Adalimumab interacts in the following cases:
There is limited safety experience of surgical procedures in patients treated with adalimumab. The long halflife of adalimumab should be taken into consideration if a surgical procedure is planned. A patient who requires surgery while on adalimumab should be closely monitored for infections, and appropriate actions should be taken. There is limited safety experience in patients undergoing arthroplasty while receiving adalimumab.
Similar antibody responses to the standard 23-valent pneumococcal vaccine and the influenza trivalent virus vaccination were observed in a study in 226 adult subjects with rheumatoid arthritis who were treated with adalimumab or placebo. No data are available on the secondary transmission of infection by live vaccines in patients receiving adalimumab.
It is recommended that paediatric patients, if possible, be brought up to date with all immunisations in agreement with current immunisation guidelines prior to initiating adalimumab therapy.
Patients on adalimumab may receive concurrent vaccinations, except for live vaccines. Administration of live vaccines (e.g. BCG vaccine) to infants exposed to adalimumab in utero is not recommended for 5 months following the mother’s last adalimumab injection during pregnancy.
In a clinical trial with another TNF-antagonist worsening congestive heart failure and increased mortality due to congestive heart failure have been observed. Cases of worsening congestive heart failure have also been reported in patients receiving adalimumab. Adalimumab should be used with caution in patients with mild heart failure (NYHA class I/II). Treatment with adalimumab must be discontinued in patients who develop new or worsening symptoms of congestive heart failure.
Adalimumab has been studied in rheumatoid arthritis, polyarticular juvenile idiopathic arthritis and psoriatic arthritis patients taking adalimumab as monotherapy and those taking concomitant methotrexate. Antibody formation was lower when adalimumab was given together with methotrexate in comparison with use as monotherapy. Administration of adalimumab without methotrexate resulted in increased formation of antibodies, increased clearance and reduced efficacy of adalimumab.
Reactivation of hepatitis B has occurred in patients receiving a TNF-antagonist including adalimumab, 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 adalimumab. For patients who test positive for hepatitis B infection, consultation with a physician with expertise in the treatment of hepatitis B is recommended.
Carriers of HBV who require treatment with adalimumab should be closely monitored for signs and symptoms of active HBV infection throughout therapy and for several months following termination of therapy. Adequate data from 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, adalimumab should be stopped and effective anti-viral therapy with appropriate supportive treatment should be initiated.
A large number (approximately 2100) of prospectively collected pregnancies exposed to adalimumab resulting in live birth with known outcomes, including more than 1500 exposed during the first trimester, does not indicate an increase in the rate of malformation in the newborn.
In a prospective cohort registry, 257 women with rheumatoid arthritis (RA) or Crohn’s disease (CD) treated with adalimumab at least during the first trimester and 120 women with RA or CD not treated with adalimumab were enrolled. The primary endpoint was the birth prevalence of major birth defects. The rate of pregnancies ending with at least one live born infant with a major birth defect was 6/69 (8.7%) in the adalimumab-treated women with RA and 5/74 (6.8%) in the untreated women with RA (unadjusted OR 1.31, 95% CI 0.38-4.52) and 16/152 (10.5%) in the adalimumab-treated women with CD and 3/32 (9.4%) in the untreated women with CD (unadjusted OR 1.14, 95% CI 0.31-4.16). The adjusted OR (accounting for baseline differences) was 1.10 (95% CI 0.45-2.73) with RA and CD combined. There were no distinct differences between adalimumab-treated and untreated women for the secondary endpoints spontaneous abortions, minor birth defects, preterm delivery, birth size and serious or opportunistic infections and no stillbirths or malignancies were reported. The interpretation of data may be impacted due to methodological limitations of the study, including small sample size and non-randomized design.
In a developmental toxicity study conducted in monkeys, there was no indication of maternal toxicity, embryotoxicity or teratogenicity. Preclinical data on postnatal toxicity of adalimumab are not available.
Due to its inhibition of TNFα, adalimumab administered during pregnancy could affect normal immune responses in the newborn. Adalimumab should only be used during pregnancy if clearly needed.
Adalimumab may cross the placenta into the serum of infants born to women treated with adalimumab during pregnancy. Consequently, these infants may be at increased risk for infection. Administration of live vaccines (e.g. BCG vaccine) to infants exposed to adalimumab in utero is not recommended for 5 months following the mother’s last adalimumab injection during pregnancy.
Limited information from the published literature indicates that adalimumab is excreted in breast milk at very low concentrations with the presence of adalimumab in human milk at concentrations of 0.1% to 1% of the maternal serum level. Given orally, immunoglobulin G proteins undergo intestinal proteolysis and have poor bioavailability. No effects on the breastfed newborns/infants are anticipated. Consequently, adalimumab can be used during breastfeeding.
Women of childbearing potential should consider the use of adequate contraception to prevent pregnancy and continue its use for at least five months after the last adalimumab treatment.
Preclinical data on fertility effects of adalimumab are not available.
Adalimumab may have a minor influence on the ability to drive and use machines. Vertigo and visual impairment may occur following administration of adalimumab.
Adalimumab was studied in 9,506 patients in pivotal controlled and open label trials for up to 60 months or more. These trials included rheumatoid arthritis patients with short term and long standing disease, juvenile idiopathic arthritis (polyarticular juvenile idiopathic arthritis and enthesitis-related arthritis) as well as axial spondyloarthritis (ankylosing spondylitis and axial spondyloarthritis without radiographic evidence of AS), psoriatic arthritis, Crohn’s disease, ulcerative colitis, psoriasis, hidradenitis suppurativa and uveitis patients. The pivotal controlled studies involved 6,089 patients receiving adalimumab and 3,801 patients receiving placebo or active comparator during the controlled period.
The proportion of patients who discontinued treatment due to adverse events during the double-blind, controlled portion of pivotal studies was 5.9% for patients taking adalimumab and 5.4% for control treated patients.
The most commonly reported adverse reactions are infections (such as nasopharyngitis, upper respiratory tract infection and sinusitis), injection site reactions (erythema, itching, haemorrhage, pain or swelling), headache and musculoskeletal pain.
Serious adverse reactions have been reported for adalimumab. TNF-antagonists, such as adalimumab affect the immune system and their use may affect the body’s defence against infection and cancer. Fatal and life-threatening infections (including sepsis, opportunistic infections and TB), HBV reactivation and various malignancies (including leukaemia, lymphoma and HSTCL) have also been reported with use of adalimumab.
Serious haematological, neurological and autoimmune reactions have also been reported. These include rare reports of pancytopenia, aplastic anaemia, central and peripheral demyelinating events and reports of lupus, lupus-related conditions and Stevens-Johnson syndrome.
In general, the adverse events in paediatric patients were similar in frequency and type to those seen in adult patients.
The following list of adverse reactions is based on experience from clinical trials and on postmarketing experience and are displayed by system organ class and frequency: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); and not known (cannot be estimated from the available data). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. The highest frequency seen among the various indications has been included.
Undesirable Effects:
Very common: Respiratory tract infections (including lower and upper respiratory tract infection, pneumonia, sinusitis, pharyngitis, nasopharyngitis and pneumonia herpes viral)
Common: Systemic infections (including sepsis, candidiasis and influenza), intestinal infections (including gastroenteritis viral), skin and soft tissue infections (including paronychia, cellulitis, impetigo, necrotising fasciitis and herpes zoster), ear infections, oral infections (including herpes simplex, oral herpes and tooth infections), reproductive tract infections (including vulvovaginal mycotic infection), urinary tract infections (including pyelonephritis), fungal infections, joint infections
Uncommon: Neurological infections (including viral meningitis), opportunistic infections and tuberculosis (including coccidioidomycosis, histoplasmosis and mycobacterium avium complex infection), bacterial infections, eye infections, diverticulitis1
Common: Skin cancer excluding melanoma (including basal cell carcinoma and squamous cell carcinoma), benign neoplasm
Uncommon: Lymphoma**, solid organ neoplasm (including breast cancer, lung neoplasm and thyroid neoplasm), melanoma**
Rare: Leukaemia1
Not known: Hepatosplenic T-cell lymphoma1, Merkel cell carcinoma (neuroendocrine carcinoma of the skin)1
Very common: Leukopenia (including neutropenia and agranulocytosis), anaemia
Common: Leucocytosis, thrombocytopenia
Uncommon: Idiopathic thrombocytopenic purpura
Rare: Pancytopenia
Common: Hypersensitivity, allergies (including seasonal allergy)
Uncommon: Sarcoidosis1, vasculitis
Rare: Anaphylaxis1
Very common: Lipids increased
Common: Hypokalaemia, uric acid increased, blood sodium abnormal, hypocalcaemia, hyperglycaemia, hypophosphatemia, dehydration
Common: Mood alterations (including depression), anxiety, insomnia
Very common: Headache
Common: Paraesthesias (including hypoesthesia), migraine, nerve root compression
Uncommon: Cerebrovascular accident1, tremor, neuropathy
Rare: Multiple sclerosis, demyelinating disorders (e.g. optic neuritis, Guillain-Barré syndrome)1
Common: Visual impairment, conjunctivitis, blepharitis, eye swelling
Uncommon: Diplopia
Common: Vertigo
Uncommon: Deafness, tinnitus
Common: Tachycardia
Uncommon: Myocardial infarction1, arrhythmia, congestive heart failure
Rare: Cardiac arrest
Common: Hypertension, flushing, haematoma
Uncommon: Aortic aneurysm, vascular arterial occlusion, thrombophlebitis
Common: Asthma, dyspnoea, cough
Uncommon: Pulmonary embolism1, interstitial lung disease, chronic obstructive pulmonary disease, pneumonitis, pleural effusion1
Rare: Pulmonary fibrosis1
Very common: Abdominal pain, nausea and vomiting
Common: GI haemorrhage, dyspepsia, gastroesophageal reflux disease, sicca syndrome
Uncommon: Pancreatitis, dysphagia, face oedema
Rare: Intestinal perforation1
Very Common: Elevated liver enzymes
Uncommon: Cholecystitis and cholelithiasis, hepatic steatosis, bilirubin increased
Rare: Hepatitis reactivation of hepatitis B1 autoimmune hepatitis1
Not known: Liver failure1
Very Common: Rash (including exfoliative rash)
Common: Worsening or new onset of psoriasis (including palmoplantar pustular psoriasis)1, urticaria, bruising (including purpura), dermatitis (including eczema), onychoclasis, hyperhidrosis, alopecia1, pruritus
Uncommon: Night sweats, scar
Rare: Erythema multiforme1, Stevens-Johnson syndrome1, angioedema1, cutaneous vasculitis1 lichenoid skin reaction1
Very common: Musculoskeletal pain
Common: Muscle spasms (including blood creatine phosphokinase increased)
Uncommon: Rhabdomyolysis, systemic lupus erythematosus
Rare: Lupus-like syndrome1
Common: Renal impairment, haematuria
Uncommon: Nocturia
Uncommon: Erectile dysfunction
Very Common: Injection site reaction (including injection site erythema)
Common: Chest pain, oedema, pyrexia1
Uncommon: Inflammation
Common: Coagulation and bleeding disorders (including activated partial thromboplastin time prolonged), autoantibody test positive (including double stranded DNA antibody), blood lactate dehydrogenase increased
Common: Impaired healing
** including open label extension studies
1 including spontaneous reporting data
The safety profile for patients with HS treated with adalimumab weekly was consistent with the known safety profile of adalimumab.
The safety profile for patients with uveitis treated with adalimumab every other week was consistent with the known safety profile of adalimumab.
In the pivotal controlled trials in adults and children, 12.9% of patients treated with adalimumab developed injection site reactions (erythema and/or itching, haemorrhage, pain or swelling), compared to 7.2% of patients receiving placebo or active control. Injection site reactions generally did not necessitate discontinuation of the medicinal product.
In the pivotal controlled trials in adults and children, the rate of infection was 1.51 per patient year in the adalimumab treated patients and 1.46 per patient year in the placebo and active control-treated patients. The infections consisted primarily of nasopharyngitis, upper respiratory tract infection, and sinusitis. Most patients continued on adalimumab after the infection resolved.
The incidence of serious infections was 0.04 per patient year in adalimumab treated patients and 0.03 per patient year in placebo and active control−treated patients.
In controlled and open label adult and paediatric studies with adalimumab, serious infections (including fatal infections, which occurred rarely) have been reported, which include reports of tuberculosis (including miliary and extra-pulmonary locations) and invasive opportunistic infections (e.g. disseminated or extrapulmonary histoplasmosis, blastomycosis, coccidioidomycosis, pneumocystis, candidiasis, aspergillosis and listeriosis). Most of the cases of tuberculosis occurred within the first eight months after initiation of therapy and may reflect recrudescence of latent disease.
No malignancies were observed in 249 paediatric patients with an exposure of 655.6 patient years during adalimumab trials in patients with juvenile idiopathic arthritis (polyarticular juvenile idiopathic arthritis and enthesitis-related arthritis). In addition, no malignancies were observed in 192 paediatric patients with an exposure of 498.1 patient years during adalimumab trials in paediatric patients with Crohn’s disease. No malignancies were observed in 77 paediatric patients with an exposure of 80.0 patient years during a adalimumab trial in paediatric patients with chronic plaque psoriasis. No malignancies were observed in 60 paediatric patients with an exposure of 58.4 patient years during a adalimumab trial in paediatric patients with uveitis.
During the controlled portions of pivotal adalimumab trials in adults of at least 12 weeks in duration in patients with moderately to severely active rheumatoid arthritis, ankylosing spondylitis, axial spondyloarthritis without radiographic evidence of AS, psoriatic arthritis, psoriasis, hidradenitis suppurativa, Crohn’s disease, ulcerative colitis and uveitis, malignancies, other than lymphoma and non-melanoma skin cancer, were observed at a rate (95% confidence interval) of 6.8 (4.4, 10.5) per 1,000 patient-years among 5,291 adalimumab treated patients versus a rate of 6.3 (3.4, 11.8) per 1,000 patient-years among 3,444 control patients (median duration of treatment was 4.0 months for adalimumab and 3.8 months for control-treated patients). The rate (95% confidence interval) of non-melanoma skin cancers was 8.8 (6.0, 13.0) per 1,000 patient-years among adalimumab-treated patients and 3.2 (1.3, 7.6) per 1,000 patient-years among control patients. Of these skin cancers, squamous cell carcinomas occurred at rates (95% confidence interval) of 2.7 (1.4, 5.4) per 1,000 patient-years among adalimumab-treated patients and 0.6 (0.1, 4.5) per 1,000 patient-years among control patients. The rate (95% confidence interval) of lymphomas was 0.7 (0.2, 2.7) per 1,000 patient-years among adalimumab-treated patients and 0.6 (0.1, 4.5) per 1,000 patient-years among control patients.
When combining controlled portions of these trials and ongoing and completed open label extension studies with a median duration of approximately 3.3 years including 6,427 patients and over 26,439 patient-years of therapy, the observed rate of malignancies, other than lymphoma and non-melanoma skin cancers is approximately 8.5 per 1,000 patient years. The observed rate of non-melanoma skin cancers is approximately 9.6 per 1,000 patient years, and the observed rate of lymphomas is approximately 1.3 per 1,000 patient years.
In post-marketing experience from January 2003 to December 2010, predominantly in patients with rheumatoid arthritis, the reported rate of malignancies is approximately 2.7 per 1,000 patient treatment years. The reported rates for non-melanoma skin cancers and lymphomas are approximately 0.2 and 0.3 per 1,000 patient treatment years, respectively.
Rare post-marketing cases of hepatosplenic T-cell lymphoma have been reported in patients treated with adalimumab.
Patients had serum samples tested for autoantibodies at multiple time points in rheumatoid arthritis studies I − V. In these trials, 11.9% of patients treated with adalimumab and 8.1% of placebo and active control−treated patients that had negative baseline anti-nuclear antibody titres reported positive titres at Week 24. Two patients out of 3,441 treated with adalimumab in all rheumatoid arthritis and psoriatic arthritis studies developed clinical signs suggestive of new-onset lupus-like syndrome. The patients improved following discontinuation of therapy. No patients developed lupus nephritis or central nervous system symptoms.
In controlled Phase 3 trials of adalimumab in patients with rheumatoid arthritis and psoriatic arthritis with a control period duration ranging from 4 to 104 weeks, ALT elevations ≥3 x ULN occurred in 3.7% of adalimumab-treated patients and 1.6% of control-treated patients.
In controlled Phase 3 trials of adalimumab in patients with polyarticular juvenile idiopathic arthritis who were 4 to 17 years and enthesitis-related arthritis who were 6 to 17 years, ALT elevations ≥3 x ULN occurred in 6.1% of adalimumab-treated patients and 1.3% of control-treated patients. Most ALT elevations occurred with concomitant methotrexate use. No ALT elevations ≥3 x ULN occurred in the Phase 3 trial of adalimumab in patients with polyarticular juvenile idiopathic arthritis who were 2 to <4 years.
In controlled Phase 3 trials of adalimumab in patients with Crohn’s disease and ulcerative colitis with a control period ranging from 4 to 52 weeks. ALT elevations ≥3 x ULN occurred in 0.9% of adalimumab-treated patients and 0.9% of controlled-treated patients.
In the Phase 3 trial of adalimumab in patients with paediatric Crohn’s disease which evaluated efficacy and safety of two body weight adjusted maintenance dose regimens following body weight adjusted induction therapy up to 52 weeks of treatment, ALT elevations ≥3 x ULN occurred in 2.6% (5/192) of patients of whom 4 were receiving concomitant immunosuppressants at baseline.
In controlled Phase 3 trials of adalimumab in patients with plaque psoriasis with a control period duration ranging from 12 to 24 weeks, ALT elevations ≥3 x ULN occurred in 1.8% of adalimumab-treated patients and 1.8% of control-treated patients.
No ALT elevations ≥3 X ULN occurred in the Phase 3 trial of adalimumab in paediatric patients with plaque psoriasis.
In controlled trials of adalimumab (initial doses of 160 mg at Week 0 and 80 mg at Week 2, followed by 40 mg every week starting at Week 4), in patients with hidradenitis suppurativa with a control period duration ranging from 12 to 16 weeks, ALT elevations ≥3 x ULN occurred in 0.3% of adalimumab-treated patients and 0.6% of control-treated patients.
In controlled trials of adalimumab (initial doses of 80 mg at Week 0 followed by 40 mg every other week starting at Week 1) in adult patients with uveitis up to 80 weeks with a median exposure of 166.5 days and 105.0 days in adalimumab-treated and control-treated patients, respectively, ALT elevations ≥3 x ULN occurred in 2.4% of adalimumab-treated patients and 2.4% of control-treated patients.
Across all indications in clinical trials patients with raised ALT were asymptomatic and in most cases elevations were transient and resolved on continued treatment. However, there have also been post-marketing reports of liver failure as well as less severe liver disorders that may precede liver failure, such as hepatitis including autoimmune hepatitis in patients receiving adalimumab.
In adult Crohn’s disease studies, higher incidences of malignant and serious infection-related adverse events were seen with the combination of adalimumab and azathioprine/6-mercaptopurine compared with adalimumab alone.
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. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.
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