Certolizumab pegol interacts in the following cases:
Patients treated with certolizumab pegol may receive vaccinations, except for live vaccines. No data are available on the response to live vaccinations or the secondary transmission of infection by live vaccines in patients receiving certolizumab pegol. Live vaccines should not be administered concurrently with certolizumab pegol.
In a placebo-controlled clinical trial in patients with rheumatoid arthritis, similar antibody response between certolizumab pegol and placebo treatment were observed when the pneumococcal polysaccharide vaccine and influenza vaccine were administered concurrently with certolizumab pegol. Patients receiving certolizumab pegol and concomitant methotrexate had a lower humoral response compared with patients receiving certolizumab pegol alone. The clinical significance of this is unknown.
Effects on sperm motility measures and a trend of reduced sperm count in male rodents have been observed with no apparent effect on fertility.
In a clinical trial to assess the effect of certolizumab pegol on semen quality parameters, 20 healthy male subjects were randomized to receive a single subcutaneous dose of 400 mg of certolizumab pegol or placebo. During the 14-week follow-up, no treatment effects of certolizumab pegol were seen on semen quality parameters compared to placebo.
The combination of certolizumab pegol and anakinra or abatacept is not recommended.Severe infections and neutropaenia were reported in clinical trials with concurrent use of anakinra (an interleukin-1 antagonist) or abatacept (a CD28 modulator) and another TNF antagonist, etanercept, with no added benefit compared to TNF antagonist therapy alone. Because of the nature of the adverse events seen with the combination of another TNF antagonist with either abatacept or anakinra therapy, similar toxicities may also result from the combination of anakinra or abatacept and other TNF antagonists. Therefore the use of certolizumab pegol in combination with anakinra or abatacept is not recommended.
Since tumour necrosis factor (TNF) mediates inflammation and modulates cellular immune responses, the possibility exists for TNF antagonists, including certolizumab pegol, to cause immunosupression, affecting host defences against infections and malignancies.
The potential role of TNF antagonist therapy in the development of malignancies is not known. Caution should be exercised when considering TNF antagonist therapy for patients with a history of malignancy or when considering continuing treatment in patients who develop malignancy.
With the current knowledge, a possible risk for the development of lymphomas, leukaemia or other malignancies in patients treated with a TNF antagonist cannot be excluded.
In clinical trials with certolizumab and other TNF antagonists, more cases of lymphoma and other malignancies have been reported among patients receiving TNF antagonists than in control patients receiving placebo. In the post marketing setting, cases of leukaemia have been reported in patients treated with a TNF antagonist. There is an increased background risk for lymphoma and leukaemia in rheumatoid arthritis patients with long-standing, highly active, inflammatory disease, which complicates the risk estimation.
No trials have been conducted that include patients with a history of malignancy, or that continue treatment in patients who develop malignancy, while receiving certolizumab.
Melanoma and Merkel cell carcinoma have been reported in patients treated with TNF-antagonists including certolizumab pegol. Periodic skin examination is recommended, particularly for patients with risk factors for skin cancer.
Malignancies, some fatal, have been reported among children, adolescents and young adults (up to 22 years of age) treated with TNF antagonists (initiation of therapy ≤18 years of age) in the post marketing setting. Approximately half the cases were lymphomas. The other cases represented a variety of different malignancies and included rare malignancies usually associated with immunosuppression. A risk for the development of malignancies in children and adolescents treated with TNF antagonists cannot be excluded.
Post-marketing cases of hepatosplenic T-cell lymphoma (HSTCL), have been reported in patients treated with TNF-antagonists. This rare type of T-cell lymphoma has a very aggressive disease course and is usually fatal. The majority of reported TNF-antagonist cases occurred in adolescent and young adult males with Crohn’s disease or ulcerative colitis. Almost all of these patients had received treatment with the immunosuppressants azathioprine and/or 6-mercaptopurine concomitantly with a TNF-antagonist at or prior to diagnosis. A risk for development of hepatosplenic T-cell lymphoma in patients treated with certolizumab pegol cannot be excluded.
In an exploratory clinical trial evaluating the use of another TNF antagonist, infliximab, in patients with moderate to severe chronic obstructive pulmonary disease (COPD), more malignancies, mostly in the lung or head and neck, were reported in infliximab-treated patients compared with control patients. All patients had a history of heavy smoking. Therefore, caution should be exercised when using any TNF antagonist in COPD patients, as well as in patients with increased risk for malignancy due to heavy smoking.
There is limited safety experience with surgical procedures in patients treated with certolizumab pegol. The 14-day half-life of certolizumab pegol should be taken into consideration if a surgical procedure is planned. A patient who requires surgery while on certolizumab pegol should be closely monitored for infections, and appropriate actions should be taken.
Interference with certain coagulation assays has been detected in patients treated with certolizumab pegol. Certolizumab pegol may cause erroneously elevated 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 lyophilised silica tests from Instrumentation Laboratories. Other aPTT assays may be affected as well. There is no evidence that certolizumab pegol therapy has an effect on coagulation in vivo. After patients receive certolizumab pegol, careful attention should be given to interpretation of abnormal coagulation results. Interference with thrombin time (TT) and prothrombin time (PT) assays have not been observed.
Reactivation of hepatitis B has occurred in patients receiving a TNF-antagonist including certolizumab, who are chronic carriers of this virus (i.e., surface antigen positive). Some cases have had a fatal outcome.
Patients should be tested for HBV infection before initiating treatment with certolizumab. For patients who test positive for HBV infection, consultation with a physician with expertise in the treatment of hepatitis B is recommended.
Carriers of HBV who require treatment with certolizumab should be closely monitored for signs and symptoms of active HBV infection throughout therapy and for several months following termination of therapy. Adequate data of treating patients who are carriers of HBV with anti-viral therapy in conjunction with TNF-antagonist therapy to prevent HBV reactivation are not available. In patients who develop HBV reactivation, certolizumab should be stopped and effective anti-viral therapy with appropriate supportive treatment should be initiated.
Use of TNF antagonists has been associated with rare cases of new onset or exacerbation of clinical symptoms and/or radiographic evidence of demyelinating disease, including multiple sclerosis. In patients with pre-existing or recent onset of demyelinating disorders, the benefits and risks of TNF antagonist treatment should be carefully considered before initiation of certolizumab pegol therapy. Rare cases of neurological disorders, including seizure disorder, neuritis and peripheral neuropathy, have been reported in patients treated with certolizumab pegol.
Reports of pancytopaenia, including aplastic anaemia, have been rare with TNF antagonists. Adverse reactions of the haematologic system, including medically significant cytopaenia (e.g. leukopaenia, pancytopaenia, thrombocytopaenia) have been reported with certolizumab pegol. All patients should be advised 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 certolizumab pegol. Discontinuation of certolizumab pegol therapy should be considered in patients with confirmed significant haematological abnormalities.
Treatment with certolizumab pegol may result in the formation of antinuclear antibodies (ANA) and, uncommonly, in the development of a lupus-like syndrome. The impact of long-term treatment with certolizumab pegol on the development of autoimmune diseases is unknown. If a patient develops symptoms suggestive of a lupus-like syndrome following treatment with certolizumab pegol, treatment must be discontinued. Certolizumab pegol has not been studied specifically in a lupus population.
Data from more than 500 prospectively collected pregnancies exposed to certolizumab pegol with known pregnancy outcomes, including more than 400 pregnancies exposed during the first trimester, does not indicate a malformative effect of certolizumab pegol. However, the available clinical experience is too limited to, with a reasonable certainty, conclude that there is no increased risk associated with certolizumab pegol administration during pregnancy.
Animal studies using a rodent anti-rat TNFα did not reveal evidence of impaired fertility or harm to the foetus. However, these are insufficient with respect to human reproductive toxicity. Due to its inhibition of TNFα, certolizumab pegol administered during pregnancy could affect normal immune response in the newborn.
Certolizumab pegol should only be used during pregnancy if clinically needed. Non-clinical studies suggest low or negligible level of placental transfer of a homologue Fab-fragment of certolizumab pegol (no Fc region).
In a clinical study 16 women were treated with certolizumab pegol (200 mg every 2 weeks or 400 mg every 4 weeks) during pregnancy. Certolizumab pegol plasma concentrations measured in 14 infants at birth were Below the Limit of Quantification (BLQ) in 13 samples; one was 0.042 μg/ml with an infant/mother plasma ratio at birth of 0.09%. At Week 4 and Week 8, all infant concentrations were BLQ.
The clinical significance of low levels certolizumab pegol for infants is unknown. It is recommended to wait a minimum of 5 months following the mother’s last certolizumab pegol administration during pregnancy before administration of live or live-attenuated vaccines (e.g. BCG vaccine), unless the benefit of the vaccination clearly outweighs the theoretical risk of administration of live or live-attenuated vaccines to the infants.
In a clinical study in 17 lactating women treated with certolizumab pegol, minimal transfer of certolizumab pegol from plasma to breast milk was observed. The percentage of the maternal certolizumab pegol dose reaching an infant during a 24 hour period was estimated to 0.04% to 0.30%. In addition, since certolizumab pegol is a protein that is degraded in the gastrointestinal tract after oral administration, the absolute bioavailability is expected to be very low in a breastfed infant.
Consequently, certolizumab pegol can be used during breastfeeding.
The use of adequate contraception should be considered for women of childbearing potential. For women planning pregnancy, continued contraception may be considered for 5 months after the last certolizumab pegol dose due to its elimination rate, but the need for treatment of the woman should also be taken into account.
Effects on sperm motility measures and a trend of reduced sperm count in male rodents have been observed with no apparent effect on fertility.
In a clinical trial to assess the effect of certolizumab pegol on semen quality parameters, 20 healthy male subjects were randomized to receive a single subcutaneous dose of 400 mg of certolizumab pegol or placebo. During the 14-week follow-up, no treatment effects of certolizumab pegol were seen on semen quality parameters compared to placebo.
Certolizumab pegol may have a minor influence on the ability to drive and use machines. Dizziness (including vertigo, vision disorder and fatigue) may occur following administration of certolizumab pegol.
Certolizumab pegol was studied in 4,049 patients with rheumatoid arthritis in controlled and open label trials for up to 92 months.
In the placebo-controlled studies, patients receiving certolizumab pegol had an approximately 4 times greater duration of exposure compared with the placebo group. This difference in exposure is primarily due to patients on placebo being more likely to withdraw early. In addition, Studies RA-I and RA-II had a mandatory withdrawal for non-responders at Week 16, the majority of whom were on placebo.
The proportion of patients who discontinued treatment due to adverse events during the controlled trials was 4.4% for patients treated with certolizumab pegol and 2.7% for patients treated with placebo.
The most common adverse reactions belonged to the system organ classes Infections and infestations, reported in 14.4% of patients on certolizumab pegol and 8.0% of patients on placebo, General disorders and administration site conditions, reported in 8.8% of patients on certolizumab pegol and 7.4% of patients on placebo, and Skin and subcutaneous tissue disorders, reported in 7.0% of patients on certolizumab pegol and 2.4% of patients on placebo.
Certolizumab pegol was studied in 325 patients with active axial spondyloarthritis (including ankylosing spondylitis and non-radiopraphic axial spondyloarthritis) in the AS001 clinical study for up to 4 years, which includes a 24-week placebo-controlled phase followed by a 24-week dose-blind period and a 156-week open-label treatment period. certolizumab pegol was also studied in 317 patients with non- radiographic axial spondyloarthritis in a placebo-controlled study for 52 weeks (AS0006). In both studies, the safety profile for these patients was consistent with the safety profile in rheumatoid arthritis and previous experience with certolizumab pegol.
Certolizumab pegol was studied in 409 patients with psoriatic arthritis in the PsA001 clinical study for up to 4 years which includes a 24-week placebo-controlled phase followed by a 24-week dose-blind period and a 168-week open-label treatment period. The safety profile for psoriatic arthritis patients treated with certolizumab pegol was consistent with the safety profile in rheumatoid arthritis and previous experience with certolizumab pegol.
Certolizumab pegol was studied in 1112 patients with psoriasis in controlled and open-label studies for up to 18 months. The safety profile of certolizumab pegol 400 mg every 2 weeks and certolizumab pegol 200 mg every 2 weeks were generally similar.
During controlled clinical trials through Week 16, the proportion of patients with serious adverse events was 3.5% for certolizumab pegol and 3.7% for placebo. The proportion of patients who discontinued treatment due to adverse events in the controlled clinical studies was 1.5% for patients treated with certolizumab pegol and 1.4% for patients treated with placebo.
The most common adverse reactions reported through Week 16 belonged to the system organ classes Infections and infestations, reported in 6.1% of patients on certolizumab pegol and 7% of patients on placebo, General disorders and administration site conditions, reported in 4.1% of patients on certolizumab pegol and 2.3% of patients on placebo, and Skin and subcutaneous tissue disorders, reported in 3.5% of patients on certolizumab pegol and 2.8% of patients on placebo.
Adverse reactions based primarily on experience from the placebo-controlled clinical trials and postmarketing cases at least possibly related to certolizumab pegol are listed below, according to frequency and system organ class. Frequency categories are defined as follows: Very common (≥1/10); Common (≥1/100 to <1/10); Uncommon (≥1/1000 to <1/100); Rare (≥1/10,000 to <1/1000); Very rare (<1/10,000), not known (cannot be estimated from the available data). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
Adverse reactions in clinical trials and postmarketing:
Common: bacterial infections (including abscess), viral infections (including herpes zoster, papillomavirus, influenza)
Uncommon: sepsis (including multi-organ failure, septic shock), tuberculosis (including miliary, disseminated and extrapulmonary disease), fungal infections (includes opportunistic)
Uncommon: blood and lymphatic system malignancies (including lymphoma and leukaemia), solid organ tumours, nonmelanoma skin cancers, pre-cancerous lesions (including oral leukoplakia, melanocytic nevus), benign tumours and cysts (including skin papilloma)
Rare: gastrointestinal tumours, melanoma
Not known: Merkel cell carcinoma*
Common: eosinophilic disorders, leukopaenia (including neutropaenia, lymphopaenia)
Uncommon: anaemia, lymphadenopathy, thrombocytopaenia, thrombocytosis
Rare: pancytopaenia, splenomegaly, erythrocytosis, white blood cell morphology abnormal
Uncommon: vasculitides, lupus erythematosus, drug hypersensitivity (including anaphylactic shock), allergic disorders, auto-antibody positive
Rare: angioneurotic oedema, sarcoidosis, serum sickness, panniculitis (including erythema nodosum), worsening of symptoms of dermatomyositis**
Rare: thyroid disorders
Uncommon: electrolyte imbalance, dyslipidaemia, appetite disorders, weight change
Rare: haemosiderosis
Uncommon: anxiety and mood disorders (including associated symptoms)
Rare: suicide attempt, delirium, mental impairment
Common: headaches (including migraine), sensory abnormalities
Uncommon: peripheral neuropathies, dizziness, tremor
Rare: seizure, cranial nerve inflammation, impaired coordination or balance
Not known: multiple sclerosis*, Guillain-Barré syndrome*
Uncommon: visual disorder (including decreased vision), eye and eyelid inflammation, lacrimation disorder
Uncommon: tinnitus, vertigo
Uncommon: cardiomyopathies (including heart failure), ischaemic coronary artery disorders, arrhythmias (including atrial fibrillation), palpitations
Rare: pericarditis, atrioventricular block
Common: hypertension
Uncommon: haemorrhage or bleeding (any site), hypercoagulation (including thrombophlebitis, pulmonary embolism), syncope, oedema (including peripheral, facial), ecchymoses (including haematoma, petechiae)
Rare: cerebrovascular accident, arteriosclerosis, Raynaud’s phenomenon, livedo reticularis, telangiectasia
Uncommon: asthma and related symptoms, pleural effusion and symptoms, respiratory tract congestion and inflammation, cough
Rare: interstitial lung disease, pneumonitis
Common: nausea
Uncommon: ascites, gastrointestinal ulceration and perforation, gastrointestinal tract inflammation (any site), stomatitis, dyspepsia, abdominal distension, oropharyngeal dryness
Rare: odynophagia, hypermotility
Common: hepatitis (including hepatic enzyme increased)
Uncommon: hepatopathy (including cirrhosis), cholestasis, blood bilirubin increased
Rare: cholelithiasis
Common: rash
Uncommon: alopecia, new onset or worsening of psoriasis (including palmoplantar pustular psoriasis) and related conditions, dermatitis and eczema, sweat gland disorder, skin ulcer, photosensitivity, acne, skin discolouration, dry skin, nail and nail bed disorders
Rare: skin exfoliation and desquamation, bullous conditions, hair texture disorder, Stevens-Johnson syndrome**, erythema multiforme**, lichenoid reactions
Uncommon: muscle disorders, blood creatine phosphokinase increased
Uncommon: renal impairment, blood in urine, bladder and urethral symptoms
Rare: nephropathy (including nephritis)
Uncommon: menstrual cycle and uterine bleeding disorders (including amenorrhea), breast disorders
Rare: sexual dysfunction
Common: pyrexia, pain (any site), asthaenia, pruritus (any site), injection site reactions
Uncommon: chills, influenza-like illness, altered temperature perception, night sweats, flushing
Rare: fistula (any site)
Uncommon: blood alkaline phosphatase increased, coagulation time prolonged
Rare: blood uric acid increased
Uncommon: skin injuries, impaired healing
* These events have been related to the class of TNF-antagonists, but incidence with certolizumab pegol is not known.
** These events have been related to the class of TNF-antagonists.
The additional following adverse reactions have been observed uncommonly with certolizumab pegol in other indications: gastrointestinal stenosis and obstructions, general physical health deterioration, abortion spontaneous and azoospermia.
The incidence rate of new cases of infections in placebo-controlled clinical trials in rheumatoid arthritis was 1.03 per patient-year for all certolizumab pegol-treated patients and 0.92 per patient-year for placebo- treated patients. The infections consisted primarily of upper respiratory tract infections, urinary tract infections, and lower respiratory tract infections and herpes viral infections.
In the placebo-controlled clinical trials, there were more new cases of serious infection in the certolizumab pegol treatment groups (0.07 per patient-year; all doses), compared with placebo (0.02 per patient-year). The most frequent serious infections included pneumonia, tuberculosis infections. Serious infections also included invasive opportunistic infections (e.g. pneumocystosis, fungal oesophagitis, nocardiosis and herpes zoster disseminated). There is no evidence of an increased risk of infections with continued exposure over time.
The incidence rate of new cases of infections in placebo-controlled clinical trials in psoriasis was 1,37 per patient-year for all certolizumab pegol-treated patients and 1.59 per patient-year for placebo-treated patients. The infections consisted primarily of upper respiratory tract infections and viral infections (including herpes infections). The incidence of serious infections was 0.02 per patient-year in certolizumab pegol treated patients. No serious infections were reported in the placebo-treated patients. There is no evidence of an increased risk of infections with continued exposure over time.
Excluding non-melanoma of the skin, 121 malignancies including 5 cases of lymphoma were observed in the certolizumab pegol RA clinical trials in which a total of 4,049 patients were treated, representing 9,277 patient-years. Cases of lymphoma occurred at an incidence rate of 0.05 per 100 patient-years and melanoma at an incidence rate of 0.08 per 100 patient-years with certolizumab pegol in rheumatoid arthritis clinical trials. One case of lymphoma was also observed in the Phase III psoriatic arthritis clinical trial.
Excluding non-melanoma skin cancer, 9 malignancies including 1 case of lymphoma were observed in the certolizumab pegol psoriasis clinical trials in which a total of 1112 patients were treated, representing 1481 patient-years.
In the pivotal studies, for subjects who were ANA negative at baseline, 16.7% of those treated with certolizumab pegol developed positive ANA titers, compared with 12.0% of subjects in the placebo group. For subjects who were anti-dsDNA antibody negative at baseline, 2.2% of those treated with certolizumab pegol developed positive anti-dsDNA antibody titers, compared with 1.0% of subjects in the placebo group. In both placebo-controlled and open-label follow-up clinical trials for rheumatoid arthritis, cases of lupus-like syndrome were reported uncommonly. There have been rare reports of other immune-mediated conditions; the causal relationship to certolizumab pegol is not known. The impact of long-term treatment with Citmzia on the development of autoimmune diseases is unknown.
In the placebo-controlled rheumatoid arthritis clinical trials, 5.8% of patients treated with certolizumab pegol developed injection site reactions such as erythema, itching, haematoma, pain, swelling or bruising, compared to 4.8% of patients receiving placebo. Injection site pain was observed in 1.5% of patients treated with certolizumab pegol with no cases leading to withdrawal.
The frequency of creatine phosphokinase (CPK) elevations was generally higher in patients with axSpA as compared to the RA population. The frequency was increased both in patients treated with placebo (2.8% vs 0.4% in axSpA and RA populations, respectively) as well as in patients treated with certolizumab pegol (4.7% vs 0.8% in axSpA and RA populations, respectively). The CPK elevations in the axSpA study were mostly mild to moderate, transient in nature and of unknown clinical significance with no cases leading to withdrawal.
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