Cimzia Information
Cimzia (Certolizumab) Dosage And Administration
Cimzia (Certolizumab) 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 (Certolizumab) does not contain preservatives; therefore, unused portions of drug remaining in the syringe or vial should be discarded.
Cimzia (Certolizumab) Contraindications
Cimzia (Certolizumab) Warnings And Precautions
(see also )
Patients treated with Cimzia (Certolizumab) are at an increased risk for developing serious infections involving various organ systems and sites that may lead to hospitalization or death.
Opportunistic infections due to bacterial, mycobacterial, invasive fungal, viral, parasitic, or other opportunistic pathogens including aspergillosis, blastomycosis, candidiasis, coccidioidomycosis, histoplasmosis, legionellosis, listeriosis, pneumocystosis and tuberculosis have been reported with TNF blockers. Patients have frequently presented with disseminated rather than localized disease.
Treatment with Cimzia (Certolizumab) should not be initiated in patients with an active infection, including clinically important localized infections. Patients greater than 65 years of age, patients with co-morbid conditions, and/or patients taking concomitant immunosuppressants (e.g. corticosteroids or methotrexate) may be at a greater risk of infection. The risks and benefits of treatment should be considered prior to initiating therapy in patients:
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 (Certolizumab) 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 (Certolizumab) -treated patients versus a rate of 0.6 (0.1, 1.7) per 100 patient-years among 1,319 placebo-treated patients. The size of the control group and limited duration of the controlled portions of the studies precludes the ability to draw firm conclusions.
Malignancies, some fatal, have been reported among children, adolescents, and young adults who received treatment with TNF-blocking agents (initiation of therapy ≤ 18 years of age), of which Cimzia (Certolizumab) is a member. Approximately half the cases were lymphomas, including Hodgkin's and non-Hodgkin's lymphoma. The other cases represented a variety of different malignancies and included rare malignancies usually associated with immunosuppression and malignancies that are not usually observed in children and adolescents. The malignancies occurred after a median of 30 months of therapy (range 1 to 84 months). Most of the patients were receiving concomitant immunosuppressants. These cases were reported post-marketing and are derived from a variety of sources including registries and spontaneous post-marketing reports.
In the controlled portions of clinical trials of all the TNF blockers, more cases of lymphoma have been observed among patients receiving TNF blockers compared to control patients. In controlled studies of Cimzia (Certolizumab) for Crohn's disease and other investigational uses, there was one case of lymphoma among 2,657 Cimzia (Certolizumab) -treated patients and one case of Hodgkin's lymphoma among 1,319 placebo-treated patients.
In the Cimzia (Certolizumab) RA clinical trials (placebo-controlled and open label) a total of three cases of lymphoma were observed among 2,367 patients. This is approximately 2-fold higher than expected in the general population. Patients with RA, particularly those with highly active disease, are at a higher risk for the development of lymphoma.
Rates in clinical studies for Cimzia (Certolizumab) cannot be compared to the rates of clinical trials of other TNF blockers and may not predict the rates observed when Cimzia (Certolizumab) is used in a broader patient population. Patients with Crohn's disease that require chronic exposure to immunosuppressant therapies may be at higher risk than the general population for the development of lymphoma, even in the absence of TNF blocker therapy . The potential role of TNF blocker therapy in the development of malignancies in adults is not known.
Cases of acute and chronic leukemia have been reported in association with post-marketing TNF-blocker use in RA and other indications. Even in the absence of TNF-blocker therapy, patients with RA may be at a higher risk (approximately 2-fold) than the general population for the development of leukemia.
Use of TNF blockers, including Cimzia (Certolizumab) , may increase the risk of reactivation of hepatitis B virus (HBV) in patients who are chronic carriers of this virus. In some instances, HBV reactivation occurring in conjunction with TNF blocker therapy has been fatal. The majority of reports have occurred in patients concomitantly receiving other medications that suppress the immune system, which may also contribute to HBV reactivation.
Evaluate patients at risk for HBV infection for prior evidence of HBV infection before initiating Cimzia (Certolizumab) therapy. Exercise caution in prescribing Cimzia (Certolizumab) for patients identified as carriers of HBV. Adequate data are not available on the safety or efficacy of treating patients who are carriers of HBV with anti-viral therapy in conjunction with TNF blocker therapy to prevent HBV reactivation. Patients who are carriers of HBV and require treatment with Cimzia (Certolizumab) should be closely monitored for clinical and laboratory signs of active HBV infection throughout therapy and for several months following termination of therapy.
In patients who develop HBV reactivation, discontinue Cimzia (Certolizumab) and initiate effective anti-viral therapy with appropriate supportive treatment. The safety of resuming TNF blocker therapy after HBV reactivation is controlled is not known. Therefore, exercise caution when considering resumption of Cimzia (Certolizumab) therapy in this situation and monitor patients closely.
Rare reports of pancytopenia, including aplastic anemia, have been reported with TNF blockers. Adverse reactions of the hematologic system, including medically significant cytopenia (e.g., leukopenia, pancytopenia, thrombocytopenia) have been infrequently reported with Cimzia (Certolizumab) . The causal relationship of these events to Cimzia (Certolizumab) remains unclear.
Although no high risk group has been identified, exercise caution in patients being treated with Cimzia (Certolizumab) who have ongoing, or a history of, significant hematologic abnormalities. Advise all patients to seek immediate medical attention if they develop signs and symptoms suggestive of blood dyscrasias or infection (e.g., persistent fever, bruising, bleeding, pallor) while on Cimzia (Certolizumab) . Consider discontinuation of Cimzia (Certolizumab) therapy in patients with confirmed significant hematologic abnormalities.
Cimzia (Certolizumab) Adverse Reactions
The most serious adverse reactions were:
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%).
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.
Cimzia (Certolizumab) Overdosage
The maximum tolerated dose of certolizumab pegol has not been established. Doses of up to 800 mg subcutaneous and 20 mg/kg intravenous have been administered without evidence of dose-limiting toxicities. In cases of overdosage, it is recommended that patients be monitored closely for any adverse reactions or effects, and appropriate symptomatic treatment instituted immediately.
Cimzia (Certolizumab) Description
Cimzia (Certolizumab) (certolizumab pegol) is a TNF blocker. Cimzia (Certolizumab) is a recombinant, humanized antibody Fab' fragment, with specificity for human tumor necrosis factor alpha (TNFα), conjugated to an approximately 40kDa polyethylene glycol (PEG2MAL40K). The Fab' fragment is manufactured in and is subsequently subjected to purification and conjugation to PEG2MAL40K, to generate certolizumab pegol. The Fab' fragment is composed of a light chain with 214 amino acids and a heavy chain with 229 amino acids. The molecular weight of certolizumab pegol is approximately 91 kiloDaltons.
Cimzia (Certolizumab) is supplied as either a sterile, white, lyophilized powder for solution or as a sterile, solution in a single-use prefilled 1 mL glass syringe for subcutaneous injection. After reconstitution of the lyophilized powder with 1 mL sterile Water for Injection, USP, the resulting pH is approximately 5.2. Each single-use vial provides approximately 200 mg certolizumab pegol, 0.9 mg lactic acid, 0.1 mg polysorbate, and 100 mg sucrose.
Each single-use prefilled syringe of Cimzia (Certolizumab) delivers 200 mg in 1 mL of solution with a pH of approximately 4.7 for subcutaneous use. Each 1 mL syringe of Cimzia (Certolizumab) contains certolizumab pegol (200 mg), sodium acetate (1.36 mg), sodium chloride (7.31 mg), and Water for Injection, USP.
Cimzia (Certolizumab) is a clear to opalescent solution that is colorless to pale yellow and essentially free from particulates. No preservatives are present.
Cimzia (Certolizumab) Clinical Pharmacology
Certolizumab pegol binds to human TNFα with a KD of 90pM. TNFα is a key pro-inflammatory cytokine with a central role in inflammatory processes. Certolizumab pegol selectively neutralizes TNFα (IC of 4 ng/mL for inhibition of human TNFα in the L929 murine fibrosarcoma cytotoxicity assay) but does not neutralize lymphotoxin α (TNFβ). Certolizumab pegol cross-reacts poorly with TNF from rodents and rabbits, therefore efficacy was evaluated using animal models in which human TNFα was the physiologically active molecule.
Certolizumab pegol was shown to neutralize membrane-associated and soluble human TNFα in a dose-dependent manner. Incubation of monocytes with certolizumab pegol resulted in a dose-dependent inhibition of LPS-induced TNFα and IL-1β production in human monocytes.
Certolizumab pegol does not contain a fragment crystallizable (Fc) region, which is normally present in a complete antibody, and therefore does not fix complement or cause antibody-dependent cell-mediated cytotoxicity . It does not induce apoptosis in human peripheral blood-derived monocytes or lymphocytes, nor does certolizumab pegol induce neutrophil degranulation.
A tissue reactivity study was carried out to evaluate potential cross-reactivity of certolizumab pegol with cryosections of normal human tissues. Certolizumab pegol showed no reactivity with a designated standard panel of normal human tissues.
Cimzia (Certolizumab) Clinical Studies
The efficacy and safety of Cimzia (Certolizumab) were assessed in four randomized, placebo-controlled, double-blind studies (RA-I, RA-II, RA-III, and RA-IV ) in patients ≥ 18 years of age with moderately to severely active rheumatoid arthritis diagnosed according to the American College of Rheumatology (ACR) criteria. Patients had ≥ 9 swollen and tender joints and had active RA for at least 6 months prior to baseline. Cimzia (Certolizumab) was administered subcutaneously in combination with MTX at stable doses of at least 10 mg weekly in Studies RA-I, RA-II, and RA-III. Cimzia (Certolizumab) was administered as monotherapy in Study RA-IV.
Study RA-I and Study RA-II evaluated patients who had received MTX for at least 6 months prior to study medication, but had an incomplete response to MTX alone. Patients were treated with a loading dose of 400 mg at Weeks 0, 2 and 4 (for both treatment arms) or placebo followed by either 200 mg or 400 mg of Cimzia (Certolizumab) or placebo every other week, in combination with MTX for 52 weeks in Study RA-I and for 24 weeks in Study RA-II. Patients were evaluated for signs and symptoms and structural damage using the ACR20 response at Week 24 (RA-I and RA-II) and modified Total Sharp Score (mTSS) at Week 52 (RA-I). The open-label extension follow-up study enrolled 846 patients who received 400 mg of Cimzia (Certolizumab) every other week.
Study RA-III evaluated 247 patients who had active disease despite receiving MTX for at least 6 months prior to study enrollment. Patients received 400 mg of Cimzia (Certolizumab) every four weeks for 24 weeks without a prior loading dose. Patients were evaluated for signs and symptoms of RA using the ACR20 at Week 24.
Study RA-IV (monotherapy) evaluated 220 patients who had failed at least one DMARD use prior to receiving Cimzia (Certolizumab) . Patients were treated with Cimzia (Certolizumab) 400 mg or placebo every 4 weeks for 24 weeks. Patients were evaluated for signs and symptoms of active RA using the ACR20 at Week 24.
Cimzia (Certolizumab) Patient Counseling Information
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After proper training by a qualified healthcare professional in subcutaneous injection technique, a patient may self inject with Cimzia (Certolizumab) using the Prefilled Syringe if a healthcare provider determines that it is appropriate. A patient's ability to administer Cimzia (Certolizumab) subcutaneous injections should be checked to ensure correct administration. Suitable sites for injection include the thigh or abdomen. Cimzia (Certolizumab) should be injected when the liquid is at room temperature. Full injection instructions are provided in the Patient Instructions for Use for the Prefilled Syringe, packaged in each Cimzia (Certolizumab) Prefilled Syringe kit
To avoid needle-stick injury, patients and healthcare providers should not attempt to place the needle cover back on the syringe or otherwise recap the needle. Be sure to properly dispose of needles and syringes in a puncture-proof container, and instruct patients and caregivers in proper syringe and needle disposal technique. Actively discourage any reuse of the injection materials.
Cimzia (Certolizumab)
Cimzia (Certolizumab)
Cimzia (Certolizumab)
Cimzia (Certolizumab)
Cimzia (Certolizumab)
