Drug Safety-related Labeling Changes (SrLC)

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CIMZIA (BLA-125160)

(CERTOLIZUMAB PEGOL)

Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)

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12/22/2022 (SUPPL-305)

Approved Drug Label (PDF)

6 Adverse Reactions

Additions and revisions underlined:

The most serious adverse reactions were:

• Serious Infections [see Warnings and Precautions (5.1)]

• Malignancies [see Warnings and Precautions (5.2)]

• Heart Failure [see Warnings and Precautions (5.3)]

• Hypersensitivity Reactions [see Warnings and Precautions (5.4)]

• Hepatitis B Virus Reactivation [see Warnings and Precautions (5.5)]

• Neurologic Reactions [see Warnings and Precautions (5.6)]

• Hematologic Reactions [see Warnings and Precautions (5.7)]

• Autoimmunity [see Warnings and Precautions (5.9)]

• Immunosuppression [see Warnings and Precautions (5.11)]

8 Use in Specific Populations

8.4 Pediatric Use

Additions and revisions underlined:

Safety and effectiveness in pediatric patients have not been established.

CIMZIA was evaluated for the treatment of pediatric patients with moderately to severely active Crohn’s disease. Efficacy was not demonstrated in an open-label, randomized, parallel-group, multiple dose study for a period of up to 62 weeks in 99 subjects aged 6 to 17 years. The study was ended prematurely because of a high number of patient discontinuations.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

Patient Counseling Information

Additions and revisions underlined:

Advise the patient to read the FDA-approved patient labeling (Medication Guide and Instructions for Use)

09/06/2019 (SUPPL-293)

Approved Drug Label (PDF)

6 Adverse Reactions

6.3 Postmarketing Experience

(Additions and/or revisions are underlined)

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, new or worsening psoriasis (all sub-types including pustular and palmoplantar), and lichenoid skin reaction have been identified during post-approval use of TNF blockers.

03/28/2019 (SUPPL-237)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience

Following Ankylosing Spondylitis Clinical Study, newly added information:

Non-radiographic Axial Spondyloarthritis Clinical Study

CIMZIA has been studied in 317 patients with non-radiographic axial Spondyloarthritis (nr-axSpA-1). The safety profile for patients with nr-axSpA treated with CIMZIA was similar to the safety profile seen in patients with RA and previous experience with CIMZIA.

6.2 Immunogenicity

Additions and/or revisions underlined:

A more sensitive and drug tolerant electrochemiluminescence (ECL)-based bridging assay was used for the first time in the nr-axSpA-1 study, resulting in a greater proportion of samples having measurable antibodies to certolizumab pegol and thus a greater incidence of patients being classed as antibody positive. In the placebo-controlled trial in patients with non-radiographic axial Spondyloarthritis, after up to 52 weeks of treatment, the overall incidence of patients who were antibody positive to certolizumab pegol was 97% (248/255 patients). Of these antibody positive patients, higher titers were associated with reduced certolizumab pegol plasma levels.

The data above reflect the percentage of patients whose test results were considered positive for antibodies to certolizumab pegol in an ELISA or ECL-based bridging assay, and are highly dependent …

02/27/2019 (SUPPL-289)

Approved Drug Label (PDF)

5 Warnings and Precautions

Additions and/or revisions underlined:

5.2 Malignancies

… Melanoma and Merkel cell carcinoma have been reported in patients treated with TNF blockers, including CIMZIA.

5.4 Hypersensitivity Reactions

Newly added information:

The needle shield inside the removable cap of the CIMZIA prefilled syringe contains a derivative of natural rubber latex which may cause an allergic reaction in individuals sensitive to latex.

6 Adverse Reactions

6.1 Clinical Trials Experience

Additions and/or revisions underlined:

Adverse Reactions of Special Interest Across Indications

Newly added information:

Hypersensitivity Reactions

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

6.2 Immunogenicity

Newly added information:

As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including 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 in the studies described below with the incidence of antibodies in other studies or to other products may be misleading.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

Risk of Serious Infections

Inform patients … including tuberculosis and reactivation of hepatitis B virus infections.

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.

Malignancies

Counsel patients about the possible …

Hypersensitivity Reactions

Advise patients to seek immediate medical attention if they experience any symptoms of severe hypersensitivity reactions. Advise latex-sensitive patients that the needle shield inside the removable cap of the CIMZIA prefilled syringe contains a derivative of natural rubber latex.

Preparation and Administration of CIMZIA Using the Prefilled Syringe

Instruct patients and caregivers on how to inject the Prefilled Syringe. Complete instructions are provided in the Instructions for Use packaged in each CIMZIA Prefilled Syringe kit.

• If refrigerated, remove the prefilled syringe from the carton and let it warm to room temperature.

• Inspect the liquid in the prefilled syringe. It should be clear and colorless to yellow and free from particulates. Discard the syringe if cloudy, discolored or contains particulates.

• Suitable sites for injection include the thigh or abdomen. Inject at least 1 inch from the previous site.

• Do not inject into areas where the skin is tender, bruised, red or hard, or where there are scars or stretch marks.

05/25/2018 (SUPPL-283)

Approved Drug Label (PDF)

4 Contraindications

(Additions and/or revisions are underlined)

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 urticarial.

5 Warnings and Precautions

5.2 Malignancies

(Additions and/or revisions are underlined)

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. During CIMZIA studies of psoriasis, malignancies (excluding non-melanoma skin cancer) were observed corresponding to an incidence rate of 0.5 (0.2, 1.0) per 100 subject-years among a total of 995 subjects who received CIMZIA…

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. In the CIMZIA PsO clinical trials (placebo-controlled and open label) there was one case of Hodgkin’s lymphoma.

5.4 Hypersensitivity Reactions

(Additions and/or revisions are underlined)

The following symptoms that could be compatible with hypersensitivity reactions have been reported rarely following CIMZIA administration to patients: angioedema, anaphylactoid reaction…

6 Adverse Reactions

6.1 Clinical Trials Experience

(Additions and/or revisions are underlined)

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.

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 greater than or equal to 5 x 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

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

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.

6.2 Immunogenicity

(Additions and/or revisions are underlined)

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.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

Medication Guide CIMZIA® (CIM-zee-uh) (certolizumab pegol) lyophilized powder or solution for subcutaneous use

(Extensive changes; please refer to labeling)

03/20/2018 (SUPPL-281)

Approved Drug Label (PDF)

8 Use in Specific Populations

8.1 Pregnancy

(additions underlined)

…

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).

…

Fetal/Neonatal Adverse Reactions

Due to its inhibition of TNF?, 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 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. 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 <0.41 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.

…

8.2 Lactation

(additions underlined)

Risk Summary

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

In 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.

01/04/2017 (SUPPL-270)

Approved Drug Label (PDF)

8 Use in Specific Populations

8.1 Pregnancy

Extensive changes; please refer to label.

8.2 Lactation

PLLR conversion:

Risk Summary

No data are available regarding the presence of certolizumab pegol in human milk, the effects on the

breast fed infant, or the effects on milk production. Published data suggest that the systemic exposure to a breastfed infant is expected to be low because certolizumab pegol is a large molecule and is degraded in the gastrointestinal tract. However, if certolizumab pegol is transferred into human milk, effects of local exposure in the gastrointestinal tract are unknown.he 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 child from CIMZIA or from the underlying maternal condition.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT COUNSELING INFORMATION

Addition of the following subsection:

17.2   Pregnancy

Advise patients that there is a pregnancy registry that monitors pregnancy outcomes in women exposed to

CIMZIA during pregnancy, patients can call 1-877-311-8972.

04/28/2016 (SUPPL-241)

Approved Drug Label (PDF)

5 Warnings and Precautions

Malignancies

Melanoma and Merkel cell carcinoma have been reported in patients treated with TNF-antagonists, including CIMZIA. Periodic skin examinations are recommended for all patients, particularly those with risk factors for skin cancer.

6 Adverse Reactions

Postmarketing Experience

Neoplasms benign, malignant and unspecified (including cysts and polyps): Melanoma, Merkel cell carcinoma (neuroendocrine carcinoma of the skin)

02/03/2016 (SUPPL-268)

Approved Drug Label (PDF)

5 Warnings and Precautions

Risk of Serious Infections

Tuberculosis

• Treatment of latent tuberculosis infection prior to therapy with TNF-blocking agents has been shown to reduce the risk of tuberculosis reactivation during therapy. Prior to initiating CIMZIA, assess if treatment for latent tuberculosis is needed; and consider an induration of 5 mm or greater a positive tuberculin skin test result, even for patients previously vaccinated with Bacille Calmette-Guerin (BCG). Consider anti-tuberculosis therapy 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. Despite previous or concomitant treatment for latent tuberculosis, cases of active tuberculosis have occurred in patients treated with CIMZIA. Some patients who have been successfully treated for active tuberculosis have redeveloped tuberculosis while being treated with CIMZIA. 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.
• 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-tuberculos Botox Cosmetic (onabotulinumtoxinA)

6 Adverse Reactions

Post-marketing Experience

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