Adverse reactions : תופעות לוואי

4.8   Undesirable effects

Summary of the safety profile
Rheumatoid arthritis
Cimzia 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 Cimzia 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 Cimzia 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 Cimzia and 8.0% of patients on placebo, General disorders and administration site conditions, reported in 8.8% of patients on Cimzia and 7.4% of patients on placebo, and Skin and subcutaneous tissue disorders, reported in 7.0% of patients on Cimzia and 2.4% of patients on placebo.

Axial spondyloarthritis
Cimzia 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. Cimzia was also studied in 317 patients with non- radiographic axial spondyloarthritis in a placebo-controlled study for 52 weeks (AS0006). Cimzia was also studied in a 96-week open-label study in 89 axSpA patients with a history of documented anterior uveitis flares. In all three studies, The safety profile for these patients was consistent with the safety profile in rheumatoid arthritis and previous experience with Cimzia.

Plaque psoriasis
Cimzia was studied in 1112 patients with psoriasis in controlled and open-label studies for up to 3 years. In the Phase III program, the initial and maintenance periods were followed by a 96-week openlabel treatment period (see section 5.1). The long-term safety profile of Cimzia 400 mg every 2 weeks and Cimzia 200 mg every 2 weeks was generally similar and consistent with previous experience with Cimzia.

During controlled clinical trials through Week 16, the proportion of patients with serious adverse events was 3.5% for Cimzia 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 Cimzia 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 Cimzia and 7% of patients on placebo, General disorders and administration site conditions, reported in 4.1% of patients on Cimzia and 2.3% of patients on placebo, and Skin and subcutaneous tissue disorders, reported in 3.5% of patients on Cimzia and 2.8% of patients on placebo.

Tabulated list of adverse reactions

Adverse reactions based primarily on experience from the placebo-controlled clinical trials and postmarketing cases at least possibly related to Cimzia are listed in Table 1 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.



Table 1      Adverse reactions in clinical trials and postmarketing
System Organ Class          Frequency Adverse reactions
Infections and infestations 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)
Neoplasms benign,           Uncommon blood and lymphatic system malignancies (including malignant and                              lymphoma and leukaemia), solid organ tumours, non- unspecified (including                     melanoma skin cancers, pre-cancerous lesions cysts and polyps)                          (including oral leukoplakia, melanocytic nevus), benign tumours and cysts (including skin papilloma)
Rare           gastrointestinal tumours, melanoma
Not known Merkel cell carcinoma*, Kaposi’s sarcoma
Blood and the               Common         eosinophilic disorders, leukopaenia (including lymphatic system                           neutropaenia, lymphopaenia) disorders                   Uncommon anaemia, lymphadenopathy, thrombocytopaenia, thrombocytosis
Rare           pancytopaenia, splenomegaly, erythrocytosis, white blood cell morphology abnormal
Immune system disorders 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**
Endocrine disorders         Rare           thyroid disorders
Metabolism and              Uncommon electrolyte imbalance, dyslipidaemia, appetite nutrition disorders                        disorders, weight change
Rare           haemosiderosis
Psychiatric disorders       Uncommon anxiety and mood disorders (including associated symptoms)
Rare           suicide attempt, delirium, mental impairment
Nervous system disorders 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*
Eye disorders               Uncommon visual disorder (including decreased vision), eye and eyelid inflammation, lacrimation disorder
Ear and labyrinth disorders Uncommon tinnitus, vertigo

Cardiac disorders            Uncommon cardiomyopathies (including heart failure), ischaemic coronary artery disorders , arrhythmias (including atrial fibrillation), palpitations
Rare     pericarditis, atrioventricular block
Vascular disorders           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
System Organ Class            Frequency Adverse reactions
Respiratory, thoracic         Uncommon asthma and related symptoms, pleural effusion and and mediastinal                         symptoms, respiratory tract congestion and disorders                               inflammation, cough
Rare      interstitial lung disease, pneumonitis
Gastrointestinal disorders    Common    nausea
Uncommon ascites, gastrointestinal ulceration and perforation,
gastrointestinal tract inflammation (any site),
stomatitis, dyspepsia, abdominal distension,
oropharyngeal dryness
Rare      odynophagia, hypermotility
Hepatobiliary disorders       Common    hepatitis (including hepatic enzyme increased) Uncommon hepatopathy (including cirrhosis), cholestasis, blood bilirubin increased
Rare      cholelithiasis
Skin and                      Common    rash subcutaneous tissue           Uncommon alopecia, new onset or worsening of psoriasis disorders                               (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
Musculoskeletal,              Uncommon muscle disorders, blood creatine phosphokinase connective tissue and                   increased bone disorders
Renal and                     Uncommon renal impairment, blood in urine, bladder and urethral urinary                                symptoms disorders                     Rare     nephropathy (including nephritis) Reproductive system           Uncommon menstrual cycle and uterine bleeding disorders and breast disorders                   (including amenorrhea), breast disorders Rare     sexual dysfunction
General disorders             Common   pyrexia, pain (any site), asthaenia, pruritus (any site), and administration                     injection site reactions site conditions               Uncommon chills, influenza-like illness, altered temperature perception, night sweats, flushing
Rare     fistula (any site)
Investigations                Uncommon blood alkaline phosphatase increased, coagulation time prolonged
Rare     blood uric acid increased
Injury, poisoning and         Uncommon skin injuries, impaired healing procedural complications
*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 Cimzia in other indications: gastrointestinal stenosis and obstructions, general physical health deterioration, abortion spontaneous and azoospermia.

Crohn’s disease
The proportion of patients 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 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).

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.

Description of selected adverse reactions

Infections
The incidence rate of new cases of infections in placebo-controlled clinical trials in rheumatoid arthritis was 1.03 per patient-year for all Cimzia-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 (see sections 4.3 and 4.4).

In the placebo-controlled clinical trials in rheumatoid arthritis, there were more new cases of serious infection in the Cimzia 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 (see section 4.4).

The incidence rate of new cases of infections in placebo-controlled clinical trials in psoriasis was 1,37 per patient-year for all Cimzia-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 Cimzia 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.

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.

Malignancies and lymphoproliferative disorders
Excluding non-melanoma of the skin, 121 malignancies including 5 cases of lymphoma were observed in the Cimzia 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 Cimzia in rheumatoid arthritis clinical trials (see section 4.4). One case of lymphoma was also observed in the Phase III psoriatic arthritis clinical trial.

Excluding non-melanoma skin cancer, 11 malignancies including 1 case of lymphoma were observed in the Cimzia psoriasis clinical trials in which a total of 1112 patients were treated, representing 2300 patient-years.

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. The size of the control group and limited duration of the controlled portions of the studies precludes the ability to draw firm conclusions.
In controlled studies of Cimzia for Crohn’s disease and other investigational uses, there was one case of lymphoma among 2,657 Cimzia-treated patients and one case of Hodgkin’s lymphoma among 1,319 placebo-treated patients.

Autoimmunity
In the rheumatoid arthritis pivotal studies, for subjects who were ANA negative at baseline, 16.7% of those treated with Cimzia 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 Cimzia 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 Cimzia is not known. The impact of long-term treatment with Cimzia on the development of autoimmune diseases is unknown.

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.

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 section 4.4).

Injection site reactions
In the placebo-controlled rheumatoid arthritis clinical trials, 5.8% of patients treated with Cimzia 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 Cimzia with no cases leading to withdrawal.

Creatine phosphokinase elevations
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 Cimzia (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.

Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product.
Any suspected adverse events should be reported to the Ministry of Health according to the National Regulation by using an online form https://sideeffects.health.gov.il/ and emailed to the Registration Holder’s Patient Safety Unit at: drugsafety@neopharmgroup.com