CIMZIA (certolizumab pegol) is a TNF blocker. CIMZIA is a recombinant, humanized antibody Fab' fragment, with specificity for human tumor necrosis factor alpha (TNFα), conjugated to an approximately 40kDa polyethylene glycol (PEG2MAL40K). The Fab' fragment is manufactured in E. coli and is subsequently subjected to purification and conjugation to PEG2MAL40K, to generate certolizumab pegol. The Fab' fragment is composed of a light chain with 214 amino acids and a heavy chain with 229 amino acids. The molecular weight of certolizumab pegol is approximately 91 kiloDaltons.

CIMZIA is supplied as either a sterile, white, lyophilized powder for solution or as a sterile, solution in a single-use prefilled 1 mL glass syringe for subcutaneous injection. After reconstitution of the lyophilized powder with 1 mL sterile Water for Injection, USP, the resulting pH is approximately 5.2. Each single-use vial provides approximately 200 mg certolizumab pegol, 100 mg sucrose, 0.9 mg lactic acid, and 0.1 mg polysorbate.

Each prefilled syringe delivers 1 mL (200 mg) of drug product with a pH of approximately 4.7. Each 1 mL syringe of CIMZIA contains 200 mg of certolizumab pegol, 1.36 mg of sodium acetate, 7.31 mg sodium chloride, and Water for Injection, USP.

CIMZIA is a clear to opalescent solution that is colorless to pale yellow and essentially free from particulates. No preservatives are present.

Last updated on RxList: 6/15/2009

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.

Rheumatoid Arthritis

CIMZIA is indicated for the treatment of adults with moderately to severely active rheumatoid arthritis (RA).

CIMZIA is administered by subcutaneous injection. Injection sites should be rotated and injections should not be given into areas where the skin is tender, bruised, red or hard. When a 400 mg dose is needed (given as two subcutaneous injections of 200 mg), injections should occur at separate sites in the thigh or abdomen.

The solution should be carefully inspected visually for particulate matter and discoloration prior to administration. The solution should be a clear 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.

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.

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].

Preparation and Administration of CIMZIA Using the Lyophilized Powder for Solution

The 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 as described below. CIMZIA should be brought to room temperature before reconstituting to facilitate dissolution.

Reconstitute each lyophilized vial of CIMZIA using appropriate aseptic technique, with 1 mL of sterile Water for Injection, USP, and a syringe with a 20 gauge needle. Gently swirl each vial of CIMZIA without shaking so that all of the lyophilized powder comes into contact with the sterile Water for Injection. Leave the vials undisturbed to fully reconstitute (this may take as long as 30 minutes). Reconstituted CIMZIA has a concentration of approximately 200 mg/mL. Once reconstituted, CIMZIA is a clear to opalescent, colorless to pale yellow liquid essentially free from particulates.

Prior to injecting, reconstituted CIMZIA should be at room temperature. Do not leave reconstituted CIMZIA at room temperature for more than 2 hours prior to administration. Using a new 20 gauge (reconstitution) needle for each vial, withdraw the reconstituted solution into a separate syringe for each vial, so that each syringe contains 1 mL of CIMZIA (200 mg of certolizumab pegol). Switch each 20 gauge needle to a 23 gauge (dosing) needle and inject the full contents of each syringe subcutaneously into the thigh or abdomen. Where a 400 mg dose is required, separate sites should be used for each 200 mg injection.

Once reconstituted, CIMZIA can be stored in the vials for up to 24 hours at 2 to 8°C (36 to 46 °F) prior to injection. Do not freeze.

Preparation and Administration of CIMZIA Using the Prefilled Syringe

A patient may self-inject CIMZIA if a physician determines that it is appropriate, with medical follow-up, as necessary, after proper training in subcutaneous injection technique.

Patients using CIMZIA should be instructed to inject the full amount in the syringe (1 mL), according to the directions provided in the Patient Instructions for Use [see FDA approved Medication Guide].

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.

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.

Dosage Forms And Strengths

• Lyophilized Powder for Reconstitution
  Sterile, white, lyophilized powder for reconstitution and then subcutaneous administration. Each single-use vial provides approximately 200 mg of CIMZIA.
• Prefilled Syringe
  A single-use, 1 mL prefilled glass syringe with a fixed 25 gauge ½ inch thin wall needle, providing 200 mg (1 mL) of CIMZIA.

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.

• Lyophilized Powder for Reconstitution:
  NDC 50474-700-62

Pack Content

Qty.	Item
2	Type I glass vials with rubber stopper and overseals each containing 200 mg of lyophilized CIMZIA for reconstitution.
2	2 mL Type I glass vials containing 1 mL sterile Water for Injection
2	3 mL plastic syringes
4	20 gauge luer-lock needles (1 inch)
2	23 gauge luer-lock needles (1 inch)
8	Alcohol swabs

         

• Prefilled Syringe
  NDC 50474-710-79
  2 alcohol swabs and 2 single use prefilled glass syringes with a fixed 25 ½ gauge thin-wall needle, each containing 200 mg (1 mL) of CIMZIA.

This Medication Guide has been approved by the U.S. Food and Drug Administration. Product developed and manufactured for: UCB, Inc. 1950 Lake Park Drive Smyrna, GA 30080. Revised 05/ 2009.

Last updated on RxList: 6/15/2009

Clinical Trials Experience

The most serious adverse reactions were:

• Serious Infections [see WARNINGS AND PRECAUTIONS]
• Malignancies [see WARNINGS AND PRECAUTIONS]
• Heart Failure [see WARNINGS AND PRECAUTIONS]

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%).

Adverse Reactions Most Commonly Leading to Discontinuation of Treatment in Premarketing Controlled Trials

The proportion of patients with Crohn's disease who discontinued treatment due to adverse reactions in the controlled clinical studies was 8% for CIMZIA and 7% for placebo. The most common adverse reactions leading to the discontinuation of CIMZIA (for at least 2 patients and with a higher incidence than placebo) were abdominal pain (0.4% CIMZIA, 0.2% placebo), diarrhea (0.4% CIMZIA, 0% placebo), and intestinal obstruction (0.4% CIMZIA, 0% placebo).

The proportion of patients with rheumatoid arthritis who discontinued treatment due to adverse reactions in the controlled clinical studies was 5% for CIMZIA and 2.5% for placebo. The most common adverse reactions leading to discontinuation of CIMZIA were tuberculosis infections (0.5%); and pyrexia, urticaria, pneumonia, and rash (0.3%).

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.

Controlled Studies with Crohn's Disease

The data described below reflect exposure to CIMZIA at 400 mg subcutaneous dosing in studies of patients with Crohn's disease. In the safety population in controlled studies, a total of 620 patients with Crohn's disease received CIMZIA at a dose of 400 mg, and 614 subjects received placebo (including subjects randomized to placebo in Study CD2 following open label dosing of CIMZIA at Weeks 0, 2, 4). In controlled and uncontrolled studies, 1,564 patients received CIMZIA at some dose level, of whom 1,350 patients received 400 mg CIMZIA. Approximately 55% of subjects were female, 45% were male, and 94% were Caucasian. The majority of patients in the active group were between the ages of 18 and 64.

During controlled clinical studies, the proportion of patients with serious adverse reactions was 10% for CIMZIA and 9% for placebo. The most common adverse reactions (occurring in ≥ 5% of CIMZIA-treated patients, and with a higher incidence compared to placebo) in controlled clinical studies with CIMZIA were upper respiratory infections (e.g. nasopharyngitis, laryngitis, viral infection) in 20% of CIMZIA-treated patients and 13% of placebo-treated patients, urinary tract infections (e.g. bladder infection, bacteriuria, cystitis) in 7% of CIMZIA-treated patients and in 6% of placebo-treated patients, and arthralgia (6% CIMZIA, 4% placebo).

Other Adverse Reactions

The most commonly occurring adverse reactions in controlled trials of Crohn's disease were described above. Other serious or significant adverse reactions reported in controlled and uncontrolled studies in Crohn's disease and other diseases, occurring in patients receiving CIMZIA at doses of 400 mg or other doses include:

Blood and lymphatic system disorders: Anemia, leukopenia, lymphadenopathy, pancytopenia, and thrombophilia.

Cardiac disorders: Angina pectoris, arrhythmias, atrial fibrillation, cardiac failure, hypertensive heart disease, myocardial infarction, myocardial ischemia, pericardial effusion, pericarditis, stroke and transient ischemic attack.

Eye disorders:Optic neuritis, retinal hemorrhage, and uveitis.

General disorders and administration site conditions: Bleeding and injection site reactions.

Hepatobiliary disorders: Elevated liver enzymes and hepatitis.

Immune system disorders:Alopecia totalis.

Psychiatric disorders: Anxiety, bipolar disorder, and suicide attempt.

Renal and urinary disorders: Nephrotic syndrome and renal failure.

Reproductive system and breast disorders: Menstrual disorder.

Skin and subcutaneous tissue disorders: Dermatitis, erythema nodosum, and urticaria.

Vascular disorders: Thrombophlebitis, vasculitis.

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 6.2 years. 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 (Preferred Term)	Placebo+ MTX# (%) N =324	CIMZIA 200 mg EOW + MTX(%) N =640
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
#EOW = Every other Week, MTX = Methotrexate.

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.

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. 0.02 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].

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. No cases of TB (0/980) have been reported in the US or Canada across all indications. Reports include cases of miliary, lymphatic, 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. [see WARNINGS AND PRECAUTIONS].

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]

Heart Failure

In placebo-controlled and open-label rheumatoid arthritis 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].

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].

Immunogenicity

Patients were tested at multiple time points for antibodies to certolizumab pegol during Studies CD1 and CD2. The overall percentage of antibody positive patients was 8% in patients continuously exposed to CIMZIA, approximately 6% were neutralizing in vitro. No apparent correlation of antibody development to adverse events or efficacy was observed. Patients treated with concomitant immunosuppressants had a lower rate of antibody development than patients not taking immunosuppressants at baseline (3% and 11%, respectively). The following adverse events were reported in Crohn's disease patients who were antibody-positive (N = 100) at an incidence at least 3% higher compared to antibody-negative patients (N = 1,242): abdominal pain, arthralgia, edema peripheral, erythema nodosum, injection site erythema, injection site pain, pain in extremity, and upper respiratory tract infection.

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. Patients treated with concomitant immunosuppressants (MTX) had a lower rate of antibody development than patients not taking immunosuppressants at baseline. Patients treated with concomitant immunosuppressant therapy (MTX) in RA-I, RA-II, RA-III had a lower rate of neutralizing antibody formation overall than patients treated with CIMZIA monotherapy in RA-IV (2% vs. 8%). Both the loading dose of 400 mg every other week at Weeks 0, 2 and 4 and concomitant use of MTX were associated with reduced immunogenicity.

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]. No association was seen between antibody development and the development of adverse events.

The data reflect the percentage of patients whose test results were considered positive for antibodies to certolizumab pegol in an ELISA, and are highly dependent on the sensitivity and specificity of the assay. The observed incidence of antibody (including neutralizing antibody) positivity in an assay is highly dependent on several factors, including assay sensitivity and specificity, assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to certolizumab pegol with the incidence of antibodies to other products may be misleading.

Hypersensitivity Reactions

The following symptoms that could be compatible with hypersensitivity reactions have been reported rarely following CIMZIA administration to patients: angioedema, dermatitis allergic, dizziness (postural), dyspnea, hot flush, hypotension, injection site reactions, malaise, pyrexia, rash, serum sickness, and (vasovagal) syncope [see WARNINGS AND PRECAUTIONS].

Adverse Reaction Information from Other Sources

Cases of severe skin reactions, including Stevens-Johnson syndrome, toxic epidermal necrolysis, and erythema multiforme, have been identified during post-approval use of other TNF blockers. 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.

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].

Live Vaccines

Do not give live (including attenuated) vaccines concurrently with CIMZIA [see WARNINGS AND PRECAUTIONS].

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.

Last updated on RxList: 6/15/2009

Included as part of the PRECAUTIONS section.

Risk of Serious Infections

(see also Boxed Warning)

Serious and sometimes fatal infection due to bacterial, mycobacterial, invasive fungal, viral, or other opportunistic pathogens has been reported in patients receiving TNF-blocking agents. Among opportunistic infections, tuberculosis, histoplasmosis, aspergillosis, candidiasis, coccidioidomycosis, listeriosis, and pneumocystosis were the most common. Patients have frequently presented with disseminated rather than localized disease, and are often taking concomitant immunosuppressants such as methotrexate or corticosteroids with CIMZIA.

Treatment with CIMZIA should not be initiated in patients with an active infection, including clinically important localized infections. 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
• 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

Cases of reactivation of tuberculosis or new tuberculosis infections have been observed in patients receiving CIMZIA, including patients who have previously received treatment for latent or active tuberculosis. Patients should be evaluated for tuberculosis risk factors and tested for latent infection prior to initiating CIMZIA and periodically during therapy.

Treatment of latent tuberculosis infection prior to therapy with TNF-blocking agents has been shown to reduce the risk of tuberculosis reactivation during therapy. Induration of 5 mm or greater with tuberculin skin testing should be considered a positive test result when assessing if treatment for latent tuberculosis is needed prior to initiating CIMZIA, even for patients previously vaccinated with Bacille Calmette-Guerin (BCG).

Anti-tuberculosis therapy should also be considered prior to initiation of CIMZIA in patients with a past history of latent or active tuberculosis in whom an adequate course of treatment cannot be confirmed, and for patients with a negative test for latent tuberculosis but having risk factors for tuberculosis infection. Consultation with a physician with expertise in the treatment of tuberculosis is recommended to aid in the decision of whether initiating anti-tuberculosis therapy is appropriate for an individual patient.

Tuberculosis should be strongly considered in patients who develop a new infection during CIMZIA treatment, especially in patients who have previously or recently traveled to countries with a high prevalence of tuberculosis, or who have had close contact with a person with active tuberculosis.

Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with CIMZIA, including the development of tuberculosis in patients who tested negative for latent tuberculosis infection prior to initiating therapy. Tests for latent tuberculosis infection may also be falsely negative while on therapy with CIMZIA.

CIMZIA should be discontinued if a patient develops a serious infection or sepsis. A patient who develops a new infection during treatment with CIMZIA should be closely monitored, undergo a prompt and complete diagnostic workup appropriate for an immunocompromised patient, and appropriate antimicrobial therapy should be initiated.

For patients who reside or travel in regions where mycoses are endemic, invasive fungal infection should be suspected if they develop a serious systemic illness. Appropriate empiric antifungal therapy should be considered while a diagnostic workup is being performed. Antigen and antibody testing for histoplasmosis may be negative in some patients with active infection. When feasible, the decision to administer empiric antifungal therapy in these patients should be made in consultation with a physician with expertise in the diagnosis and treatment of invasive fungal infections and should take into account both the risk for severe fungal infection and risks of antifungal therapy.

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.

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. The potential role of TNF blocker therapy in the development of malignancies is not known [see ADVERSE REACTIONS].

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].

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].

Hepatitis B Virus Reactivation

Use of TNF blockers, including CIMZIA, may increase the risk of 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.

Evaluate patients at risk for HBV infection for prior evidence of HBV infection before initiating CIMZIA therapy. Exercise caution in prescribing CIMZIA for patients identified as carriers of HBV. 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 antiviral 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.

Neurologic Reactions

Use of TNF blockers, including CIMZIA, has been associated with rare cases of new onset or exacerbation of clinical symptoms and/or radiographic evidence of demyelinating disease. Exercise caution in considering the use of CIMZIA in patients with pre-existing or recent-onset central 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; the causal relationship to CIMZIA remains unclear [see ADVERSE REACTIONS].

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]. 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.

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].

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].

Immunizations

No data are available on the response to vaccinations or the secondary transmission of infection by live vaccines in patients receiving CIMZIA. Do not administer live vaccines or attenuated vaccines concurrently with CIMZIA.

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 and ADVERSE REACTIONS]. The safety and efficacy of CIMZIA in patients with immunosuppression has not been formally evaluated.

Patient Counseling Information

See Medication Guide.

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.

• Immunosuppression
  Inform patients that CIMZIA may lower the ability of the immune system to fight infections. Instruct patients of the importance of contacting their doctor if they develop any symptoms of infection, including tuberculosis and reactivation of hepatitis B virus infections.
  Counsel patients about the possible risk of lymphoma and other malignancies while receiving CIMZIA.

• Allergic Reactions
  Advise patients to seek immediate medical attention if they experience any symptoms of severe allergic reactions. The prefilled syringe components do not contain any latex or dry natural rubber.

• Other Medical Conditions
  Advise patients to report any signs of new or worsening medical conditions such as heart disease, neurological disease, or autoimmune disorders. Advise patients to report promptly any symptoms suggestive of a cytopenia such as bruising, bleeding, or persistent fever.

Instruction on Prefilled Syringe Self-Injection Technique

In the event that the patient or caregiver is giving the CIMZIA injection, they need to be instructed by a qualified healthcare professional in proper injection technique, and their 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 [see FDA-approved Medication Guide]

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.

Nonclinical Toxicology

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.

Use In Specific populations

Pregnancy

Pregnancy Category B – Because 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. Reproduction studies have been performed in rats at doses up to 100 mg/kg and have revealed no evidence of impaired fertility or harm to the fetus due to cTN3 PF. There are, however, no adequate and well-controlled studies of CIMZIA in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Nursing Mothers

It is not known whether this drug 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.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

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].

Last updated on RxList: 6/15/2009

The maximum tolerated dose of certolizumab pegol has not been established. Doses of up to 800 mg subcutaneous and 20 mg/kg intravenous have been administered without serious adverse reactions. In cases of overdosage, it is recommended that patients be monitored closely for any adverse reactions or effects, and appropriate symptomatic treatment instituted immediately.

None.

Last updated on RxList: 6/15/2009

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.

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.

Pharmacokinetics

• 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 (Cmax), and the Area Under the certolizumab pegol plasma concentration versus time Curve (AUC). A mean Cmax of approximately 43 to 49 mcg/mL occurred at Week 5 during the initial loading dose period using the recommended dose regimen for the treatment of patients with rheumatoid arthritis (400 mg sc at Weeks 0, 2 and 4 followed by 200 mg every other week).
  Certolizumab pegol plasma concentrations were broadly dose-proportional and pharmacokinetics observed in patients with rheumatoid arthritis and Crohn's disease 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.

• Distribution
  The steady state volume of distribution (Vss) was estimated as 6 to 8 L in the population pharmacokinetic analysis for patients with Crohn's disease and patients with rheumatoid arthritis.

• 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 (t1/2) of the Fab'. The terminal elimination phase half-life (t_1/2) was approximately 14 days for all doses tested. The clearance following IV administration to healthy subjects ranged from 9.21 mL/h to 14.38 mL/h. The clearance following sc dosing was estimated 17 mL/h in the Crohn's disease population PK analysis with an inter-subject variability of 38% (CV) and an inter-occasion variability of 16%.
  Similarly, the clearance following sc dosing was estimated as 21.0 mL/h in the RA population PK analysis, with an inter-subject variability of 30.8% (%CV) and inter-occasion variability 22.0%. The route of elimination of certolizumab pegol has not been studied in human subjects. Studies in animals indicate that the major route of elimination of the PEG component is via urinary excretion.

• Special Populations
  Population pharmacokinetic analysis was conducted on data from 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.
  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. The presence of anti-certolizumab antibodies was associated with a 3.6-fold increase in clearance.
  Age: Pharmacokinetics of certolizumab pegol was not different in elderly compared to young adults.
  Gender: Pharmacokinetics of certolizumab pegol was similar in male and female subjects.
  Renal Impairment: Specific clinical studies have not been performed to assess the effect of renal impairment on the pharmacokinetics of CIMZIA. The pharmacokinetics of the PEG (polyethylene glycol) fraction of certolizumab pegol is expected to be dependent on renal function but has not been assessed in renal impairment. There are insufficient data to provide a dosing recommendation in moderate and severe renal impairment.
  Race: A specific clinical study showed no difference in pharmacokinetics between Caucasian and Japanese subjects.

• 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 immunosupressants.

Clinical Studies

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.

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 2. 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 2: Study CD1 – Clinical Response and Remission, Overall Study Population

Timepoint	% Response or Remission (95% CI)
	Placebo (N = 328)	CIMZIA 400 mg (N = 331)
Week 6
Clinical Response#	27% (22%, 32%)	35% (30%, 40%)*
Clinical Remission#	17% (13%, 22%)	22% (17%, 26%)
Week 26
Clinical Response	27% (22%, 31%)	37% (32%, 42%)*
Clinical Remission	18% (14%, 22%)	29% (25%, 34%)*
Both Weeks 6 & 26
Clinical Response	16% (12%, 20%)	23% (18%, 28%)*
Clinical Remission	10% (7%, 13%)	14% (11%, 18%)
* p-value < 0.05 logistic regression test # Clinical response is defined as decrease in CDAI of at least 100 points, and clinical remission is defined as CDAI ≤ 150 points

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 3. 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 3: Study CD2 - Clinical Response and Clinical Remission

	% Response or Remission (95% CI)
	CIMZIA 400 mg x3 + Placebo N = 210	CIMZIA 400 mg N = 215
Week 26
Clinical Response#	36% (30%, 43%)	63% (56%, 69%)*
Clinical Remission#	29% (22%, 35%)	48% (41%, 55%)*
* p < 0.05 # Clinical response is defined as decrease in CDAI of at least 100 points, and clinical remission is defined as CDAI ≤ 150 points

Baseline use of immunosuppressants or corticosteroids had no impact on the clinical response to CIMZIA.

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)

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

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

Parameter+	Study RA-I				Study RA-IV
	Placebo + MTX N= 199		CIMZIA(a) 200 mg + MTX q 2 weeks N= 393		Placebo + MTX N= 109		CIMZIA(b) 400 mg q 4 weeks Monotherapy N= 111
	Baseline	Week 24	Baseline	Week 24	Baseline	Week 24	Baseline	Week 24
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(c)	66	56	65	25	4 (0.6)	3 (1.0)	4 (0.7)	3 (1.1)
Patient global assessment(c)	67	60	64	32	3 (0.8)	3 (1.0)	3 (0.8)	3 (1.0)
Pain(c)(d)	65	60	65	32	55 (20.8)	60 (26.7)	58 (21.9)	39 (29.6)
Disability index (HAQ)(e)	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
(a) CIMZIA administered every 2 weeks preceded by a loading dose of 400 mg at Weeks 0, 2 and 4 (b) CIMZIA administered every 4 weeks not preceded by a loading dose regimen (c) Study RA-I - Visual Analog Scale: 0 = best, 100 = worst. Study RA-IV - Five Point Scale: 1 = best, 5 = worst (d) Patient Assessment of Arthritis Pain. Visual Analog Scale: 0=best, 100=worst (e) 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. +For Study RA-I, median is presented. For Study RA-IV, mean (SD) is presented except for CRP which presents geometric mean

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

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 6. 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 6: Radiographic Changes at 6 and 12 months in Study RA-I

	Placebo + MTX N=199 Mean (SD)	CIMZIA 200 mg + MTX N=393 Mean (SD)	CIMZIA 200 mg + MTX – Placebo + MTX Mean Difference
mTSS
Baseline	40 (45)	38 (49)	--
Week 24	1.3 (3.8)	0.2 (3.2)	-1.1
Week 52	2.8 (7.8)	0.4 (5.7)	-2.4
Erosion Score
Baseline	14 (21)	15 (24)	--
Week 24	0.7 (2.1)	0.0 (1.5)	-0.7
Week 52	1.5 (4.3)	0.1 (2.5)	-1.4
JSN Score
Baseline	25 (27)	24 (28)	--
Week 24	0.7 (2.4)	0.2 (2.5)	-0.5
Week 52	1.4 (5.0)	0.4 (4.2)	-1.0

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.

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 – Disability Index (HAQ-DI) at Week 24 (RA-II, RA-III and RA-IV) and at Week 52 (RA-I).

REFERENCES

1. Best WR, Becktel JM, Singleton JW, Kern F: Development of a Crohn's Disease Activity Index, National Cooperative Crohn's Disease Study. Gastroenterology 1976; 70(3): 439-444

Last updated on RxList: 6/15/2009

MEDICATION GUIDE

CIMZIA®
(CIM-zee-uh)
(certolizumab pegol)

Read the Medication Guide that comes with CIMZIA before you start using it, and before each injection of CIMZIA. This Medication Guide does not take the place of talking with your doctor about your medical condition or treatment.

What is the most important information I should know about CIMZIA?

CIMZIA is a medicine that affects your immune system. CIMZIA can lower the ability of the immune system to fight infections. Serious infections have happened in patients taking CIMZIA. These infections include tuberculosis (TB) and infections caused by viruses, fungi or bacteria that have spread throughout the body. Some patients have died from these infections.

• Your doctor should test you for TB before starting CIMZIA.
• Your doctor should monitor you closely for signs and symptoms of TB during treatment with CIMZIA.

Before starting CIMZIA, tell your doctor if you:

• think you have an infection. You should not start taking CIMZIA if you have any kind of infection.
• are being treated for an infection
• have signs of an infection, such as a fever, cough, flu-like symptoms
• have any open cuts or sores on your body
• get a lot of infections or have infections that keep coming back
• have diabetes
• have HIV
• have tuberculosis (TB), or have been in close contact with someone with TB
• were born in, lived in, or traveled to countries where there is more risk for getting TB. Ask your doctor if you are not sure.
• live or have lived in certain parts of the country (such as the Ohio and Mississippi River valleys) where there is an increased risk for getting certain kinds of fungal infections (histoplasmosis, coccidioidomycosis, blastomycosis). These infections may develop or become more severe if you take CIMZIA. If you do not know if you have lived in an area where histoplasmosis, coccidioidomycosis, or blastomycosis is common, ask your doctor.
• have or have had hepatitis B
• use the medicine Kineret® (anakinra), Orencia® (abatacept), Rituxan® (rituximab), or Tysabri® (natalizumab)

After starting CIMZIA, if you get an infection, any sign of an infection including a fever, cough, flu-like symptoms, or have open cuts or sores on your body, call your doctor right away. CIMZIA can make you more likely to get infections or make any infection that you may have worse.

What is CIMZIA?

CIMZIA is a medicine called a Tumor Necrosis Factor (TNF) blocker. CIMZIA is used in adult patients to:

• Lessen the signs and symptoms of moderately to severely active Crohn's disease (CD) in adults who have not been helped enough by usual treatments.
• Treat moderately to severely active rheumatoid arthritis (RA).

It is not known whether CIMZIA is safe and effective in children.

What should I tell my doctor before starting treatment with CIMZIA?

CIMZIA may not be right for you. Before starting CIMZIA, tell your doctor about all of your medical conditions, including if you:

• have an infection. (See, ‘What is the most important information I should know about CIMZIA?”)
• have or have had any type of cancer.
• have congestive heart failure.
• have seizures, any numbness or tingling, or a disease that affects your nervous system such as multiple sclerosis.
• are scheduled to receive a vaccine. Do not receive a live vaccine while taking CIMZIA.
• are allergic to any of the ingredients in CIMZIA. See the end of this Medication Guide for a list of the ingredients in CIMZIA.

Tell your doctor if you are pregnant, planning to become pregnant, or breastfeeding. CIMZIA has not been studied in pregnant or nursing women.

Tell your doctor about all the medicines you take including prescription and nonprescription medicines, vitamins and herbal supplements. Your doctor will tell you if it is okay to take your other medicines while taking CIMZIA. Especially, tell your doctor if you take:

• Kineret® (anakinra), Orencia® (abatacept), Rituxan® (rituximab), Tysabri® (natalizumab). You have a higher chance for serious infections when taking CIMZIA with Kineret®, Orencia®, Rituxan®, or Tysabri®.
• A TNF blocker: Remicade® (infliximab), Humira® (adalimumab), Enbrel® (etanercept).

You should not take CIMZIA while you take one of these medicines.

How should I use CIMZIA?

Lyophilized Powder for Reconstitution:

• If your doctor prescribes the CIMZIA lyophilized pack, CIMZIA should be injected by a healthcare provider. Each dose of CIMZIA will be given as two separate injections under the skin in your stomach area (abdomen) or upper leg (thigh).
• Make sure to keep all of your injection and follow-up appointments with your doctor.

Prefilled Syringe:

• If your doctor prescribes the CIMZIA prefilled syringe, see the section “Patient Instructions for Use” at the end of the Medication Guide for complete instructions for use.
• Do not give yourself an injection of CIMZIA unless you have been shown by your doctor or nurse. Call your doctor if you have questions. Someone you know can also help you with your injection after they have been trained by your doctor or nurse.
• CIMZIA is given by an injection under the skin. Your doctor will tell you how much CIMZIA to inject and how often to inject CIMZIA, based on your condition to be treated. Do not use more CIMZIA or inject more often than prescribed.
• Depending on the amount of CIMZIA prescribed by your doctor, you may need more than one injection at a time.
• If you are prescribed to take 400 mg of CIMZIA, you will need two injections. You will need to use two CIMZIA prefilled syringes.
• CIMZIA may be injected into your abdomen or thigh area. If you are prescribed to have more than one injection, each injection should be given at a different site in your abdomen or thigh.
• Make sure the solution in the prefilled syringe is clear and colorless to light yellow. The solution should be essentially free from particles. Do not use the CIMZIA prefilled syringe if the medicine looks cloudy or if there are large or colored particles.
• Do not miss any doses of CIMZIA. If you forget to take CIMZIA, inject a dose as soon as you remember. Then, take your next dose at your regularly scheduled time.
• Make sure to keep all follow-up appointments with your doctor.

What are the possible side effects of CIMZIA?

Serious side effects have happened in patients taking CIMZIA including:

• Serious infections including TB. See “What is the most important information I should know about CIMZIA?”
• Certain Types of Cancer. There have been cases of certain types of cancer in people taking CIMZIA or other TNF blockers. People with RA, especially more serious RA, may have a higher chance for getting a kind of cancer called lymphoma.
• Heart Failure including new heart failure or worsening of heart failure you already have. Symptoms include shortness of breath, swelling of your ankles or feet, or sudden weight gain.
• Nervous System Problems such as multiple sclerosis, seizures, or inflammation of the nerves of the eyes. Symptoms include dizziness, numbness or tingling, problems with your vision, and weakness in your arms or legs.
• Allergic Reactions. Signs of an allergic reaction include a skin rash, swelling of the face, tongue, lips, or throat, or trouble breathing.
• Hepatitis B virus reactivation in patients who carry the virus in their blood. In some cases patients have died as a result of hepatitis B virus being reactivated. Your doctor should monitor you carefully during treatment with CIMZIA if you carry the hepatitis B virus in your blood. Tell your doctor if you have any of the following symptoms:
  • feel unwell
  • poor appetite
  • tiredness (fatigue)
  • fever, skin rash, or joint pain
• Blood Problems. Your body may not make enough of the blood cells that help fight infections or help stop bleeding. Symptoms include a fever that doesn't go away, bruising or bleeding very easily, or looking very pale.
• Immune reactions including a lupus-like syndrome. Symptoms include shortness of breath, joint pain, or a rash on the cheeks or arms that worsens with sun exposure.

Call your doctor right away if you develop any of the above side effects or symptoms.

The most common side effects in people taking CIMZIA are:

• upper respiratory infections (flu, cold)
• rash
• urinary tract infections (bladder infections)

Injection site reactions such as redness, rash, swelling, itching or bruising can happen in some people. These symptoms will usually go away within a few days. If you have pain, redness, or swelling around the injection site that doesn't go away within a few days or gets worse, call your doctor right away.

Tell your doctor about any side effect that bothers you or does not go away.

These are not all of the side effects with CIMZIA. Ask your doctor or pharmacist for more information.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

General information about CIMZIA

Medicines are sometimes prescribed for purposes that are not mentioned in Medication Guides. Do not use CIMZIA for a condition for which it was not prescribed. Do not give CIMZIA to other people, even if they have the same condition. It may harm them.

This Medication Guide summarizes the most important information about CIMZIA. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about CIMZIA that is written for health professionals.

For more information go to www.CIMZIA.com or you can enroll in a patient support program by calling 1-866-4CIMZIA (424-6942).

How should I store CIMZIA?

• Keep CIMZIA in the refrigerator at 36ºF – 46ºF (2ºC – 8ºC)
• Let CIMZIA to come to room temperature before injecting it.
• Do not freeze CIMZIA.
• Protect CIMZIA from light. Store CIMZIA in the carton.
• Do not use CIMZIA if the medication is expired (today's date is past the date printed on the vial, prefilled syringe or carton), or if the liquid looks cloudy or discolored.

The vials and prefilled syringe are glass. Do not drop or crush them.

Always keep CIMZIA, injection supplies, puncture-proof container, and all other medicines out of the reach of children.

What are the ingredients in CIMZIA?

CIMZIA lyophilized powder:

Active ingredient: certolizumab pegol.

Inactive ingredients: sucrose, lactic acid, polysorbate.

The pack contains Water for Injection, for reconstitution of the lyophilized powder.

CIMZIA prefilled syringe:

Active ingredient: certolizumab pegol

Inactive ingredients: sodium acetate, sodium chloride, and Water for Injection.

CIMZIA has no preservatives.

Patient Instructions for Use

The instructions below are only to be used with CIMZIA in Prefilled Syringes.

What do I need to do to prepare and give an injection of CIMZIA?

Do not use the CIMZIA prefilled syringe if:

• any name other than “CIMZIA” is on the package and prefilled syringe label
• the expiration date on the container has passed
• the packaging is torn or if the tamper evident seals are missing or broken on the top and bottom of carton when you receive it. If this is the case, contact your pharmacist
• the prefilled syringe is frozen or has been left in direct sunlight
• the medicine in the prefilled syringe is not clear to pale yellow, or has large, colored particles in it.

Preparing to use the CIMZIA prefilled syringe

Each CIMZIA prefilled syringe package comes with these items in a tray:

• 2 glass prefilled syringes of CIMZIA. Each has a fixed needle.
• 2 alcohol swabs

For each injection you will use-

• 1 prefilled syringe of CIMZIA with needle
• 1 alcohol swab

For each injection you will also need:

• 1 clean cotton ball or gauze pads. These are not included in CIMZIA prefilled syringe package.
• a puncture-proof container for disposing of used needles and syringes. (See the section entitled “How do I dispose of needles and syringes?”)

If you do not have all the supplies you need, talk to your pharmacist.

• Each prefilled syringe contains the right dose of medicine for one injection (200 mg).
• Depending on the amount of CIMZIA prescribed by your doctor, you may need to take more than one injection.
• If you are prescribed to take 400 mg of CIMZIA, you will need to take two injections. You will need to use two CIMZIA prefilled syringes.
• CIMZIA may be injected into your abdomen or thigh area. If you are prescribed to take more than one injection, each injection should be given at a different injection site, in your abdomen and thigh.

1. Take either one or two CIMZIA prefilled syringes and alcohol swabs out of the refrigerator for injection, depending on your prescribed dose. If there is still a prefilled syringe in the carton, put it back in the refrigerator right away. If both prefilled syringes are used, throw away the empty carton after you finish your injection.

2. Let the medicine in the syringe come to room temperature before injection. This will take about 30 minutes.

For your protection, it's important that you carefully follow these instructions:

Choosing and preparing an injection site

3. Wash your hands thoroughly.

4. Choose a different site on your abdomen or thigh for each injection. Each new injection should be given at least one inch from a site you used before. If you choose the abdomen, avoid the 2 inches around your navel. Do not inject into areas where the skin is tender, bruised, red or hard or where you have scars or stretch marks. Change injection sites between your abdomen and thighs to reduce the risk of reaction. You may find it helpful to keep notes on the locations of injection sites you use.

5. Use an alcohol swab to wipe over the site where you will inject CIMZIA. Do not touch the clean area again until you are ready for the injection.

Using the CIMZIA prefilled syringe

6. Remove the needle cover by pulling straight up on the plastic ring. Take care not to touch the needle and do not allow the needle to touch any surface. Place the needle cover to the side.

7. Hold the syringe so the needle is pointing up. Lightly tap the syringe to push any air bubbles to the top. Push the plunger slowly to remove any bubbles. Stop pushing the plunger once all of the air bubbles are gone. If a small drop of liquid comes out of the needle that is okay.

8. Hold the syringe with the needle facing down. Do not touch the needle with your fingers or let it touch any surface.

9. Hold the syringe in one hand. Use the other hand to gently pinch a fold of cleaned area of skin. Insert the needle at about a 45 degree angle with a quick, short, “dart-like” motion.

10. Release the skin pinch, keeping the syringe in position. Pull back slowly on the plunger. If blood enters the syringe, this means you have entered a blood vessel. Do not inject CIMZIA. Pull the needle out and throw away the prefilled syringe and needle in a puncture-proof container. Repeat the steps to prepare for an injection using a new prefilled syringe. Do not use the same prefilled syringe.

11. If no blood appears, inject all of the medicine in the prefilled syringe under the skin.

12. When the syringe is empty, remove the needle from the skin and press the clean cotton ball or gauze pad over the injection site for ten seconds. Do not rub the injection site. You may have a slight amount of bleeding. This is normal.

13. To avoid needle-stick injury, do not try to recap the needle. Throw away the used prefilled syringe and needle in a special puncture-proof container (see the section entitled “How should I dispose of needles and syringes?”)

14. Repeat steps 5-13 above if you are prescribed to take a second injection of CIMZIA (total 400 mg dose).

How should I throw away (dispose of) needles and syringes?

To avoid needle-stick injury, do not try to recap the needle. Before you start injecting CIMZIA at home, check with your doctor for instructions on the right way to throw away your used needles and used prefilled syringes. There may be special state or local laws about throwing away used needles and syringes.

Ask your doctor or pharmacist about how to get a puncture-proof container (“sharps” container) that will meet the requirements of your particular state or town.

When the container is about two-thirds full, tape the lid closed. Dispose of the container as instructed by your doctor, nurse or pharmacist. Do not throw away the container in the trash or recycle.

Alcohol swabs may be placed in the trash, unless you are instructed otherwise.

Always keep CIMZIA, injection supplies, puncture-proof container, and all other medicines out of the reach of children.

This Medication Guide has been approved by the U.S. Food and Drug Administration.

Last updated on RxList: 6/15/2009

IMPORTANT NOTE: This is a summary and does not contain all possible information about this product. For complete information about this product or your specific health needs, ask your health care professional. Always seek the advice of your health care professional if you have any questions about this product or your medical condition. This information is not intended as individual medical advice and does not substitute for the knowledge and judgment of your health care professional. This information does not contain any assurances that this product is safe, effective, or appropriate for you.

CERTOLIZUMAB - INJECTION

(SER-toe-LIZ-oo-mab)

COMMON BRAND NAME(S): Cimzia

WARNING: This medication can decrease your body's ability to fight an infection and may make you more likely to get a serious (possibly fatal) infection such as tuberculosis (TB). You should be tested for TB before and during treatment with this medication. If you have TB, you must be treated for it before you start using certolizumab. Tell your doctor if you have lived or traveled in areas where TB is common or if you have had close contact with someone who has active TB. Also tell your doctor immediately if you notice any signs of infection such as persistent cough, fever, or sudden weight loss.

USES: This medication is used to treat a bowel condition called Crohn's disease when it has not improved with other drugs. Certolizumab belongs to a class of drugs known as tumor necrosis factor (TNF) blockers. It works by blocking TNF, a substance made by the body that causes swelling (inflammation).

HOW TO USE: Read the Medication Guide provided by your pharmacist before you start using certolizumab and each time you get a refill. If you have any questions, consult your doctor or pharmacist.

This medication is given by injection under the skin, in the stomach or thigh area, by a health care professional. Each dose is given as 2 separate injections. The first 3 doses are given every 2 weeks. After the third dose, this medication is usually given every 4 weeks or as directed by your doctor.

Use this medication regularly to get the most benefit from it. To help you remember, mark the days on a calendar when you need to receive the medication.

Tell your doctor if your condition persists or worsens.

SIDE EFFECTS: See also Warning section.

Fever, cough, sore throat, stuffy/runny nose, burning/painful/frequent urination, or joint pain may occur. If any of these effects persist or worsen, tell your doctor or pharmacist promptly.

Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.

Though unlikely, you may have a slightly increased risk of developing cancer such as lymphoma due to this medication or due to your medical condition. Tell your doctor immediately if you develop symptoms such as: unusual lumps/growths, swollen glands, unexplained weight loss.

Tell your doctor immediately if any of these rare but very serious side effects occur: shortness of breath, swelling ankles/feet, severe/unusual tiredness, easy bruising/bleeding, swollen joints, rash on nose and cheeks, eye pain, vision changes, dizziness, numbness/tingling of arms/legs, seizures.

A very serious allergic reaction to this drug is rare. However, seek immediate medical attention if you notice any symptoms of a serious allergic reaction, including: rash, itching/swelling (especially of the face/tongue/throat), severe dizziness, trouble breathing.

This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.

Contact your doctor for medical advice about side effects. The following numbers do not provide medical advice, but in the US you may report side effects to the Food and Drug Administration (FDA) at 1-800-FDA-1088. In Canada, you may call Health Canada at 1-866-234-2345.

PRECAUTIONS: Before using certolizumab, tell your doctor or pharmacist if you are allergic to it; or if you have any other allergies.

This medication should not be used if you have certain medical conditions. Before using this medicine, consult your doctor or pharmacist if you have: any current infection.

Before using this medication, tell your doctor or pharmacist your medical history, especially of: any infection that keeps coming back, hepatitis B infection, HIV infection, tuberculosis (TB), cuts or open sores, cancer, diabetes, heart failure, blood/bone marrow disorders, brain/nervous system disorders (such as multiple sclerosis, seizures).

Because certolizumab can make you more likely to get infections or may worsen any current infections, do not have immunizations/vaccinations without the consent of your doctor. Avoid contact with people who have recently received the polio vaccine taken by mouth or flu vaccine inhaled through the nose. Also avoid contact with people who have infections that may spread to others (such as chickenpox, flu). Wash your hands well to prevent the spread of infections.

To lower the chance of getting cut, bruised, or injured, use caution with sharp objects like razors and nail cutters, and avoid activities such as contact sports.

Older adults are more sensitive to the effects of this drug, especially the risk of infections.

During pregnancy, this medication should be used only when clearly needed. Discuss the risks and benefits with your doctor.

It is not known whether this drug passes into breast milk. Consult your doctor before breast-feeding.

DRUG INTERACTIONS: Your doctor or pharmacist may already be aware of any possible drug interactions and may be monitoring you for them. Do not start, stop, or change the dosage of any medicine before checking with your doctor or pharmacist first.

This drug should not be used with the following products because very serious interactions may occur: anakinra, live vaccines (such as polio vaccine taken by mouth, flu vaccine inhaled through the nose).

If you are using anakinra or have recently received a live vaccine, tell your doctor or pharmacist before starting certolizumab.

Before using this medication, tell your doctor or pharmacist of all prescription and nonprescription/herbal products you may use, especially of: other drugs that weaken the immune system (such as azathioprine, cancer chemotherapy, cyclosporine).

This medication may interfere with certain laboratory tests (including aPTT tests), possibly causing false test results. Make sure laboratory personnel and all your doctors know you use this drug.

This document does not contain all possible interactions. Therefore, before using this product, tell your doctor or pharmacist of all the products you use. Keep a list of all your medications with you, and share the list with your doctor and pharmacist.

OVERDOSE: If overdose is suspected, contact your local poison control center or emergency room immediately. US residents can call the US National Poison Hotline at 1-800-222-1222. Canada residents can call a provincial poison control center.

NOTES: Laboratory and/or medical tests (such as complete blood count, liver function test) may be performed periodically to monitor your progress or check for side effects. Consult your doctor for more details.

MISSED DOSE: For the best possible benefit, it is important to receive each scheduled dose of this medication as directed. If you miss a dose, contact your doctor or pharmacist immediately to establish a new dosing schedule.

STORAGE: Store the entire carton in the refrigerator between 36-46 degrees F (2-8 degrees C). Do not freeze. Keep all medications away from children and pets.

MEDICAL ALERT: Your condition can cause complications in a medical emergency. For information about enrolling in MedicAlert, call 1-800-854-1166 (USA) or 1-800-668-1507 (Canada).

Information last revised July 2008 Copyright(c) 2008 First DataBank, Inc.