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).

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 Preparation and Administration of CIMZIA Using the Lyophilized Powder for Injection

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)]. Step-by-step preparation and administration instructions are provided below.

Preparation and Storage

1. CIMZIA should be brought to room temperature before reconstituting.
2. Use appropriate aseptic technique when preparing and administering CIMZIA.
3. Reconstitute the vial(s) of CIMZIA with 1 mL of Sterile Water for Injection, USP using the 20-gauge needle provided.
4. Gently swirl each vial of CIMZIA without shaking , assuring that all of the powder comes in contact with the Sterile Water for Injection.
5. Leave the vial(s) undisturbed to fully reconstitute, which may take approximately 30 minutes.
6. The final reconstituted solution contains 200 mg/mL and should be clear to opalescent, colorless to pale yellow liquid essentially free from particulates.
7. Once reconstituted, CIMZIA can be stored in the vials for up to 24 hours at 2° - 8° C (36° to 46° F) prior to injection. Do not freeze.

Administration

1. 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.
2. 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 1 mL of CIMZIA (200 mg of certolizumab pegol).
3. Replace the 20-gauge needle(s) on the syringes with a 23-gauge(s) for administration.
4. Inject the full contents of the syringe(s) subcutaneously into thigh or abdomen. Where a 400 mg dose is required, two injections are required, therefore, separate sites should be used for each 200 mg injection.

2.4 Preparation and Administration of CIMZIA Using the Prefilled Syringe

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.

Patients using the CIMZIA Prefilled Syringe should be instructed to inject the full amount in the syringe (1 mL), according to the directions provided in the Patient Instructions for Use.

2.5 Monitoring to Assess Safety

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.g. tuberculin skin test and chest x-ray) should be performed in all patients.

2.6 Concomitant Medications

CIMZIA may be used as monotherapy or concomitantly with non-biological disease modifying anti-rheumatic drugs (DMARDs). In rheumatoid arthritis clinical studies, patients on CIMZIA therapy also took concomitant methotrexate (MTX) with the recommended CIMZIA dose of 200 mg every other week. CIMZIA should not be used in combination with biological DMARDs or other tumor necrosis factor (TNF) blocker therapy.

5.1 Risk of Serious Infections

(see also Boxed Warning)

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

5.2 Malignancies

In the controlled portions of clinical studies of some TNF blockers, more cases of malignancies have been observed among patients receiving TNF blockers compared to control patients. During controlled and open-labeled portions of CIMZIA studies of Crohn's disease and other diseases, malignancies (excluding non-melanoma skin cancer) were observed at a rate (95% confidence interval) of 0.5 (0.4, 0.7) per 100 patient-years among 4,650 CIMZIA-treated patients versus a rate of 0.6 (0.1, 1.7) per 100 patient-years among 1,319 placebo-treated patients. The size of the control group and limited duration of the controlled portions of the studies precludes the ability to draw firm conclusions.

Malignancies, some fatal, have been reported among children, adolescents, and young adults who received treatment with TNF-blocking agents (initiation of therapy ≤ 18 years of age), of which CIMZIA is a member. Approximately half the cases were lymphomas, including Hodgkin's and non-Hodgkin's lymphoma. The other cases represented a variety of different malignancies and included rare malignancies usually associated with immunosuppression and malignancies that are not usually observed in children and adolescents. The malignancies occurred after a median of 30 months of therapy (range 1 to 84 months). Most of the patients were receiving concomitant immunosuppressants. These cases were reported post-marketing and are derived from a variety of sources including registries and spontaneous post-marketing reports.

In the controlled portions of clinical trials of all the TNF blockers, more cases of lymphoma have been observed among patients receiving TNF blockers compared to control patients. In controlled studies of CIMZIA for Crohn's disease and other investigational uses, there was one case of lymphoma among 2,657 Cimzia-treated patients and one case of Hodgkin's lymphoma among 1,319 placebo-treated patients.

In the CIMZIA RA clinical trials (placebo-controlled and open label) a total of three cases of lymphoma were observed among 2,367 patients. This is approximately 2-fold higher than expected in the general population. Patients with RA, particularly those with highly active disease, are at a higher risk for the development of lymphoma.

Rates in clinical studies for CIMZIA cannot be compared to the rates of clinical trials of other TNF blockers and may not predict the rates observed when CIMZIA is used in a broader patient population. Patients with Crohn's disease that require chronic exposure to immunosuppressant therapies may be at higher risk than the general population for the development of lymphoma, even in the absence of TNF blocker therapy [see Adverse Reactions (6.1)]. The potential role of TNF blocker therapy in the development of malignancies in adults is not known.

Cases of acute and chronic leukemia have been reported in association with post-marketing TNF-blocker use in RA and other indications. Even in the absence of TNF-blocker therapy, patients with RA may be at a higher risk (approximately 2-fold) than the general population for the development of leukemia.

Periodic skin examinations are recommended for all patients, particularly those with risk factors for skin cancer.

5.3 Heart Failure

Cases of worsening congestive heart failure (CHF) and new onset CHF have been reported with TNF blockers, including CIMZIA. CIMZIA has not been formally studied in patients with CHF; however, in clinical studies in patients with CHF with another TNF blocker, worsening congestive heart failure (CHF) and increased mortality due to CHF were observed. Exercise caution in patients with heart failure and monitor them carefully [see Adverse Reactions (6.1)].

5.4 Hypersensitivity Reactions

The following symptoms that could be compatible with hypersensitivity reactions have been reported rarely following CIMZIA administration to patients: angioedema, dyspnea, hypotension, rash, serum sickness, and urticaria. If such reactions occur, discontinue further administration of CIMZIA and institute appropriate therapy. There are no data on the risks of using CIMZIA in patients who have experienced a severe hypersensitivity reaction towards another TNF blocker; in these patients caution is needed [see Adverse Reactions (6.1)].

5.5 Hepatitis B Virus Reactivation

Use of TNF blockers, including CIMZIA, has been associated with reactivation of hepatitis B virus (HBV) in patients who are chronic carriers of this virus. In some instances, HBV reactivation occurring in conjunction with TNF blocker therapy has been fatal. The majority of reports have occurred in patients concomitantly receiving other medications that suppress the immune system, which may also contribute to HBV reactivation.

Test patients for HBV infection before initiating treatment with CIMZIA. For patients who test positive for HBV infection, consultation with a physician with expertise in the treatment of hepatitis B is recommended. Adequate data are not available on the safety or efficacy of treating patients who are carriers of HBV with anti-viral therapy in conjunction with TNF blocker therapy to prevent HBV reactivation. Patients who are carriers of HBV and require treatment with CIMZIA should be closely monitored for clinical and laboratory signs of active HBV infection throughout therapy and for several months following termination of therapy.

In patients who develop HBV reactivation, discontinue CIMZIA and initiate effective anti-viral therapy with appropriate supportive treatment. The safety of resuming TNF blocker therapy after HBV reactivation is controlled is not known. Therefore, exercise caution when considering resumption of CIMZIA therapy in this situation and monitor patients closely.

5.6 Neurologic Reactions

Use of TNF blockers, of which CIMZIA is a member, has been associated with rare cases of new onset or exacerbation of clinical symptoms and/or radiographic evidence of central nervous system demyelinating disease, including multiple sclerosis, and with peripheral demyelinating disease, including Guillain-Barré syndrome. Exercise caution in considering the use of CIMZIA in patients with pre-existing or recent-onset central or peripheral nervous system demyelinating disorders. Rare cases of neurological disorders, including seizure disorder, optic neuritis, and peripheral neuropathy have been reported in patients treated with CIMZIA [see Adverse Reactions (6.1)].

5.7 Hematological Reactions

Rare reports of pancytopenia, including aplastic anemia, have been reported with TNF blockers. Adverse reactions of the hematologic system, including medically significant cytopenia (e.g., leukopenia, pancytopenia, thrombocytopenia) have been infrequently reported with CIMZIA [see Adverse Reactions (6.1)]. The causal relationship of these events to CIMZIA remains unclear.

Although no high risk group has been identified, exercise caution in patients being treated with CIMZIA who have ongoing, or a history of, significant hematologic abnormalities. Advise all patients to seek immediate medical attention if they develop signs and symptoms suggestive of blood dyscrasias or infection (e.g., persistent fever, bruising, bleeding, pallor) while on CIMZIA. Consider discontinuation of CIMZIA therapy in patients with confirmed significant hematologic abnormalities.

5.8 Use with Biological Disease-Modifying Antirheumatic Drugs (Biological DMARDs)

Serious infections were seen in clinical studies with concurrent use of anakinra (an interleukin-1 antagonist) and another TNF blocker, etanercept, with no added benefit compared to entanercept alone. A higher risk of serious infections was also observed in combination use of TNF blockers with abatacept and rituximab. Because of the nature of the adverse events seen with this combination therapy, similar toxicities may also result from the use of CIMZIA in this combination. Therefore, the use of CIMZIA in combination with other biological DMARDs is not recommended [see Drug Interactions (7.1)].

5.9 Autoimmunity

Treatment with CIMZIA may result in the formation of autoantibodies and rarely, in the development of a lupus-like syndrome. If a patient develops symptoms suggestive of a lupus-like syndrome following treatment with CIMZIA, discontinue treatment [see Adverse Reactions (6.1)].

5.10 Immunizations

Patients treated with CIMZIA may receive vaccinations, except for live or live attenuated vaccines. No data are available on the response to live vaccinations or the secondary transmission of infection by live vaccines in patients receiving CIMZIA.

In a placebo-controlled clinical trial of patients with rheumatoid arthritis, no difference was detected in antibody response to vaccine between CIMZIA and placebo treatment groups when the pneumococcal polysaccharide vaccine and influenza vaccine were administered concurrently with CIMZIA. Similar proportions of patients developed protective levels of anti-vaccine antibodies between CIMZIA and placebo treatment groups; however patients receiving CIMZIA and concomitant methotrexate had a lower humoral response compared with patients receiving CIMZIA alone. The clinical significance of this is unknown.

5.11 Immunosuppression

Since TNF mediates inflammation and modulates cellular immune responses, the possibility exists for TNF blockers, including CIMZIA, to affect host defenses against infections and malignancies. The impact of treatment with CIMZIA on the development and course of malignancies, as well as active and/or chronic infections, is not fully understood [see Warnings and Precautions (5.1, 5.2, 5.5) and Adverse Reactions (6.1)]. The safety and efficacy of CIMZIA in patients with immunosuppression has not been formally evaluated.

6.1 Clinical Trials Experience

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)]

In premarketing controlled trials of all patient populations combined the most common adverse reactions (≥ 8%) were upper respiratory infections (18%), rash (9%) and urinary tract infections (8%).

6.2 Postmarketing Experience

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: systemic vasculitis has been identified during post-approval use of TNF blockers.

Skin: case of severe skin reactions, including Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme, and new or worsening psoriasis (all sub-types including pustular and palmoplantar) have been identified during post-approval use of TNF blockers.

Immune System Disorders: sarcoidosis

7.1 Use with Anakinra, Abatacept, Rituximab, and Natalizumab

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)] .

7.2 Live Vaccines

Do not give live (including attenuated) vaccines concurrently with CIMZIA [see Warnings and Precautions (5.10)] .

7.3 Laboratory Tests

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 coagulation.

8.1 Pregnancy

8.3 Nursing Mothers

It is not known whether certolizumab pegol is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from CIMZIA, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

8.4 Pediatric Use

Safety and effectiveness in pediatric patients have not been established. Due to its inhibition of TNFα, CIMZIA administered during pregnancy could affect immune responses in the in utero-exposed newborn and infant. Although certolizumab pegol levels were low in 12 infants exposed to CIMZIA in utero, the clinical significance of these low levels is unknown. Additional data available from one exposed infant suggests that CIMZIA may be eliminated at a slower rate in infants than in adults [see Use in Specific Populations (8.1)]. The safety of administering live or live-attenuated vaccines in exposed infants is unknown. Risks and benefits should be considered prior to vaccinating (live or live-attenuated) exposed infants.

8.5 Geriatric Use

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 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 (5.1)].

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 (IC90 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.

12.2 Pharmacodynamics

Biological activities ascribed to TNFα 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. TNFα stimulates the production of downstream inflammatory mediators, including interleukin-1, prostaglandins, platelet activating factor, and nitric oxide. Elevated levels of TNFα have been implicated in the pathology of Crohn's disease and rheumatoid arthritis. Certolizumab pegol binds to TNFα, inhibiting its role as a key mediator of inflammation. TNFα is strongly expressed in the bowel wall in areas involved by Crohn's disease and fecal concentrations of TNFα 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 TNFα 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.

12.3 Pharmacokinetics

13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility

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 TNFα, reproduction studies were performed in rats using a rodent anti-murine TNFα 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.

14.1 Crohn's Disease

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 (CDAI1) 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.

14.2 Rheumatoid Arthritis

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 4. 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 4: ACR Responses in Studies RA-I, and RA-IV (Percent of Patients)

	Study RA-I Methotrexate Combination (24 and 52 weeks)			Study RA-IV Monotherapy (24 weeks)
Response	Placebo + MTX	CIMZIA* 200 mg + MTX q 2 weeks	CIMZIA* 200 mg + MTX - Placebo + MTX	Placebo	CIMZIA† 400 mg q 4 weeks	CIMZIA† 400 mg - Placebo
	N=199	N=393	(95% CI)‡	N=109	N=111	(95% CI)‡
* CIMZIA administered every 2 weeks preceded by a loading dose of 400 mg at Weeks 0, 2 and 4 † CIMZIA administered every 4 weeks not preceded by a loading dose regimen ‡ 95% Confidence Intervals constructed using the large sample approximation to the Normal Distribution. § Major clinical response is defined as achieving ACR70 response over a continuous 6-month period
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§	1%	13%	12% (8%, 15%)

Table 5: Components of ACR Response in Studies RA-I and RA-IV

	Study RA-I				Study RA-IV
Parameter*	Placebo + MTX N=199		CIMZIA† 200 mg + MTX q 2 weeks N=393		Placebo + MTX N=109		CIMZIA‡ 400 mg q 4 weeks Monotherapy N=111
	Baseline	Week 24	Baseline	Week 24	Baseline	Week 24	Baseline	Week 24
* For Study RA-I, median is presented. For Study RA-IV, mean (SD) is presented except for CRP which presents geometric mean † CIMZIA administered every 2 weeks preceded by a loading dose of 400 mg at Weeks 0, 2 and 4 ‡ CIMZIA administered every 4 weeks not preceded by a loading dose regimen § Study RA-I - Visual Analog Scale: 0 = best, 100 = worst. Study RA-IV - Five Point Scale: 1 = best, 5 = worst ¶ Patient Assessment of Arthritis Pain. Visual Analog Scale: 0=best, 100=worst # 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 All values are last observation carried forward.
Number of tender joints (0-68)	28	27	29	9	28 (12.5)	24 (15.4)	30 (13.7)	16 (15.8)
Number of swollen joints (0-66)	20	19	20	4	20 (9.3)	16 (12.5)	21 (10.1)	12 (11.2)
Physician global assessment§	66	56	65	25	4 (0.6)	3 (1.0)	4 (0.7)	3 (1.1)
Patient global assessment§	67	60	64	32	3 (0.8)	3 (1.0)	3 (0.8)	3 (1.0)
Pain§¶	65	60	65	32	55 (20.8)	60 (26.7)	58 (21.9)	39 (29.6)
Disability index (HAQ)#	1.75	1.63	1.75	1.00	1.55 (0.65)	1.62 (0.68)	1.43 (0.63)	1.04 (0.74)
CRP (mg/L)	16.0	14.0	16.0	4.0	11.3	13.5	11.6	6.4

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.

* The same patients may not have responded at each time point

Figure 1 Study RA-I ACR20 Response Over 52 Weeks*

Storage and Stability

Refrigerate intact carton at 2 to 8 °C (36 to 46 °F). Do not freeze. Do not separate contents of carton prior to use. Do not use beyond expiration date, which is located on the drug label and carton. Protect solution from light.

17.1 Patient Counseling

Advise patients of the potential risks and benefits of CIMZIA therapy. Be sure that patients receive the Medication Guide and allow them time to read it prior to starting CIMZIA therapy and to review it periodically. Any questions resulting from the patient's reading of the Medication Guide should be discussed. Because caution should be exercised in prescribing CIMZIA to patients with clinically important active infections, advise patients of the importance of informing their health care providers about all aspects of their health.

17.2 Instruction on Prefilled Syringe Self-Injection Technique

After proper training by a qualified healthcare professional in subcutaneous injection technique, a patient may self inject with CIMZIA using the Prefilled Syringe if a healthcare provider determines that it is appropriate. A patient's ability to administer CIMZIA subcutaneous injections should be checked to ensure correct administration. Suitable sites for injection include the thigh or abdomen. CIMZIA should be injected when the liquid is at room temperature.

Full injection instructions are provided in the Patient Instructions for Use for the Prefilled Syringe, packaged in each CIMZIA Prefilled Syringe kit

To avoid needle-stick injury, patients and healthcare providers should not attempt to place the needle cover back on the syringe or otherwise recap the needle. Be sure to properly dispose of needles and syringes in a puncture-proof container, and instruct patients and caregivers in proper syringe and needle disposal technique. Actively discourage any reuse of the injection materials.