolizumab pegol may be eliminated at a slower rate in infants than adults. Animal Data Because certolizumab pegol does not cross-react with mouse or rat TNFalpha, reproduction studies were performed in rats using a rodent anti-murine TNFalpha pegylated Fab' fragment (cTN3 PF) similar to certolizumab pegol. Animal reproduction studies have been performed in rats during organogenesis at intravenous doses up to 100 mg/kg (about 2. 4 times the recommended human dose of 400 mg, based on the surface area) and have revealed no evidence of harm to the fetus due to cTN3 PF. Risk Summary In a multicenter clinical study of 17 lactating women treated with CIMZIA at 200 mg every 2 weeks or 400 mg every 4 weeks, minimal certolizumab pegol concentrations were observed in breast milk. No serious adverse reactions were noted in the 17 infants in the study. There are no data on the effects on milk production. In a separate study, certolizumab pegol concentrations were not detected in the plasma of 9 breastfed infants at 4 weeks post-partum (see Data Data A multicenter clinical study designed to evaluate breast milk was conducted in 17 lactating women who were at least 6 weeks post-partum and had received at least 3 consecutive doses of CIMZIA 200 mg every 2 weeks or 400 mg every 4 weeks for rheumatological disease or Crohn's disease. The effects of certolizumab pegol on milk production were not studied. The concentration of certolizumab pegol in breast milk was not measurable in 77 (56 %) of the 137 samples taken over the dosing periods using an assay that can measure certolizumab pegol concentrations at or above 0. The median of the estimated average daily infant doses was 0. 0035 mg/kg/day (range: 0 to 0. 01 mg/kg/day). The percentage of the maternal dose (200 mg CIMZIA dosed once every 2 weeks), that reaches an infant ranged from 0. 25% based on samples with measurable certolizumab pegol concentration. No serious adverse reactions were noted in the 17 breastfed infants in the study. In a separate study, plasma certolizumab pegol concentrations were collected 4 weeks after birth in 9 breastfed infants whose mothers had been currently taking CIMZIA (regardless of being exclusively breastfed or not). Certolizumab pegol in infant plasma was not measurable i. The safety and effectiveness of CIMZIA for active polyarticular juvenile idiopathic arthritis has been established in pediatric patients 2 years of age and older. The use of CIMZIA in this age group is supported by evidence from adequate and well-controlled studies of CIMZIA in adults with RA, pharmacokinetic data from adults with RA and pediatric patients with JIA with active polyarthritis, and safety data from an open-label clinical study in 193 pediatric patients 2 to < 18 years of age with JIA with active polyarthritis. The observed pre-dose (trough) concentrations are generally comparable between adults with RA and pediatric patients with JIA with active polyarthritis [see Pharmacokinetics (12. 3) The safety and effectiveness for CIMZIA in pediatric patients less than 2 years of age with pJIA have not been established. The safety and effectiveness of CIMZIA have not been established in pediatric patients for other indications. CIMZIA was evaluated for the treatment of pediatric patients with moderately to severely active Crohn's disease. Effectiveness was not demonstrated in an open-label, randomized, parallel-group, multiple dose study for a period of up to 62 weeks in 99 subjects aged 6 to 17 years. The study was ended prematurely because of a high number of patient discontinuations. Due to its inhibition of TNFalpha, CIMZIA administered during pregnancy could affect immune responses in the in utero [see Use in Specific Populations (8. 1) Clinical studies of CIMZIA did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger adult patients. Population pharmacokinetic analyses of patients enrolled in CIMZIA clinical studies concluded that there was no apparent difference in drug concentration regardless of age. Because there is a higher incidence of infections in the elderly population in general, use caution when treating the elderly with CIMZIA [see Warnings and Precautions (5.

Laboratory Tests 7. 3 An increased risk of serious infections has been seen in clinical studies of other TNF-blocking agents used in combination with anakinra or abatacept, with no added benefit. Formal drug interaction studies have not been performed with rituximab or natalizumab. Because of the nature of the adverse events seen with these combinations with TNF blocker therapy, similar toxicities may also result from the use of CIMZIA in these combinations. There is not enough information to assess the safety and efficacy of such combination therapy. Therefore, the use of CIMZIA in combination with anakinra, abatacept, rituximab, or natalizumab is not recommended [see Warnings and Precautions (5. 8) Avoid use of live (including attenuated) vaccines during or immediately prior to initiation of therapy with CIMZIA [see Warnings and Precautions (5. 10) Interference with certain coagulation assays has been detected in patients treated with CIMZIA. Certolizumab pegol may cause erroneously elevated activated partial thromboplastin time (aPTT) assay results in patients without coagulation abnormalities. This effect has been observed with the PTT-Lupus Anticoagulant (LA) test and Standard Target Activated Partial Thromboplastin time (STA-PTT) Automate tests from Diagnostica Stago, and the HemosIL APTT-SP liquid and HemosIL lyophilized silica tests from Instrumentation Laboratories. Other aPTT assays may be affected as well. Interference with thrombin time (TT) and prothrombin time (PT) assays has not been observed. There is no evidence that CIMZIA therapy has an effect on in vivo.

= 12, and body surface area (BSA) involvement of >= 10%. Studies PS-1 (234 subjects) and PS-2 (227 subjects) randomized subjects to placebo, CIMZIA 200 mg every other week (following a loading dose of CIMZIA 400 mg at Weeks 0, 2, and 4), or CIMZIA 400 mg every other week. Studies PS-1 and PS-2 assessed the co-primary endpoints of the proportion of patients who achieved a PASI 75 and PGA of "clear" or "almost clear" with at least a 2-point improvement at Week 16. Other evaluated outcomes were PASI 90 at Week 16 and maintenance of efficacy to Week 48. Study PS-3 randomized 559 subjects to receive placebo, CIMZIA 200 mg every other week (following a loading dose of CIMZIA 400 mg at Weeks 0, 2, and 4), CIMZIA 400 mg every other week up to Week 16, or a biologic comparator (up to Week 12). Study PS-3 assessed the proportion of patients who achieved a PASI 75 at Week 12 as the primary endpoint. Other evaluated outcomes were PGA of "clear" or "almost clear" at Week 16, PASI 75 at Week 16, PASI 90 at Week 16, and maintenance of efficacy to Week 48. Of the 850 subjects randomized to receive placebo or CIMZIA in these placebo-controlled studies, 29% of patients were naïve to prior systemic therapy for the treatment of psoriasis, 47% had received prior phototherapy or chemophototherapy, and 30% had received prior biologic therapy for the treatment of psoriasis. Of the 850 subjects, 14% had received at least one TNF alpha agent and 16% had received an anti-IL agent. Eighteen percent of subjects reported a history of psoriatic arthritis at baseline. Across all studies and treatment groups, the mean PASI score at baseline was 20 and ranged from 12 to 69. The baseline PGA score ranged from moderate (70%) to severe (30%). Mean baseline BSA was 25% and ranged from 10% to 96%. Subjects were predominantly men (64%) and White (94%), with a mean age of 46 years. Clinical Response Table 15 presents the efficacy results of PS-1, PS-2, and PS-3 at Week 16. Table 15: Efficacy Results at Week 16 in Adults with Plaque Psoriasis in PS-1, PS-2, and PS-3 [MI Missing data was imputed using multiple imputation based on the MCMC method. Study PS-1 Study PS-2 Study PS-3 The primary endpoint in PS-3 was PASI 75 at Week 12. Placebo CIMZIA 200mg Subjects received 400 mg of CIMZIA at Weeks 0, 2, and 4, followed by 200 mg every other week. CIMZIA 400mg Placebo CIMZIA 200mg CIMZIA 400mg Placebo CIMZIA 200mg CIMZIA 400mg PGA of 0 or 1 The co-primary efficacy endpoints at Week 16 in PS-1 and PS-2. , PGA score of 0 (clear) or 1 (almost clear). 4% 45% 55% 3% 61% 65% 4% 52% 62% PASI 75 7% 65% 75% 13% 81% 82% 4% 69% 75% PASI 90 0% 36% 44% 5% 50% 52% 0% 40% 49% Examination of age, gender, prior use of biologics, and prior use of systemic therapies did not identify difference in response to CIMZIA among these subgroups. Based on a post-hoc subgroup analysis in subjects with moderate-to-severe psoriasis, stratified by <=90 kg or >90 kg, subjects with both lower body weight and lower disease severity may achieve an acceptable response with CIMZIA 200 mg. Maintenance of Response In PS-1 and PS-2, among subjects who were PASI 75 responders at Week 16 and received CIMZIA 400 mg every other week, the PASI 75 response rates at Week 48 were 94% and 81%, respectively. In subjects who were PASI 75 responders at Week 16 and received CIMZIA 200 mg every other week, the PASI 75 response rates at Week 48 were 81% and 74%, respectively. In PS-1 and PS-2, among subjects who were PGA clear or almost clear responders at Week 16 and received CIMZIA 400 mg every other week, the PGA response rates at Week 48 were 79% and 73%, respectively. In subjects who were PGA clear or almost clear responders at Week 16 and received CIMZIA 200 mg every other week, the PGA response rates at Week 48 were 79% and 76%, respectively. In PS-3 study, subjects who achieved a PASI 75 response at Week 16 were re-randomized to either continue treatment with CIMZIA or be withdrawn from therapy (i. , receive placebo). At Week 48, 98% of subjects who continued on CIMZIA 400 mg every other week were PASI 75 responders as compared to 36% of subjects who were re-randomized to placebo. Among PASI 75 responders at Week 16 who received CIMZIA 200 mg every other week and were re-randomized to either CIMZIA 200 mg every other week or placebo, there was also a higher percentage of PASI 75 responders at Week 48 in the CIMZIA group as compared to placebo (80% and 46%, respectively).">NONCLINICAL TOXICOLOGY
Long-term animal studies of CIMZIA have not been conducted to assess its carcinogenic potential. Certolizumab pegol was not genotoxic in the Ames test, the human peripheral blood lymphocytes chromosomal aberration assay, or the mouse bone marrow micronucleus assay. Since certolizumab pegol does not cross-react with mouse or rat TNFalpha, reproduction studies were performed in rats using a rodent anti-murine TNFalpha pegylated Fab fragment (cTN3 PF), similar to certolizumab pegol. The cTN3 PF had no effects on the fertility and general reproductive performance of male and female rats at intravenous doses up 100 mg/kg, administered twice weekly.
CLINICAL STUDIES
The efficacy and safety of CIMZIA were assessed in two double-blind, randomized, placebo-controlled studies in patients aged 18 years and older with moderately to severely active Crohn''s disease, as defined by a Crohn''s Disease Activity Index (CDAI) of 220 to 450 points, inclusive. CIMZIA was administered subcutaneously at a dose of 400 mg in both studies. Stable concomitant medications for Crohn''s disease were permitted. Study CD1 Study CD1 was a randomized placebo-controlled study in 662 patients with active Crohn''s disease. CIMZIA or placebo was administered at Weeks 0, 2, and 4 and then every four weeks to Week 24. Assessments were done at Weeks 6 and 26. Clinical response was defined as at least a 100-point reduction in CDAI score compared to baseline, and clinical remission was defined as an absolute CDAI score of 150 points or lower. The results for Study CD1 are provided in Table 3. At Week 6, the proportion of clinical responders was statistically significantly greater for CIMZIA-treated patients compared to controls. The difference in clinical remission rates was not statistically significant at Week 6. The difference in the proportion of patients who were in clinical response at both Weeks 6 and 26 was also statistically significant, demonstrating maintenance of clinical response. Table 3: Study CD1 en dash Clinical Response and Remission, Overall Study Population Timepoint % Response or Remission (95% CI) Placebo CIMZIA 400 mg Week 6 Clinical Response Clinical response is defined as decrease in CDAI of at least 100 points, and clinical remission is defined as CDAI <= 150 points 27% 35% p-value < 0. 05 logistic regression test Clinical Remission 17% 22% Week 26 Clinical Response 27% 37% Clinical Remission 18% 29% Both Weeks 6 & 26 Clinical Response 16% 23% Clinical Remission 10% 14% Study CD2 Study CD2 was a randomized treatment-withdrawal study in patients with active Crohn''s disease. All patients who entered the study were dosed initially with CIMZIA 400 mg at Weeks 0, 2, and 4 and then assessed for clinical response at Week 6 (as defined by at least a 100-point reduction in CDAI score). At Week 6, a group of 428 clinical responders was randomized to receive either CIMZIA 400 mg or placebo, every four weeks starting at Week 8, as maintenance therapy through Week 24. Non-responders at Week 6 were withdrawn from the study. Final evaluation was based on the CDAI score at Week 26. Patients who withdrew or who received rescue therapy were considered not to be in clinical response. Three randomized responders received no study injections, and were excluded from the ITT analysis. The results for clinical response and remission are shown in Table 4. At Week 26, a statistically significantly greater proportion of Week 6 responders were in clinical response and in clinical remission in the CIMZIA-treated group compared to the group treated with placebo. Table 4: Study CD2 - Clinical Response and Clinical Remission % Response or Remission (95% CI) CIMZIA 400 mg ×3 + Placebo CIMZIA Week 26 Clinical Response Clinical response is defined as decrease in CDAI of at least 100 points, and clinical remission is defined as CDAI <= 150 points 36% 63% p < 0. 05 Clinical Remission 29% 48% Baseline use of immunosuppressants or corticosteroids had no impact on the clinical response to CIMZIA. The efficacy and safety of CIMZIA were assessed in four randomized, placebo-controlled, double-blind studies (RA-I, RA-II, RA-III, and RA-IV) in patients >= 18 years of age with moderately to severely active rheumatoid arthritis diagnosed according to the American College of Rheumatology (ACR) criteria. Patients had >= 9 swollen and tender joints and had active RA for at least 6 months prior to baseline. CIMZIA was administered subcutaneously in combination with MTX at stable doses of at least 10 mg weekly in Studies RA-I, RA-II, and RA-III. CIMZIA was administered as monotherapy in Study RA-IV. Study RA-I and Study RA-II evaluated patients who had received MTX for at least 6 months prior to study medication, but had an incomplete response to MTX alone. Patients were treated with a loading dose of 400 mg at Weeks 0, 2 and 4 (for both treatment arms) or placebo followed by either 200 mg or 400 mg of CIMZIA or placebo every other week, in combination with MTX for 52 weeks in Study RA-I and for 24 weeks in Study RA-II. Patients were evaluated for signs and symptoms and structural damage using the ACR20 response at Week 24 (RA-I and RA-II) and modified Total Sharp Score (mTSS) at Week 52 (RA-I). The open-label extension follow-up study enrolled 846 patients who received 400 mg of CIMZIA every other week. Study RA-III evaluated 247 patients who had active disease despite receiving MTX for at least 6 months prior to study enrollment. Patients received 400 mg of CIMZIA every four weeks for 24 weeks without a prior loading dose. Patients were evaluated for signs and symptoms of RA using the ACR20 at Week 24. Study RA-IV (monotherapy) evaluated 220 patients who had failed at least one DMARD use prior to receiving CIMZIA. Patients were treated with CIMZIA 400 mg or placebo every 4 weeks for 24 weeks. Patients were evaluated for signs and symptoms of active RA using the ACR20 at Week 24. Clinical Response The percent of CIMZIA-treated patients achieving ACR20, 50, and 70 responses in Studies RA-I and RA-IV are shown in Table 5. CIMZIA-treated patients had higher ACR20, 50 and 70 response rates at 6 months compared to placebo-treated patients. The results in study RA-II (619 patients) were similar to the results in RA-I at Week 24. The results in study RA-III (247 patients) were similar to those seen in study RA-IV. Over the one-year Study RA-I, 13% of CIMZIA-treated patients achieved a major clinical response, defined as achieving an ACR70 response over a continuous 6-month period, compared to 1% of placebo-treated patients. Table 5: ACR Responses in Studies RA-I, and RA-IV (Percent of Patients) Study RA-I Study RA-IV Response Placebo + MTX CIMZIA CIMZIA administered every 2 weeks preceded by a loading dose of 400 mg at Weeks 0, 2 and 4 CIMZIA Placebo CIMZIA CIMZIA administered every 4 weeks not preceded by a loading dose regimen CIMZIA N=199 N=393 (95% CI) 95% Confidence Intervals constructed using the large sample approximation to the Normal Distribution. N=109 N=111 (95% CI) ACR20 Week 24 14% 59% 45% (38%, 52%) 9% 46% 36% (25%, 47%) Week 52 13% 53% 40% (33%, 47%) N/A N/A ACR50 Week 24 8% 37% 30% (24%, 36%) 4% 23% 19% (10%, 28%) Week 52 8% 38% 30% (24%, 37%) N/A N/A ACR70 Week 24 3% 21% 18% (14%, 23%) 0% 6% 6% (1%, 10%) Week 52 4% 21% 18% (13%, 22%) N/A N/A Major Clinical Response Major clinical response is defined as achieving ACR70 response over a continuous 6-month period 1% 13% 12% (8%, 15%) Table 6: Components of ACR Response in Studies RA-I and RA-IV Study RA-I Study RA-IV Parameter For Study RA-I, median is presented. For Study RA-IV, mean (SD) is presented except for CRP which presents geometric mean Placebo + CIMZIA CIMZIA administered every 2 weeks preceded by a loading dose of 400 mg at Weeks 0, 2 and 4 Placebo CIMZIA CIMZIA administered every 4 weeks not preceded by a loading dose regimen Baseline Week 24 Baseline Week 24 Baseline Week 24 Baseline Week 24 Number of tender joints (0-68) 28 27 29 9 28 (12. 8) Number of swollen joints (0-66) 20 19 20 4 20 (9. 2) Physician global assessment Study RA-I - Visual Analog Scale: 0 = best, 100 = worst. Study RA-IV - Five Point Scale: 1 = best, 5 = worst 66 56 65 25 4 (0. 1) Patient global assessment 67 60 64 32 3 (0. 0) Pain Patient Assessment of Arthritis Pain. 65 60 65 32 55 (20. 6) Disability index (HAQ) Health Assessment Questionnaire Disability Index; 0 = best, 3 = worst, measures the patient''s ability to perform the following: dress/groom, arise, eat, walk, reach, grip, maintain hygiene, and maintain daily activity 1. 74) CRP (mg/L) 16. 4 The percent of patients achieving ACR20 responses by visit for Study RA-I is shown in Figure 1. Among patients receiving CIMZIA, clinical responses were seen in some patients within one to two weeks after initiation of therapy. Figure 1 Study RA-I ACR20 Response Over 52 Weeks The same patients may not have responded at each time point Figure Radiographic Response In Study RA-I, inhibition of progression of structural damage was assessed radiographically and expressed as the change in modified Total Sharp Score (mTSS) and its components, the Erosion Score (ES) and Joint Space Narrowing (JSN) score, at Week 52, compared to baseline. CIMZIA inhibited the progression of structural damage compared to placebo plus MTX after 12 months of treatment as shown in Table 7. In the placebo group, 52% of patients experienced no radiographic progression (mTSS <=0. 0) at Week 52 compared to 69% in the CIMZIA 200 mg every other week treatment group. Study RA-II showed similar results at Week 24. Table 7: Radiographic Changes at 6 and 12 months in Study RA-I Placebo + MTX CIMZIA 200 mg + MTX CIMZIA 200 mg + MTX en dash An ANCOVA was fitted to the ranked change from baseline for each measure with region and treatment as factors and rank baseline as a covariate. mTSS Baseline 40 (45) 38 (49) -- Week 24 1. 1 Week 52 2. 4 Erosion Score Baseline 14 (21) 15 (24) -- Week 24 0. 7 Week 52 1. 4 JSN Score Baseline 25 (27) 24 (28) -- Week 24 0. 5 Week 52 1. 0 Physical Function Response In studies RA-I, RA-II, RA-III, and RA-IV, CIMZIA-treated patients achieved greater improvements from baseline than placebo-treated patients in physical function as assessed by the Health Assessment Questionnaire en dash Disability Index (HAQ-DI) at Week 24 (RA-II, RA-III and RA-IV) and at Week 52 (RA-I). The efficacy of CIMZIA in pediatric patients with pJIA is based on pharmacokinetic exposure and extrapolation of the established efficacy of CIMZIA in RA patients. The efficacy of CIMZIA was also assessed in a multi-center, open-label study NCT01550003 in 193 patients 2 to 17 years of age with JIA with active polyarthritis with an inadequate response or intolerance to at least 1 DMARD (nonbiologic or biologic). Of those, 105 received the recommended dose. The patients had the following subtypes of JIA: polyarthritis rheumatoid factor-positive (20. 0%), polyarthritis rheumatoid factor-negative (44. 8%), extended oligoarthritis (13. 3%), juvenile psoriatic arthritis (4. 8%), and enthesitis-related arthritis (19. Patients could be on stable methotrexate, glucocorticoids, and/or NSAIDs. Efficacy was assessed as secondary endpoints through Week 24. The efficacy was generally consistent with responses in patients with RA. The efficacy and safety of CIMZIA were assessed in a multi-center, randomized, double-blind, placebo controlled trial (PsA001) in 409 patients aged 18 years and older with active psoriatic arthritis despite DMARD therapy. Patients in this study had >= 3 swollen and tender joints and adult-onset PsA of at least 6 months'' duration as defined by the Classification Criteria for Psoriatic Arthritis (CASPAR) criteria, and increased acute phase reactants. Patients had failed one or more DMARDs. Previous treatment with one anti-TNF biologic therapy was allowed, and 20% of patients had prior anti-TNF biologic exposure. Patients receiving concomitant NSAIDs and conventional DMARDs were 73% and 70 % respectively. Patients received a loading dose of CIMZIA 400 mg at Weeks 0, 2 and 4 (for both treatment arms) or placebo followed by either CIMZIA 200 mg every other week or CIMZIA 400 mg every 4 weeks or placebo every other week. Patients were evaluated for signs and symptoms and structural damage using the ACR20 response at Week 12 and modified Total Sharp Score (mTSS) at Week 24. Clinical Response The percentage of CIMZIA-treated patients achieving ACR20, 50 and 70 responses in study PsA001 are shown in Table 8. ACR20 response rates at weeks 12 and 24 were higher for each CIMZIA dose group relative to placebo (95% confidence intervals for CIMZIA 200 mg minus placebo at weeks 12 and 24 of (23%, 45%) and (30%, 51%), respectively and 95% confidence intervals for CIMZIA 400 mg minus placebo at weeks 12 and 24 of (17%, 39%) and (22%, 44%), respectively). The results of the components of the ACR response criteria are shown in Table 9. Patients with enthesitis at baseline were evaluated for mean improvement in Leeds Enthesitis Index (LEI). CIMZIA-treated patients receiving either 200 mg every 2 weeks or 400 mg every 4 weeks showed a reduction in enthesitis of 1. 7, respectively as compared with a reduction in placebo-treated patients of 0. 9 at week 12. Similar results were observed for this endpoint at week 24. Treatment with CIMZIA resulted in improvement in skin manifestations in patients with PsA. Table 8: ACR Responses in Study PsA001 (Percent of Patients) Response Results are from the randomized set. Non-responder Imputation (NRI) is used for patients who escaped therapy or had missing data. Placebo CIMZIA CIMZIA administered every 2 weeks preceded by a loading dose of 400 mg at Weeks 0, 2 and 4 CIMZIA CIMZIA administered every 4 weeks preceded by a loading dose of 400 mg at Weeks 0, 2 and 4 N=136 N=138 N=135 ACR20 Week 12 24% 58% 52% Week 24 24% 64% 56% ACR50 Week 12 11% 36% 33% Week 24 13% 44% 40% ACR70 Week 12 3% 25% 13% Week 24 4% 28% 24% Table 9: Components of ACR Response in Study PsA001 Parameter Placebo Results are from the entire placebo group CIMZIA CIMZIA administered every 2 weeks preceded by a loading dose of 400 mg at Weeks 0, 2 and 4 CIMZIA CIMZIA administered every 4 weeks preceded by a loading dose of 400 mg at Weeks 0, 2 and 4 Baseline Week 12 Baseline Week 12 Baseline Week 12 All values presented represent the mean Results are from the randomized set (either with imputation or observed case) Number of tender joints (0-68) Last Observation Carried Forward is used for missing data, early withdrawals or placebo escape 20 17 22 11 20 11 Number of swollen joints (0-66) 10 9 11 4 11 5 Physician global assessment , Patient and Physician Global Assessment of Disease Activity, VAS 0=best 100= worst 59 44 57 25 58 29 Patient global assessment , 57 50 60 33 60 40 Pain , The Patient Assessment of Arthritis Pain, VAS 0=no pain and 100= most severe pain 60 50 60 33 61 39 Disability index (HAQ) , The HAQ-DI, 4 point scale 0=without difficulty and 3=unable to do 1. 90 CRP (mg/L) 18. 34 The percent of patients achieving ACR20 responses by visit for PsA001 is shown in Figure 2. Randomized Set. Non-responder imputation used for patients with missing data or those who escaped therapy. Figure 2: Study PsA001-ACR20 Response Over 24 Weeks The same patients may not have responded at each time point. Figure 2 Radiographic Response In study PsA001, inhibition of progression of structural damage was assessed radiographically and expressed as the change in modified total Sharp score (mTSS) and its components, the Erosion Score (ES) and Joint Space Narrowing score (JSN) at week 24, compared to baseline. The mTSS score was modified for psoriatic arthritis by addition of hand distal interphalangeal (DIP) joints. Patients treated with CIMZIA 200 mg every other week demonstrated greater reduction in radiographic progression compared with placebo-treated patients at Week 24 as measured by change from baseline in total modified mTSS Score (estimated mean score was 0. 18 in the placebo group compared with -0. 02 in the CIMZIA 200 mg group; 95% CI for the difference was (-0. Patients treated with CIMZIA 400 mg every four weeks did not demonstrate greater inhibition of radiographic progression compared with placebo-treated patients at Week 24. Physical Function Response In Study PsA001, CIMZIA-treated patients showed improvement in physical function as assessed by the Health Assessment Questionnaire en dash Disability Index (HAQ-DI) at Week 24 as compared to placebo (estimated mean change from baseline was 0. 19 in the placebo group compared with 0. 54 in the CIMZIA 200 mg group; 95% CI for the difference was (-0. 46 in the CIMZIA 400 mg group; 95% CI for the difference was (-0. The efficacy and safety of CIMZIA were assessed in one multicenter, randomized, double-blind, placebo-controlled study (AS-1) in 325 patients >=18 years of age with adult-onset active axial spondyloarthritis for at least 3 months. The majority of patients in the study had active AS. Patients had active disease as defined by the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) >=4, and spinal pain >=4 on a 0 to 10 Numerical Rating Scale (NRS). Patients must have been intolerant to or had an inadequate response to at least one NSAID. Patients were treated with a loading dose of CIMZIA 400 mg at Weeks 0, 2 and 4 (for both treatment arms) or placebo followed by either 200 mg of CIMZIA every 2 weeks or 400 mg of CIMZIA every 4 weeks or placebo. Concomitant NSAIDs were received by 91% of the AS patients. The primary efficacy variable was the proportion of patients achieving an ASAS20 response at Week 12. Clinical Response In study AS-1, at Week 12, a greater proportion of AS patients treated with CIMZIA 200 mg every 2 weeks or 400 mg every 4 weeks achieved ASAS 20 response compared to AS patients treated with placebo (Table 10). Responses were similar in patients receiving CIMZIA 200 mg every 2 weeks and CIMZIA 400 mg every 4 weeks. The results of the components of the ASAS response criteria and other measures of disease activity are shown in Table 11. Table 10: ASAS Responses in AS patients at Weeks 12 and 24 in study AS-1 Parameters Placebo CIMZIA CIMZIA administered every 2 weeks preceded by a loading dose of 400 mg at Weeks 0, 2 and 4 CIMZIA CIMZIA administered every 4 weeks preceded by a loading dose of 400 mg at Weeks 0, 2 and 4 All percents reflect the proportion of patients who responded in the full analysis set ASAS20 Week 12 37% 57% 64% Week 24 33% 68% 70% ASAS40 Week 12 19% 40% 50% Week 24 16% 48% 59% Table 11: Components of the ASAS response criteria and other measures of disease activity in AS patients at baseline and Week 12 in study AS-1 Placebo CIMZIA CIMZIA administered every 2 weeks preceded by a loading dose of 400 mg at Weeks 0, 2 and 4 CIMZIA CIMZIA administered every 4 weeks preceded by a loading dose of 400 mg at Weeks 0, 2 and 4 Baseline Week 12 Baseline Week 12 Baseline Week 12 All values presented represent the mean in the full analysis set ASAS20 response criteria -Patient Global Assessment (0-10) 6. 8 -Total spinal pain (0-10) 7. 0 -BASFI (0-10) BASFI is Bath Ankylosing Spondylitis Functional Index 6. 8 -Inflammation (0-10) 6. 4 BASDAI (0-10) BASDAI is Bath Ankylosing Spondylitis Disease Activity Index 6. 7 BASMI BASMI is Bath Ankylosing Spondylitis Metrology Index 4. 9 The percent of AS patients achieving ASAS20 responses by visit for Study AS001 is shown in Figure 3. Among patients receiving CIMZIA, clinical responses were seen in some AS patients within one to two weeks after initiation of therapy. Figure 3: Study AS-1: ASAS20 response over 24 weeks in AS patients * Figure 3 The efficacy and safety of CIMZIA were assessed in a multicenter, randomized, double-blind, placebo-controlled study (nr-axSpA-1) (NCT02552212) in 317 subjects >=18 years of age with adult-onset active axial spondyloarthritis for at least 12 months. Patients must have had objective signs of inflammation indicated by C-reactive protein (CRP) levels above the upper limit of normal and/or sacroiliitis on magnetic resonance imaging (MRI), indicative of inflammatory disease [positive CRP (> ULN) and/or positive MRI], but without definitive radiographic evidence of structural damage on sacroiliac joints. Patients must have been intolerant to or had an inadequate response to at least two NSAIDs. Patients were treated with a loading dose of CIMZIA 400 mg at Weeks 0, 2 and 4 or placebo followed by 200 mg of CIMZIA every 2 weeks or placebo. Utilization and dose adjustment of concomitant medications (including NSAIDs, DMARDs, corticosteroids, opioids) were permitted at any time. Patients were allowed to transition to use of open-label CIMZIA at any time at the discretion of the investigator. However, no patients transitioned before Week 12. The primary endpoint was the proportion of patients achieving an Ankylosing Spondylitis Disease Activity Score-Major Improvement (ASDAS-MI) response at Week 52. The ASDAS is a composite weighted scoring system that assesses disease activity, including patient-reported outcomes and CRP levels. A response in ASDAS-Major Improvement (MI) is indicated by a change from baseline of >=2. 0 in the ASDAS and/or reaching the lowest possible ASDAS value. Clinical Response In study nr-axSpA-1, at Week 52, a greater proportion of nr-axSpA patients treated with CIMZIA had ASDAS-MI response compared to patients treated with placebo. At both Weeks 12 and 52, ASAS40 responses were greater for patients treated with CIMZIA compared to patients treated with placebo (Table 12). The components of the ASDAS-MI and ASAS response criteria are shown in Table 13. Table 12: Clinical Responses in nr-axSpA patients at Weeks 12 and 52 in study nr-axSpA-1 Parameters Placebo CIMZIA CIMZIA administered every 2 weeks preceded by a loading dose of 400 mg at Weeks 0, 2, and 4 All percents reflect the proportion of patients who were responders and remained in the study and on randomized treatment in the full analysis set. Patients who initiated open-label CIMZIA, or discontinued randomized treatment and remained in the study, or were missing Week 52 visit data were imputed as non-responders. CIMZIA 200 mg versus Placebo Odds ratio N=158 N=159 ASDAS-MI Week 52 7% 47% 15. 2 ASAS-40 Week 12 11% 48% 7. 4 Week 52 16% 57% 7. 4 Table 13: Components of the ASDAS-MI and ASAS response criteria and other measures of disease activity in nr-axSpA patients at baseline, and at Week 12 in study nr-axSpA-1 Placebo CIMZIA CIMZIA administered every 2 weeks preceded by a loading dose of 400 mg at Weeks 0, 2, and 4 N=158 N=159 Baseline Week 12 Baseline Week 12 Mean and standard deviation in parenthesis were presented based on full analysis set. Total Spinal Pain (0-10) 6. 6) Patient Global Assessment of Disease Activity (0-10) 6. 6) C-Reactive Protein (mg/L) 15. 1) BASDAI (0-10) (BASDAI is Bath Ankylosing Spondylitis Disease Activity Index 6. 2) - Back Pain 7. 5) - Peripheral pain and swelling (0-10) 6. 4) - Inflammation The average of BASDAI question 5 and 6 concerning morning stiffness intensity and duration. 4) BASFI (0-10) BASFI is Bath Ankylosing Spondylitis Functional Index 5. 3) BASMI BASMI is Bath Ankylosing Spondylitis Metrology Index 2. 4) The percentage of nr-axSpA patients achieving ASDAS-MI response by visit for study nr-axSpA-1 is shown in Figure 4. Figure 4: Study nr-axSpA-1: ASDAS-MI response over 12 weeks The same patients may not have responded at each time point. In study AS-1, at Week 12, patients with nr-axSpA treated with CIMZIA 200 mg every 2 weeks and CIMZIA 400 mg every 4 weeks had an ASAS 20 response of 42% and 47%, respectively, compared to 20% of patients treated with placebo. The ASAS 40 response in patients treated with CIMZIA 200 mg every 2 weeks and 400 mg every 4 weeks was 30% and 37%, respectively, compared to 11% of patients treated with placebo at Week 12 (see Section 14. 4 Figure 4 Other Health Related Outcomes In study nr-axSpA-1, at Week 12, patients treated with CIMZIA achieved significantly greater improvement from baseline in the Ankylosing Spondylitis Quality of Life Questionnaire (ASQoL) score compared to patients treated with placebo. Three multicenter, randomized, double-blind studies (Study PS-1 [NCT02326298], Study PS-2 [NCT02326272], and Study PS-3 [NCT02346240]) enrolled subjects 18 years of age or older with moderate-to-severe plaque psoriasis who were eligible for systemic therapy or phototherapy. Subjects had a Physician Global Assessment (PGA) of >= 3 ("moderate") on a 5-category scale of overall disease severity, a Psoriasis Area and Severity Index (PASI) score >= 12, and body surface area (BSA) involvement of >= 10%. Studies PS-1 (234 subjects) and PS-2 (227 subjects) randomized subjects to placebo, CIMZIA 200 mg every other week (following a loading dose of CIMZIA 400 mg at Weeks 0, 2, and 4), or CIMZIA 400 mg every other week. Studies PS-1 and PS-2 assessed the co-primary endpoints of the proportion of patients who achieved a PASI 75 and PGA of "clear" or "almost clear" with at least a 2-point improvement at Week 16. Other evaluated outcomes were PASI 90 at Week 16 and maintenance of efficacy to Week 48. Study PS-3 randomized 559 subjects to receive placebo, CIMZIA 200 mg every other week (following a loading dose of CIMZIA 400 mg at Weeks 0, 2, and 4), CIMZIA 400 mg every other week up to Week 16, or a biologic comparator (up to Week 12). Study PS-3 assessed the proportion of patients who achieved a PASI 75 at Week 12 as the primary endpoint. Other evaluated outcomes were PGA of "clear" or "almost clear" at Week 16, PASI 75 at Week 16, PASI 90 at Week 16, and maintenance of efficacy to Week 48. Of the 850 subjects randomized to receive placebo or CIMZIA in these placebo-controlled studies, 29% of patients were naïve to prior systemic therapy for the treatment of psoriasis, 47% had received prior phototherapy or chemophototherapy, and 30% had received prior biologic therapy for the treatment of psoriasis. Of the 850 subjects, 14% had received at least one TNF alpha agent and 16% had received an anti-IL agent. Eighteen percent of subjects reported a history of psoriatic arthritis at baseline. Across all studies and treatment groups, the mean PASI score at baseline was 20 and ranged from 12 to 69. The baseline PGA score ranged from moderate (70%) to severe (30%). Mean baseline BSA was 25% and ranged from 10% to 96%. Subjects were predominantly men (64%) and White (94%), with a mean age of 46 years. Clinical Response Table 15 presents the efficacy results of PS-1, PS-2, and PS-3 at Week 16. Table 15: Efficacy Results at Week 16 in Adults with Plaque Psoriasis in PS-1, PS-2, and PS-3 [MI Missing data was imputed using multiple imputation based on the MCMC method. Study PS-1 Study PS-2 Study PS-3 The primary endpoint in PS-3 was PASI 75 at Week 12. Placebo CIMZIA 200mg Subjects received 400 mg of CIMZIA at Weeks 0, 2, and 4, followed by 200 mg every other week. CIMZIA 400mg Placebo CIMZIA 200mg CIMZIA 400mg Placebo CIMZIA 200mg CIMZIA 400mg PGA of 0 or 1 The co-primary efficacy endpoints at Week 16 in PS-1 and PS-2. , PGA score of 0 (clear) or 1 (almost clear). 4% 45% 55% 3% 61% 65% 4% 52% 62% PASI 75 7% 65% 75% 13% 81% 82% 4% 69% 75% PASI 90 0% 36% 44% 5% 50% 52% 0% 40% 49% Examination of age, gender, prior use of biologics, and prior use of systemic therapies did not identify difference in response to CIMZIA among these subgroups. Based on a post-hoc subgroup analysis in subjects with moderate-to-severe psoriasis, stratified by <=90 kg or >90 kg, subjects with both lower body weight and lower disease severity may achieve an acceptable response with CIMZIA 200 mg. Maintenance of Response In PS-1 and PS-2, among subjects who were PASI 75 responders at Week 16 and received CIMZIA 400 mg every other week, the PASI 75 response rates at Week 48 were 94% and 81%, respectively. In subjects who were PASI 75 responders at Week 16 and received CIMZIA 200 mg every other week, the PASI 75 response rates at Week 48 were 81% and 74%, respectively. In PS-1 and PS-2, among subjects who were PGA clear or almost clear responders at Week 16 and received CIMZIA 400 mg every other week, the PGA response rates at Week 48 were 79% and 73%, respectively. In subjects who were PGA clear or almost clear responders at Week 16 and received CIMZIA 200 mg every other week, the PGA response rates at Week 48 were 79% and 76%, respectively. In PS-3 study, subjects who achieved a PASI 75 response at Week 16 were re-randomized to either continue treatment with CIMZIA or be withdrawn from therapy (i. , receive placebo). At Week 48, 98% of subjects who continued on CIMZIA 400 mg every other week were PASI 75 responders as compared to 36% of subjects who were re-randomized to placebo. Among PASI 75 responders at Week 16 who received CIMZIA 200 mg every other week and were re-randomized to either CIMZIA 200 mg every other week or placebo, there was also a higher percentage of PASI 75 responders at Week 48 in the CIMZIA group as compared to placebo (80% and 46%, respectively).

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