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Certolizumab Pegol

Pronunciation

(cer to LIZ u mab PEG ol)

Index Terms

  • CDP870

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Kit, Subcutaneous [preservative free]:

Cimzia: 200 mg

Cimzia Prefilled: 200 mg/mL

Cimzia Starter Kit: 6 X 200 mg/mL

Brand Names: U.S.

  • Cimzia
  • Cimzia Prefilled
  • Cimzia Starter Kit

Pharmacologic Category

  • Antirheumatic, Disease Modifying
  • Gastrointestinal Agent, Miscellaneous
  • Tumor Necrosis Factor (TNF) Blocking Agent

Pharmacology

Certolizumab pegol is a pegylated humanized antibody Fab’ fragment of tumor necrosis factor alpha (TNF-alpha) monoclonal antibody. Certolizumab pegol binds to and selectively neutralizes human TNF-alpha activity. (Elevated levels of TNF-alpha have a role in the inflammatory process associated with Crohn disease and in joint destruction associated with rheumatoid arthritis.) Since it is not a complete antibody (lacks Fc region), it does not induce complement activation, antibody-dependent cell-mediated cytotoxicity, or apoptosis. Pegylation of certolizumab allows for delayed elimination and therefore an extended half-life.

Distribution

Vss: 6 to 8 L

Time to Peak

Plasma: 54 to 171 hours

Half-Life Elimination

~14 days

Special Populations Note

Body weight: Pharmacokinetic exposure is inversely related to body weight; however, no therapeutic benefit is expected from a weight-adjusted dose regimen.

Use: Labeled Indications

Ankylosing spondylitis: Treatment of adults with active ankylosing spondylitis (AS)

Crohn disease: Treatment of moderately to severely active Crohn disease in patients who have inadequate response to conventional therapy

Psoriatic arthritis: Treatment of adult patients with active psoriatic arthritis

Rheumatoid arthritis: Treatment of adults with moderately to severely active rheumatoid arthritis (RA) (as monotherapy or in combination with nonbiological disease-modifying antirheumatic drugs [DMARDS])

Contraindications

There are no contraindications listed within the manufacturer’s US labeling.

Canadian labeling: Hypersensitivity to certolizumab pegol or any component of the formulation; active tuberculosis or other severe infections (eg, sepsis, abscesses, opportunistic infections); moderate to severe heart failure (NYHA Class III/IV)

Dosing: Adult

Note: Each 400 mg dose should be administered as 2 injections of 200 mg each

Ankylosing spondylitis: SubQ: Initial: 400 mg, repeat dose 2 and 4 weeks after initial dose; Maintenance: 200 mg every 2 weeks or 400 mg every 4 weeks

Crohn disease: SubQ: Initial: 400 mg, repeat dose 2 and 4 weeks after initial dose; Maintenance: 400 mg every 4 weeks

Psoriatic arthritis: SubQ: Initial: 400 mg, repeat dose 2 and 4 weeks after initial dose; Maintenance: 200 mg every other week. May consider maintenance dose of 400 mg every 4 weeks.

Rheumatoid arthritis: SubQ: Initial: 400 mg, repeat dose 2 and 4 weeks after initial dose; Maintenance: 200 mg every other week. May consider maintenance dose of 400 mg every 4 weeks. May be administered alone or in combination with methotrexate.

Missed doses: Canadian labeling: Wait until the next scheduled dose if within 1 week; if the next scheduled dose is ≥1 week, administer as soon as possible then follow with next scheduled dose.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Renal Impairment

There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied); pharmacokinetics of the pegylated (polyethylene glycol) component of certolizumab pegol is expected to be dependent on renal function.

Dosing: Hepatic Impairment

There are no dosage adjustments provided in the manufacturer’s labeling.

Dosing: Adjustment for Toxicity

Hypersensitivity, lupus-like syndrome, serious infection, sepsis, or hepatitis B reactivation: Discontinue treatment.

Reconstitution

Vials: Allow to sit at room temperature for 30 minutes prior to reconstitution; do not warm vial in any other way. Reconstitute each vial with 1 mL sterile water for injection (provided) to a concentration of 200 mg/mL; the manufacturer recommends using a 20-gauge needle (provided). Direct sterile water for injection at the vial wall and gently swirl (avoid foaming) for about one minute to facilitate wetting of powder; do not shake. Continue swirling every 5 minutes until fully reconstituted (may take up to 30 minutes).

Administration

SubQ: Bring to room temperature prior to administration. After reconstitution (of vials), draw each vial into separate syringes (using 20-gauge needles).

Administer subcutaneously (using provided 23-gauge needle) into the abdomen or thigh. For a 400 mg (2 syringes) dose, administer each 200 mg syringe at a separate site; rotate injection sites. Do not administer to areas where skin is tender, bruised, red, or hard.

Storage

Store intact vials and syringes at 2°C to 8°C (36°F to 46°F); do not freeze. Do not separate contents of carton prior to use. Protect from light. Bring to room temperature prior to administration.

Reconstituted vials may be retained at room temperature for up to 2 hours or refrigerated (do not freeze) for up to 24 hours prior to administration. Discard unused portion of vial or syringe.

Drug Interactions

Abatacept: Anti-TNF Agents may enhance the adverse/toxic effect of Abatacept. An increased risk of serious infection during concomitant use has been reported. Avoid combination

Anakinra: Anti-TNF Agents may enhance the adverse/toxic effect of Anakinra. An increased risk of serious infection during concomitant use has been reported. Avoid combination

Anti-TNF Agents: May enhance the immunosuppressive effect of Certolizumab Pegol. Avoid combination

BCG (Intravesical): Immunosuppressants may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

Canakinumab: Anti-TNF Agents may enhance the adverse/toxic effect of Canakinumab. Specifically, the risk for serious infections and/or neutropenia may be increased. Avoid combination

Coccidioides immitis Skin Test: Immunosuppressants may diminish the diagnostic effect of Coccidioides immitis Skin Test. Monitor therapy

Denosumab: May enhance the adverse/toxic effect of Immunosuppressants. Specifically, the risk for serious infections may be increased. Monitor therapy

Echinacea: May diminish the therapeutic effect of Immunosuppressants. Consider therapy modification

Fingolimod: Immunosuppressants may enhance the immunosuppressive effect of Fingolimod. Management: Avoid the concomitant use of fingolimod and other immunosuppressants when possible. If combined, monitor patients closely for additive immunosuppressant effects (eg, infections). Consider therapy modification

Leflunomide: Immunosuppressants may enhance the adverse/toxic effect of Leflunomide. Specifically, the risk for hematologic toxicity such as pancytopenia, agranulocytosis, and/or thrombocytopenia may be increased. Management: Consider not using a leflunomide loading dose in patients receiving other immunosuppressants. Patients receiving both leflunomide and another immunosuppressant should be monitored for bone marrow suppression at least monthly. Consider therapy modification

Natalizumab: Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased. Avoid combination

Nivolumab: Immunosuppressants may diminish the therapeutic effect of Nivolumab. Consider therapy modification

Pegloticase: May diminish the therapeutic effect of Certolizumab Pegol. Monitor therapy

Pimecrolimus: May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Rilonacept: Anti-TNF Agents may enhance the adverse/toxic effect of Rilonacept. Avoid combination

RiTUXimab: May enhance the immunosuppressive effect of Certolizumab Pegol. Avoid combination

Roflumilast: May enhance the immunosuppressive effect of Immunosuppressants. Consider therapy modification

Sipuleucel-T: Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Monitor therapy

Tacrolimus (Topical): May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Tocilizumab: May enhance the immunosuppressive effect of Anti-TNF Agents. Avoid combination

Tofacitinib: Anti-TNF Agents may enhance the adverse/toxic effect of Tofacitinib. Avoid combination

Tofacitinib: Immunosuppressants may enhance the immunosuppressive effect of Tofacitinib. Management: Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted, and this warning seems particularly focused on more potent immunosuppressants. Avoid combination

Trastuzumab: May enhance the neutropenic effect of Immunosuppressants. Monitor therapy

Vaccines (Inactivated): Immunosuppressants may diminish the therapeutic effect of Vaccines (Inactivated). Management: Vaccine efficacy may be reduced. Complete all age-appropriate vaccinations at least 2 weeks prior to starting an immunosuppressant. If vaccinated during immunosuppressant therapy, revaccinate at least 3 months after immunosuppressant discontinuation. Consider therapy modification

Vaccines (Live): Immunosuppressants may enhance the adverse/toxic effect of Vaccines (Live). Immunosuppressants may diminish the therapeutic effect of Vaccines (Live). Management: Avoid use of live organism vaccines with immunosuppressants; live-attenuated vaccines should not be given for at least 3 months after immunosuppressants. Avoid combination

Vedolizumab: Anti-TNF Agents may enhance the adverse/toxic effect of Vedolizumab. Avoid combination

Test Interactions

Tests for latent tuberculosis may be falsely negative while on certolizumab pegol treatment. Falsely elevated aPTT assays have been reported with PTT-Lupus Anticoagulant (LA) and Standard Target Activated Partial Thromboplastin time (STA-PTT) tests from Diagnostica Stago, and with HemosiL APTT-SP liquid and HemosiL lyophilized silica tests from Instrumentation Laboratories.

Adverse Reactions

>10%:

Gastrointestinal: Nausea (≤11% [Schreiber 2005])

Immunologic: Antibody development (7% to 23%)

Infection: Infection (38%; serious: 3%)

Respiratory: Upper respiratory tract infection (6% to 20%)

1% to 10%:

Cardiovascular: Hypertension (≤5%), angina pectoris (<5%), atrial fibrillation (<5%), cardiac arrhythmia (<5%), cardiac failure (<5%; new or worsening), cerebrovascular accident (<5%), hypertensive heart disease (<5%), ischemic heart disease (<5%), myocardial infarction (<5%), pericardial effusion (<5%), pericarditis (<5%), transient ischemic attacks (<5%), vasculitis (<5%)

Central nervous system: Headache (5%), anxiety (<5%), bipolar mood disorder (<5%), suicidal tendencies (<5%), fatigue (≤3%)

Dermatologic: Skin rash (≤9%), alopecia (<5%), dermatitis (<5%), erythema nodosum (<5%), urticaria (<5%)

Endocrine & metabolic: Menstrual disease (<5%)

Genitourinary: Urinary tract infection (≤8%), nephrotic syndrome (<5%)

Hematologic & oncologic: Anemia (<5%), hemorrhage (<5%), hypercoagulability state (<5%), leukopenia (<5%), lymphadenopathy (<5%), pancytopenia (<5%), thrombophlebitis (<5%), positive ANA titer (≤4%)

Hepatic: Hepatitis (<5%), increased serum transaminases (<5%)

Neuromuscular & skeletal: Arthralgia (6% to 7%), back pain (≤4%)

Ophthalmic: Optic neuritis (<5%), retinal hemorrhage (<5%), uveitis (<5%)

Renal: Renal failure (<5%)

Respiratory: Cough (≤6%), nasopharyngitis (5%), tuberculosis (<5%; peritoneal, pulmonary, and disseminated), bronchitis (≤3%), pharyngitis (≤3%)

Miscellaneous: Fever (3%)

<1% (Limited to important or life-threatening): Aplastic anemia, cytopenia, demyelinating disease (exacerbation), fistula, hepatosplenic T-cell lymphoma, hepatotoxicity (idiosyncratic) (Chalasani 2014), herpes virus infection, hypersensitivity reaction (eg, dyspnea, hot flush, hypotension, malaise, serum sickness, syncope), intestinal obstruction, leukemia, lupus erythematosus, lupus-like syndrome, lymphoma, malignant melanoma, malignant neoplasm, Merkel cell carcinoma, neoplasm (benign, malignant, and unspecified; including cysts and polyps), opportunistic infection (rare), peripheral edema, peripheral neuropathy, pneumonia, psoriasis (including new onset, palmoplantar, pustular, or exacerbation), pyelonephritis, reactivation of HBV, sarcoidosis, seizure, thrombocytopenia, viral infection

ALERT: U.S. Boxed Warning

Serious infections:

Patients treated with certolizumab are at an increased risk for developing serious infections that may lead to hospitalization or death. Most patients who developed these infections were taking concomitant immunosuppressants, such as methotrexate or corticosteroids.

Certolizumab should be discontinued if a patient develops a serious infection or sepsis.

Reported infections include the following:

Active tuberculosis (TB), including reactivation of latent TB. Patients with TB have frequently presented with disseminated or extrapulmonary disease. Patients should be tested for latent TB before certolizumab use and during therapy. Treatment for latent infections should be initiated prior to certolizumab 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 antifungal therapy should be considered in patients at risk for invasive fungal infections who develop severe systemic illness.

Bacterial, viral, and other infections caused by opportunistic pathogens, including Legionella and Listeria.

The risks and benefits of treatment with certolizumab 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 certolizumab, including the possible development of TB in patients who tested negative for latent TB infection prior to initiating therapy.

Malignancy:

Lymphoma and other malignancies, some fatal, have been reported in children and adolescent patients treated with tumor necrosis factor (TNF) blockers. Certolizumab is not indicated for use in pediatric patients.

Warnings/Precautions

Concerns related to adverse effects:

• Autoimmune disorder: Autoantibody formation may develop; rarely resulting in autoimmune disorder, including lupus-like syndrome; monitor and discontinue if symptoms develop.

• Demyelinating CNS disease: Rare cases of optic neuritis, seizure, peripheral neuropathy, and demyelinating disease (eg, multiple sclerosis, Guillain-Barré syndrome; new onset or exacerbation) have been reported. Use with caution in patients with preexisting or recent-onset CNS demyelinating disorders.

• Hematologic effects: Rare cases of pancytopenia and other significant cytopenias, including aplastic anemia, have been reported with TNF-blocking agents. Leukopenia and thrombocytopenia have occurred with certolizumab. Consider discontinuing therapy with significant hematologic abnormalities. Use with caution in patients with underlying hematologic disorders.

• Hepatitis B: Rare reactivation of hepatitis B virus (HBV) has occurred in chronic carriers of the virus, usually in patients receiving concomitant immunosuppressants; evaluate for HBV prior to initiation in all patients. Patients who test positive for HBV surface antigen should be referred for hepatitis B evaluation/treatment prior to certolizumab initiation. Monitor for clinical and laboratory signs of active infection during and for several months following discontinuation of treatment in HBV carriers; interrupt therapy if reactivation occurs and treat appropriately with antiviral therapy; if resumption of therapy is deemed necessary, exercise caution and monitor patient closely.

• Hypersensitivity: Hypersensitivity reactions, including angioedema, dyspnea, hypotension, rash, serum sickness and urticaria have been reported (rarely) with treatment. Some of these reactions have occurred after the first dose. Discontinue and do not resume therapy if hypersensitivity occurs. Use with caution in patients who have experienced hypersensitivity with other TNF blockers.

• Immunogenicity: A small number of patients (8%) develop antibodies to certolizumab during therapy. Antibody-positive patients may have an increased incidence of adverse events (including injection site pain/erythema, abdominal pain, and erythema nodosum).

• Infections: [US Boxed Warning]: Patients receiving certolizumab are at increased risk for serious infections which may result in hospitalization and/or fatality; infections usually developed in patients receiving concomitant immunosuppressive agents (eg, methotrexate or corticosteroids) and may present as disseminated (rather than local) disease. Active tuberculosis (or reactivation of latent tuberculosis), invasive fungal (including aspergillosis, blastomycosis, candidiasis, coccidioidomycosis, histoplasmosis, and pneumocystosis) and bacterial, viral or other opportunistic infections (including legionellosis and listeriosis) have been reported in patients receiving TNF-blocking agents, including certolizumab. Monitor closely for signs/symptoms of infection. Discontinue for serious infection or sepsis. Consider risks versus benefits prior to use in patients with a history of chronic or recurrent infection. Consider empiric antifungal therapy in patients who are at risk for invasive fungal infection and develop severe systemic illness. Caution should be exercised when considering use in the elderly or in patients with conditions that predispose them to infections (eg, diabetes) or residence/travel from areas of endemic mycoses (blastomycosis, coccidioidomycosis, histoplasmosis), or with latent or localized infections. Do not initiate certolizumab therapy with active infection, including clinically important localized infection. Patients who develop a new infection while undergoing treatment should be monitored closely.

• Malignancy: [US Boxed Warning]: Lymphoma and other malignancies (some fatal) have been reported in children and adolescent patients receiving TNF-blocking agents. Approximately half of the malignancies reported in children were lymphomas (Hodgkin and non-Hodgkin) while other cases varied and included malignancies not typically observed in this population. The onset of malignancy was after a median of 30 months (range: 1-84 months) after the initiation of the TNF-blocking agent. Use of TNF blockers may affect defenses against malignancies; impact on the development and course of malignancies is not fully defined. Chronic immunosuppressant therapy use may be a predisposing factor for malignancy development; rheumatoid arthritis alone has been previously associated with an increased rate of lymphoma. Hepatosplenic T-cell lymphoma (HSTCL), a rare T-cell lymphoma, has also been associated with TNF-blocking agents, including certolizumab, primarily reported in adolescent and young adult males with Crohn disease or ulcerative colitis, most of whom had received concurrent treatment with azathioprine and/or 6-mercaptopurine. Melanoma and Merkel cell carcinoma have been reported with TNF-blocking agents including certolizumab. Perform periodic skin examinations in all patients during therapy, particularly those at increased risk for skin cancer.

• Tuberculosis: [US Boxed Warning]: Tuberculosis (disseminated or extrapulmonary disease) has been reported in patients receiving certolizumab; both reactivation of latent infection and new infections have been reported. Patients should be tested for latent tuberculosis infection before and during therapy; consider treatment of latent tuberculosis prior to certolizumab treatment. Monitor for development of tuberculosis throughout treatment in patients with initial negative skin tests, patients currently receiving treatment for latent tuberculosis, or patients previously treated for tuberculosis; active tuberculosis has developed in this population during treatment with TNF-blocking agents. Use with caution in patients who have resided in regions where tuberculosis is endemic. Consider antituberculosis treatment (prior to certolizumab treatment) in patients with a history of latent or active tuberculosis if adequate treatment course cannot be confirmed, and for patients with risk factors for tuberculosis despite a negative test. Carefully consider benefits and risks of initiating certolizumab treatment in patients who have been exposed to tuberculosis.

Disease-related concerns:

• Heart failure: Use with caution in heart failure patients; worsening heart failure and new-onset heart failure have been reported with TNF blockers, including certolizumab pegol; monitor closely. The Canadian labeling contraindicates use in moderate to severe heart failure (NYHA Class III/IV).

• Renal impairment: Use has not been studied in patients with renal impairment; however, the pharmacokinetics of the pegylated (polyethylene glycol) component may be dependent on renal function.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special populations:

• Elderly: Use with caution in elderly patients, may be at higher risk for infections.

• Pediatric: Malignancies have been reported among children and adolescents receiving TNF-blocking agents.

Other warnings/precautions:

• Immunizations: Patients should be up to date with all immunizations before initiating therapy; patients may receive vaccines other than live or live attenuated vaccines during therapy. There is no data available concerning the effects of therapy on vaccination or secondary transmission of live vaccines in patients receiving therapy.

Monitoring Parameters

Monitor improvement of symptoms and physical function assessments. Latent TB screening prior to initiating and during therapy; signs/symptoms of infection (prior to, during, and following therapy); CBC with differential; signs/symptoms/worsening of heart failure; HBV screening prior to initiating (all patients), HBV carriers (during and for several months following therapy); signs and symptoms of hypersensitivity reaction; symptoms of lupus-like syndrome; signs/symptoms of malignancy (eg, splenomegaly, hepatomegaly, abdominal pain, persistent fever, night sweats, weight loss) including periodic skin examinations.

Pregnancy Risk Factor

B

Pregnancy Considerations

Adverse effects were not observed in animal reproduction studies. Certolizumab pegol was found to cross the human placenta. Serum concentrations in 12 infants of 10 mothers were ≥75% lower than the maternal serum at delivery (last maternal dose of 400 mg given 5-42 days prior to birth). Although placental transfer was low, infants may have a slower rate of elimination than adults. In one infant, certolizumab pegol serum concentrations decreased from 1.02 to 0.84 mcg/mL over 4 weeks. Adverse events were not reported. The safety of administering live or live-attenuated vaccines to exposed infants is not known. If a biologic agent such as certolizumab pegol is needed to treat inflammatory bowel disease during pregnancy, it is recommended to hold therapy after 30 weeks gestation (Habal, 2012).

Healthcare providers are encouraged to enroll women exposed to certolizumab pegol during pregnancy in the MotherToBaby Autoimmune Diseases Study by contacting the Organization of Teratology Information Specialists (OTIS) (877-311-8972). The Canadian labeling recommends that women of childbearing potential use reliable contraception during therapy and for at least 5 months after the last dose of certolizumab.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Have patient report immediately to prescriber signs of infection, signs of liver problems (dark urine, feeling tired, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin or eyes), signs of depression (ie, suicidal ideation, anxiety, emotional instability, illogical thinking), signs of lupus (rash on the cheeks or other body parts, sunburn easy, muscle or joint pain, chest pain or shortness of breath, or swelling in the arms or legs), signs of severe cerebrovascular disease (change in strength on one side is greater than the other, trouble speaking or thinking, change in balance, or change in eyesight), angina, arrhythmia, severe dizziness, passing out, severe headache, vision changes, bruising, bleeding, excessive weight gain or loss, night sweats, severe injection site irritation, burning or numbness feeling, shortness of breath, swelling of arm or leg, seizures, enlarged lymph nodes, loss of strength and energy, pale skin, urinary retention, or change in amount of urine passed (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

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