Data from FDA - Curated by EPG Health - Last updated 05 July 2018

Indication(s)

1 INDICATIONS AND USAGE CIMZIA is a tumor necrosis factor (TNF) blocker indicated for: Reducing signs and symptoms of Crohn's disease and maintaining clinical response in adult patients with moderately to severely active disease who have had an inadequate response to conventional therapy (1.1) Treatment of adults with moderately to severely active rheumatoid arthritis (1.2) Treatment of adult patients with active psoriatic arthritis. (1.3) Treatment of adults with active ankylosing spondylitis (1.4) Treatment of adults with moderate-to-severe plaque psoriasis who are candidates for systemic therapy or phototherapy (1.5) 1.1 Crohn's Disease CIMZIA is indicated for reducing signs and symptoms of Crohn's disease and maintaining clinical response in adult patients with moderately to severely active disease who have had an inadequate response to conventional therapy. 1.2 Rheumatoid Arthritis CIMZIA is indicated for the treatment of adults with moderately to severely active rheumatoid arthritis (RA). 1.3 Psoriatic Arthritis CIMZIA is indicated for the treatment of adult patients with active psoriatic arthritis (PsA). 1.4 Ankylosing Spondylitis CIMZIA is indicated for the treatment of adults with active ankylosing spondylitis (AS). [see Clinical Studies (14.4)] 1.5 Plaque Psoriasis CIMZIA is indicated for the treatment of adults with moderate-to-severe plaque psoriasis (PsO) who are candidates for systemic therapy or phototherapy [see Clinical Studies (14.5)]

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contraindications
4 CONTRAINDICATIONS CIMZIA is contraindicated in patients with a history of hypersensitivity reaction to certolizumab pegol or to any of the excipients. Reactions have included angioedema, anaphylactoid reaction, serum sickness, and urticaria [see Warnings and Precautions (5.4)]. Serious hypersensitivity reaction to certolizumab pegol or to any of the excipients. (4)
Adverse reactions
6 ADVERSE REACTIONS The most serious adverse reactions were: Serious Infections [see Warnings and Precautions (5.1)] Malignancies [see Warnings and Precautions (5.2)] Heart Failure [see Warnings and Precautions (5.3)] The most common adverse reactions (incidence ≥7% and higher than placebo): upper respiratory tract infection, rash, and urinary tract infection (6.1) To report SUSPECTED ADVERSE REACTIONS, contact UCB, Inc. at 1-866-822-0068 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical studies are conducted under widely varying and controlled conditions, adverse reaction rates observed in clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug, and may not predict the rates observed in a broader patient population in clinical practice. In premarketing controlled trials of all patient populations combined the most common adverse reactions (≥ 8%) were upper respiratory infections (18%), rash (9%) and urinary tract infections (8%). Adverse Reactions Most Commonly Leading to Discontinuation of Treatment in Premarketing Controlled Trials The proportion of patients with Crohn's disease who discontinued treatment due to adverse reactions in the controlled clinical studies was 8% for CIMZIA and 7% for placebo. The most common adverse reactions leading to the discontinuation of CIMZIA (for at least 2 patients and with a higher incidence than placebo) were abdominal pain (0.4% CIMZIA, 0.2% placebo), diarrhea (0.4% CIMZIA, 0% placebo), and intestinal obstruction (0.4% CIMZIA, 0% placebo). The proportion of patients with rheumatoid arthritis who discontinued treatment due to adverse reactions in the controlled clinical studies was 5% for CIMZIA and 2.5% for placebo. The most common adverse reactions leading to discontinuation of CIMZIA were tuberculosis infections (0.5%); and pyrexia, urticaria, pneumonia, and rash (0.3%). Controlled Studies with Crohn's Disease The data described below reflect exposure to CIMZIA at 400 mg subcutaneous dosing in studies of patients with Crohn's disease. In the safety population in controlled studies, a total of 620 patients with Crohn's disease received CIMZIA at a dose of 400 mg, and 614 subjects received placebo (including subjects randomized to placebo in Study CD2 following open label dosing of CIMZIA at Weeks 0, 2, 4). In controlled and uncontrolled studies, 1,564 patients received CIMZIA at some dose level, of whom 1,350 patients received 400 mg CIMZIA. Approximately 55% of subjects were female, 45% were male, and 94% were Caucasian. The majority of patients in the active group were between the ages of 18 and 64. During controlled clinical studies, the proportion of patients with serious adverse reactions was 10% for CIMZIA and 9% for placebo. The most common adverse reactions (occurring in ≥ 5% of CIMZIA-treated patients, and with a higher incidence compared to placebo) in controlled clinical studies with CIMZIA were upper respiratory infections (e.g. nasopharyngitis, laryngitis, viral infection) in 20% of CIMZIA-treated patients and 13% of placebo-treated patients, urinary tract infections (e.g. bladder infection, bacteriuria, cystitis) in 7% of CIMZIA-treated patients and in 6% of placebo-treated patients, and arthralgia (6% CIMZIA, 4% placebo). Other Adverse Reactions The most commonly occurring adverse reactions in controlled trials of Crohn's disease were described above. Other serious or significant adverse reactions reported in controlled and uncontrolled studies in Crohn's disease and other diseases, occurring in patients receiving CIMZIA at doses of 400 mg or other 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+ MTXEOW = Every other Week, MTX = Methotrexate. (%) 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 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. Psoriatic Arthritis Clinical Study CIMZIA has been studied in 409 patients with psoriatic arthritis (PsA) in a placebo-controlled trial. The safety profile for patients with PsA treated with CIMZIA was similar to the safety profile seen in patients with RA and previous experience with CIMZIA. Ankylosing Spondylitis Clinical Study CIMZIA has been studied in 325 patients with axial spondyloarthritis of whom the majority had ankylosing spondylitis (AS) in a placebo-controlled study (AS-1). The safety profile for patients in study AS-1 treated with CIMZIA was similar to the safety profile seen in patients with RA. Plaque Psoriasis Clinical Studies In clinical studies, a total of 1112 subjects with plaque psoriasis were treated with CIMZIA. Of these, 779 subjects were exposed for at least 12 months, 551 for 18 months, and 66 for 24 months. Data from three placebo-controlled studies (Studies PS-1, PS-2, and PS-3) in 1020 subjects (mean age 46 years, 66% males, 94% white) were pooled to evaluate the safety of CIMZIA [see Clinical Studies (14)]. Placebo-Controlled Period (Week 0-16) In the placebo-controlled period of Studies PS-1, PS-2 and PS-3 in the 400 mg group, adverse events occurred in 63.5% of subjects in the CIMZIA group compared to 61.8% of subjects in the placebo group. The rates of serious adverse events were 4.7% in the CIMZIA group and 4.5% in the placebo group. Table 2 summarizes the adverse reactions that occurred at a rate of at least 1% and at a higher rate in the CIMZIA group than in the placebo group. Table 2: Adverse Reactions Occurring in ≥1% of Subjects in the CIMZIA Group and More Frequently than in the Placebo Group in the Plaque Psoriasis Studies PS-1, PS-2, and PS-3. Adverse Reactions Cimzia 400 mg every other week n (%) N=342 Cimzia 200 mg Subjects received 400 mg of CIMZIA at Weeks 0, 2, and 4, followed by 200 mg every other week. every other week n (%) N=350 Placebo n (%) N=157 Upper respiratory tract infectionsUpper respiratory tract infection cluster includes upper respiratory tract infection, pharyngitis bacterial, pharyngitis streptococcal, upper respiratory tract infection bacterial, viral upper respiratory tract infection, viral pharyngitis, viral sinusitis, and nasopharyngitis. 75 (21.9) 68 (19.4) 33 (21.0) HeadacheHeadache includes headache and tension headache. 13 (3.8) 10 (2.9) 4 (2.5) Injection site reactionsInjection site reactions cluster includes injection site reaction, injection site erythema, injection site bruising, injection site discoloration, injection site pain, and injection site swelling. 11 (3.2) 6 (1.7) 1 (0.6) Cough 11 (3.2) 4 (1.1) 3 (1.9) Herpes infectionsHerpes infections cluster includes oral herpes, herpes dermatitis, herpes zoster, and herpes simplex. 5 (1.5) 5 (1.4) 2 (1.3) Elevated Liver Enzymes Elevated liver enzymes were reported more frequently in the CIMZIA-treated subjects (4.3% in the 200 mg group and 2.3% in the 400 mg group) than in the placebo-treated subjects (2.5%). Of CIMZIA-treated subjects who had elevation of liver enzymes, two subjects were discontinued from the trial. In controlled Phase 3 studies of CIMZIA in adults with PsO with a controlled period duration ranging from 0 to 16 weeks, AST and/or ALT elevations ≥5 × ULN occurred in 0.9% of CIMZIA 200 mg or CIMZIA 400 mg arms and none in placebo arm. Psoriasis-Related Adverse Events In controlled clinical studies in psoriasis, change of plaque psoriasis into a different psoriasis sub-types (including erythrodermic, pustular and guttate), was observed in <1% of Cimzia treated subjects. Adverse Reactions of Special Interest Across Indications Infections The incidence of infections in controlled studies in Crohn's disease was 38% for CIMZIA-treated patients and 30% for placebo-treated patients. The infections consisted primarily of upper respiratory infections (20% for CIMZIA, 13% for placebo). The incidence of serious infections during the controlled clinical studies was 3% per patient-year for CIMZIA-treated patients and 1% for placebo-treated patients. Serious infections observed included bacterial and viral infections, pneumonia, and pyelonephritis. The incidence of new cases of infections in controlled clinical studies in rheumatoid arthritis was 0.91 per patient-year for all CIMZIA-treated patients and 0.72 per patient-year for placebo-treated patients. The infections consisted primarily of upper respiratory tract infections, herpes infections, urinary tract infections, and lower respiratory tract infections. In the controlled rheumatoid arthritis studies, there were more new cases of serious infection adverse reactions in the CIMZIA treatment groups, compared to the placebo groups (0.06 per patient-year for all CIMZIA doses vs. 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 (5.1)]. In controlled clinical studies in psoriasis, the incidence rates of infections were similar in the CIMZIA and placebo groups. The infections consisted primarily of upper respiratory tract infections and viral infections (including herpes infections). Serious adverse events of infection occurred in CIMZIA-treated patients during the placebo-controlled periods of the pivotal studies (pneumonia, abdominal abscess, and hematoma infection) and Phase 2 study (urinary tract infection, gastroenteritis, and disseminated tuberculosis). Tuberculosis and Opportunistic Infections In completed and ongoing global clinical studies in all indications including 5,118 CIMZIA-treated patients, the overall rate of tuberculosis is approximately 0.61 per 100 patient-years across all indications. The majority of cases occurred in countries with high endemic rates of TB. Reports include cases of disseminated (miliary, lymphatic, and peritoneal) as well as pulmonary TB. The median time to onset of TB for all patients exposed to CIMZIA across all indications was 345 days. In the studies with CIMZIA in RA, there were 36 cases of TB among 2,367 exposed patients, including some fatal cases. Rare cases of opportunistic infections have also been reported in these clinical trials. In Phase 2 and Phase 3 studies with CIMZIA in plaque psoriasis, there were 2 cases of TB among 1112 exposed patients [see Warnings and Precautions (5.1)]. Malignancies In clinical studies of CIMZIA, the overall incidence rate of malignancies was similar for CIMZIA-treated and control patients. For some TNF blockers, more cases of malignancies have been observed among patients receiving those TNF blockers compared to control patients [see Warnings and Precautions (5.2)]. Heart Failure In placebo-controlled and open-label studies, cases of new or worsening heart failure have been reported for CIMZIA-treated patients. The majority of these cases were mild to moderate and occurred during the first year of exposure [see Warnings and Precautions (5.3)]. Autoantibodies In clinical studies in Crohn's disease, 4% of patients treated with CIMZIA and 2% of patients treated with placebo that had negative baseline ANA titers developed positive titers during the studies. One of the 1,564 Crohn's disease patients treated with CIMZIA developed symptoms of a lupus-like syndrome. In clinical trials of TNF blockers, including CIMZIA, in patients with RA, some patients have developed ANA. Four patients out of 2,367 patients treated with CIMZIA in RA clinical studies developed clinical signs suggestive of a lupus-like syndrome. The impact of long-term treatment with CIMZIA on the development of autoimmune diseases is unknown [see Warnings and Precautions (5.9)]. 6.2 Immunogenicity Patients with Crohn's disease were tested at multiple time points for antibodies to certolizumab pegol during Studies CD1 and CD2. In patients continuously exposed to CIMZIA, the overall percentage of patients who were antibody positive to CIMZIA on at least one occasion was 8%; approximately 6% were neutralizing in vitro. 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. In two long-term (up to 7 years of exposure), open-label Crohn's disease studies, overall 23% (207/903) of patients developed antibodies against certolizumab pegol on at least one occasion. Of the 207 patients who were antibody positive, 152 (73%) had a persistent reduction of drug plasma concentration, which represents 17% (152/903) of the study population. The data from these two studies do not suggest an association between the development of antibodies and adverse events. The overall percentage of patients with antibodies to certolizumab pegol detectable on at least one occasion was 7% (105 of 1,509) in the rheumatoid arthritis placebo-controlled trials. Approximately one third (3%, 39 of 1,509) of these patients had antibodies with neutralizing activity in vitro. 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 (12.3)]. No association was seen between antibody development and the development of adverse events. Approximately 8 % (22/265) and 19% (54/281) of subjects with psoriasis who received CIMZIA 400 mg every 2 weeks and CIMZIA 200 mg every 2 weeks for 48 weeks, respectively, developed antibodies to certolizumab pegol. Of the subjects who developed antibodies to certolizumab pegol, 45% (27/60) had antibodies that were classified as neutralizing. Antibody formation was associated with lowered drug plasma concentration and reduced efficacy. 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 methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. The assay used to measure antibodies to certolizumab pegol is subject to interference by serum certolizumab pegol, possibly resulting in an underestimation of the incidence of antibody formation. For these reasons, comparison of the incidence of antibody positivity 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 (5.4)]. 6.3 Postmarketing Experience The following adverse reactions have been identified during post-approval use of CIMZIA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to estimate reliably their frequency or establish a causal relationship to drug exposure. Vascular disorder: 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 Neoplasms benign, malignant and unspecified (including cysts and polyps): Melanoma, Merkel cell carcinoma (neuroendocrine carcinoma of the skin) [see Warnings and Precautions (5.2)].

Usage information

Dosing and administration
2 DOSAGE AND ADMINISTRATION CIMZIA is administered by subcutaneous injection. Injection sites should be rotated and injections should not be given into areas where the skin is tender, bruised, red or hard. When a 400 mg dose is needed (given as two subcutaneous injections of 200 mg), injections should occur at separate sites in the thigh or abdomen. The solution should be carefully inspected visually for particulate matter and discoloration prior to administration. The solution should be a clear colorless to yellow liquid, essentially free from particulates and should not be used if cloudy or if foreign particulate matter is present. CIMZIA does not contain preservatives; therefore, unused portions of drug remaining in the syringe or vial should be discarded. CIMZIA is administered by subcutaneous injection. The initial dose of CIMZIA is 400 mg (given as two subcutaneous injections of 200 mg)(2). Crohn's Disease (2.1) 400 mg initially and at Weeks 2 and 4. If response occurs, follow with 400 mg every four weeks Rheumatoid Arthritis (2.2) 400 mg initially and at Weeks 2 and 4, followed by 200 mg every other week; for maintenance dosing, 400 mg every 4 weeks can be considered Psoriatic Arthritis (2.3) 400 mg initially and at week 2 and 4, followed by 200 mg every other week; for maintenance dosing, 400 mg every 4 weeks can be considered. Ankylosing Spondylitis (2.4) 400 mg (given as 2 subcutaneous injections of 200 mg each) initially and at weeks 2 and 4, followed by 200 mg every other week or 400 mg every 4 weeks. Plaque Psoriasis (2.5, 14.5) 400 mg (given as 2 subcutaneous injections of 200 mg each) every other week. For some patients (with body weight ≤ 90 kg), a dose of 400 mg (given as 2 subcutaneous injections of 200 mg each) initially and at Weeks 2 and 4, followed by 200 mg every other week may be considered. 2.1 Crohn's Disease The recommended initial adult dose of CIMZIA is 400 mg (given as two subcutaneous injections of 200 mg) initially, and at Weeks 2 and 4. In patients who obtain a clinical response, the recommended maintenance regimen is 400 mg every four weeks. 2.2 Rheumatoid Arthritis The recommended dose of CIMZIA for adult patients with rheumatoid arthritis is 400 mg (given as two subcutaneous injections of 200 mg) initially and at Weeks 2 and 4, followed by 200 mg every other week. For maintenance dosing, CIMZIA 400 mg every 4 weeks can be considered [see Clinical Studies (14.2)]. 2.3 Psoriatic Arthritis The recommended dose of CIMZIA for adult patients with psoriatic arthritis is 400 mg (given as 2 subcutaneous injections of 200 mg each) initially and at week 2 and 4, followed by 200 mg every other week. For maintenance dosing, CIMZIA 400 mg every 4 weeks can be considered [see Clinical Studies (14.3)]. 2.4 Ankylosing Spondylitis The recommended dose of CIMZIA for adult patients with ankylosing spondylitis is 400 mg (given as 2 subcutaneous injections of 200 mg each) initially and at weeks 2 and 4, followed by 200 mg every 2 weeks or 400 mg every 4 weeks. 2.5 Plaque Psoriasis The recommended dose of CIMZIA for adults with moderate-to-severe plaque psoriasis is 400 mg (given as 2 subcutaneous injections of 200 mg each) every other week. For some patients (with body weight ≤ 90 kg), CIMZIA 400 mg (given as 2 subcutaneous injections of 200 mg each) initially and at Weeks 2 and 4, followed by 200 mg every other week can be considered [see Clinical Studies (14.5)]. 2.6 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 Remove CIMZIA from the refrigerator and allow the vial(s) to sit at room temperature for 30 minutes before reconstituting. Do not warm the vial in any other way. Use appropriate aseptic technique when preparing and administering CIMZIA. Reconstitute the vial(s) of CIMZIA with 1 mL of Sterile Water for Injection, USP using the 20-gauge needle provided. The sterile water for injection should be directed at the vial wall rather than directly on CIMZIA. Gently swirl each vial of CIMZIA for about one minute without shaking, assuring that all of the powder comes in contact with the Sterile Water for Injection. The swirling should be as gentle as possible in order to avoid creating a foaming effect. Continue swirling every 5 minutes as long as non-dissolved particles are observed. Full reconstitution may take as long as 30 minutes. The final reconstituted solution contains 200 mg/mL and should be clear to opalescent, colorless to pale yellow liquid essentially free from particulates. Once reconstituted, CIMZIA can be stored in the vials for up to 24 hours between 2° to 8° C (36° to 46° F) prior to injection. Do not freeze. Administration Prior to injecting, reconstituted CIMZIA should be at room temperature but do not leave reconstituted CIMZIA at room temperature for more than two hours prior to administration. Withdraw the reconstituted solution into a separate syringe for each vial using a new 20-gauge needle for each vial so that each syringe contains 1 mL of CIMZIA (200 mg of certolizumab pegol). Replace the 20-gauge needle(s) on the syringes with a 23-gauge(s) for administration. Inject the full contents of the syringe(s) subcutaneously, by pinching the skin of the 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. 2.7 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 Instructions for Use booklet. The needle shield inside the removable cap of the CIMZIA prefilled syringe contains a derivative of natural rubber latex and should be handled with caution by latex-sensitive individuals [see Warnings and Precautions (5.4)]. 2.8 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. 2.9 Concomitant Medications CIMZIA may be used as monotherapy or concomitantly with non-biological disease modifying anti-rheumatic drugs (DMARDs). The use of CIMZIA in combination with biological DMARDs or other tumor necrosis factor (TNF) blocker therapy is not recommended.
Use in special populations
8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to CIMZIA during pregnancy. For more information, healthcare providers or patients can contact: MotherToBaby Pregnancy Studies conducted by the Organization of Teratology Information Specialists (OTIS). The OTIS AutoImmune Diseases Study at 1-877-311-8972 or visit http://mothertobaby.org/pregnancy-studies/ Risk Summary Limited data from the ongoing pregnancy registry on use of CIMZIA in pregnant women are not sufficient to inform a risk of major birth defects or other adverse pregnancy outcomes. However, certolizumab pegol plasma concentrations obtained from two studies of CIMZIA use during the third trimester of pregnancy demonstrated that placental transfer of certolizumab pegol was negligible in most infants at birth, and low in other infants at birth (see Data). There are risks to the mother and fetus associated with active rheumatoid arthritis or Crohn's disease. The theoretical risks of administration of live or live-attenuated vaccines to the infants exposed in utero to CIMZIA should be weighed against the benefits of vaccinations (see Clinical Considerations). No adverse developmental effects were observed in animal reproduction studies during which pregnant rats were administered intravenously a rodent anti-murine TNFα pegylated Fab' fragment (cTN3 PF) similar to certolizumab pegol during organogenesis at up to 2.4 times the recommended human dose of 400 mg every four weeks. The estimated background risk of major birth defects and miscarriage for the indicated population(s) are unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risks of major birth defects and miscarriage in clinically recognized pregnancies are 2 to 4% and 15 to 20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk Published data suggest that the risk of adverse pregnancy outcomes in women with rheumatoid arthritis or Crohn's disease is correlated with maternal disease activity and that active disease increases the risk of adverse pregnancy outcomes, including fetal loss, preterm delivery (before 37 weeks of gestation), low birth weight (less than 2500 g) and small for gestational age birth. Fetal/Neonatal Adverse Reactions Due to its inhibition of TNFα, CIMZIA administered during pregnancy could affect immune responses in the in utero-exposed newborn and infant. The clinical significance of BLQ or low levels is unknown for in utero-exposed infants. Additional data available from one exposed infant suggest that CIMZIA may be eliminated at a slower rate in infants than in adults (see Data). The safety of administering live or live-attenuated vaccines in exposed infants is unknown. Data Human Data A limited number of pregnancies have been reported in the ongoing pregnancy exposure registry. Due to the small number of CIMZIA-exposed pregnancies with known outcomes (n=54), no meaningful comparisons between the exposed group and control groups may be conducted to determine an association with CIMZIA and major birth defects or adverse pregnancy outcomes. A multicenter clinical study was conducted in 16 women treated with CIMZIA at a maintenance dose of 200 mg every 2 weeks or 400 mg every 4 weeks during the third trimester of pregnancy for rheumatological diseases or Crohn's disease. The last dose of CIMZIA was given on average 11 days prior to delivery (range 1 to 27 days). Certolizumab pegol plasma concentrations were measured in samples from mothers and infants using an assay that can measure certolizumab pegol concentrations at or above 0.032 mcg/mL. Certolizumab pegol plasma concentrations measured in the mothers at delivery (range: 4.96 to 49.4 mcg/mL) were consistent with non-pregnant women's plasma concentrations in Study RA-I [see Clinical Studies (14.2)]. Certolizumab pegol plasma concentrations were not measurable in 13 out of 15 infants at birth. The concentration of certolizumab pegol in one infant was 0.0422 mcg/mL at birth (infant/mother plasma ratio of 0.09%). In a second infant, delivered by emergency Caesarean section, the concentration was 0.485 mcg/mL (infant/mother plasma ratio of 4.49%). At Week 4 and Week 8, all 15 infants had no measurable concentrations. Among 16 exposed infants, one serious adverse reaction was reported in a neonate who was treated empirically with intravenous antibiotics due to an increased white blood cell count; blood cultures were negative. The certolizumab pegol plasma concentrations for this infant were not measurable at birth, Week 4, or Week 8. In another clinical study conducted in 10 pregnant women with Crohn´s disease treated with CIMZIA (400 mg every 4 weeks for every mother), certolizumab pegol concentrations were measured in maternal blood as well as in cord and infant blood at the day of birth with an assay that can measure concentrations at or above 0.41 mcg/mL. The last dose of CIMZIA was given on average 19 days prior to delivery (range 5 to 42 days). Plasma certolizumab pegol concentrations ranged from not measurable to 1.66 mcg/mL in cord blood and 1.58 mcg/mL in infant blood; and ranged from 1.87 to 59.57 mcg/mL in maternal blood. Plasma certolizumab pegol concentrations were lower (by at least 75%) in the infants than in mothers suggesting low placental transfer of certolizumab pegol. In one infant, the plasma certolizumab pegol concentration declined from 1.02 to 0.84 mcg/mL over 4 weeks suggesting that certolizumab pegol may be eliminated at a slower rate in infants than adults. Animal Data Because certolizumab pegol does not cross-react with mouse or rat TNFα, reproduction studies were performed in rats using a rodent anti-murine TNFα pegylated Fab' fragment (cTN3 PF) similar to certolizumab pegol. Animal reproduction studies have been performed in rats during organogenesis at intravenous doses up to 100 mg/kg (about 2.4 times the recommended human dose of 400 mg, based on the surface area) and have revealed no evidence of harm to the fetus due to cTN3 PF. 8.2 Lactation Risk Summary In a multicenter clinical study of 17 lactating women treated with CIMZIA at 200 mg every 2 weeks or 400 mg every 4 weeks, minimal certolizumab pegol concentrations were observed in breast milk. No serious adverse reactions were noted in the 17 infants in the study. There are no data on the effects on milk production. In a separate study, certolizumab pegol concentrations were not detected in the plasma of 9 breastfed infants at 4 weeks post-partum (see Data). The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for CIMZIA and any potential adverse effects on the breastfed infant from CIMZIA or from the underlying maternal condition. Data A multicenter clinical study designed to evaluate breast milk was conducted in 17 lactating women who were at least 6 weeks post-partum and had received at least 3 consecutive doses of CIMZIA 200 mg every 2 weeks or 400 mg every 4 weeks for rheumatological disease or Crohn's disease. The effects of certolizumab pegol on milk production were not studied. The concentration of certolizumab pegol in breast milk was not measurable in 77 (56 %) of the 137 samples taken over the dosing periods using an assay that can measure certolizumab pegol concentrations at or above 0.032 mcg/mL. The median of the estimated average daily infant doses was 0.0035 mg/kg/day (range: 0 to 0.01 mg/kg/day). The percentage of the maternal dose (200 mg CIMZIA dosed once every 2 weeks), that reaches an infant ranged from 0.56% to 4.25% based on samples with measurable certolizumab pegol concentration. No serious adverse reactions were noted in the 17 breastfed infants in the study. In a separate study, plasma certolizumab pegol concentrations were collected 4 weeks after birth in 9 breastfed infants whose mothers had been currently taking CIMZIA (regardless of being exclusively breastfed or not). Certolizumab pegol in infant plasma was not measurable i.e., below 0.032 mcg/mL. 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 [see Use in Specific Populations (8.1)]. 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)].

Interactions

7 DRUG INTERACTIONS Use with Biological DMARDs – increased risk of serious infections (5.8, 7.1) Live vaccines – avoid use with CIMZIA (5.10, 7.2) Laboratory tests – may interfere with aPTT tests (7.3) 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 Avoid use of 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.

More information

Category Value
Authorisation number BLA125160
Agency product number UMD07X179E
Orphan designation No
Product NDC 50474-700,50474-710
Date Last Revised 30-05-2018
Type HUMAN PRESCRIPTION DRUG
Storage and handling Storage and Stability Refrigerate carton between 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.
Marketing authorisation holder UCB, Inc.
Warnings WARNING: SERIOUS INFECTIONS AND MALIGNANCY SERIOUS INFECTIONS Patients treated with CIMZIA are at increased risk for developing serious infections that may lead to hospitalization or death [see Warnings and Precautions (5.1) and Adverse Reactions (6.1)]. Most patients who developed these infections were taking concomitant immunosuppressants such as methotrexate or corticosteroids. CIMZIA should be discontinued if a patient develops a serious infection or sepsis. Reported infections include: Active tuberculosis, including reactivation of latent tuberculosis. Patients with tuberculosis have frequently presented with disseminated or extrapulmonary disease. Patients should be tested for latent tuberculosis before CIMZIA use and during therapy. Treatment for latent infection should be initiated prior to CIMZIA use. Invasive fungal infections, including histoplasmosis, coccidioidomycosis, candidiasis, aspergillosis, blastomycosis, and pneumocystosis. Patients with histoplasmosis or other invasive fungal infections may present with disseminated, rather than localized disease. Antigen and antibody testing for histoplasmosis may be negative in some patients with active infection. Empiric anti-fungal therapy should be considered in patients at risk for invasive fungal infections who develop severe systemic illness. Bacterial, viral and other infections due to opportunistic pathogens, including Legionella and Listeria. The risks and benefits of treatment with CIMZIA should be carefully considered prior to initiating therapy in patients with chronic or recurrent infection. Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with CIMZIA, including the possible development of tuberculosis in patients who tested negative for latent tuberculosis infection prior to initiating therapy. [see Warnings and Precautions (5.1) and Adverse Reactions (6.1)]. MALIGNANCY Lymphoma and other malignancies, some fatal, have been reported in children and adolescent patients treated with TNF blockers, of which CIMZIA is a member [see Warnings and Precautions (5.2)]. CIMZIA is not indicated for use in pediatric patients. WARNING: SERIOUS INFECTIONS AND MALIGNANCY See full prescribing information for complete boxed warning. Increased risk of serious infections leading to hospitalization or death including tuberculosis (TB), bacterial sepsis, invasive fungal infections (such as histoplasmosis), and infections due to other opportunistic pathogens (5.1). CIMZIA should be discontinued if a patient develops a serious infection or sepsis (5.1). Perform test for latent TB; if positive, start treatment for TB prior to starting CIMZIA (5.1). Monitor all patients for active TB during treatment, even if initial latent TB test is negative (5.1) Lymphoma and other malignancies, some fatal, have been reported in children and adolescent patients treated with TNF blockers, of which CIMZIA is a member (5.2). CIMZIA is not indicated for use in pediatric patients. (8.4)