- 1. Name of the medicinal product
- 2. Qualitative and quantitative composition
- 3. Pharmaceutical form
- 4. Clinical particulars
- 4.1 Therapeutic indications
- 4.2 Posology and method of administration
- 4.3 Contraindications
- 4.4 Special warnings and precautions for use
- 4.5 Interaction with other medicinal products and other forms of interaction
- 4.6 Fertility, pregnancy and lactation
- 4.7 Effects on ability to drive and use machines
- 4.8 Undesirable effects
- 4.9 Overdose
- 5. Pharmacological properties
- 5.1 Pharmacodynamic properties
- 5.2 Pharmacokinetic properties
- 5.3 Preclinical safety data
- 6. Pharmaceutical particulars
- 6.1 List of excipients
- 6.2 Incompatibilities
- 6.3 Shelf life
- 6.4 Special precautions for storage
- 6.5 Nature and contents of container
- 6.6 Special precautions for disposal and other handling
- 7. Marketing authorisation holder
- 8. Marketing authorisation number(s)
- 9. Date of first authorisation/renewal of the authorisation
- 10. Date of revision of the text
Rheumatoid arthritisHumira in combination with methotrexate, is indicated for: • the treatment of moderate to severe, active rheumatoid arthritis in adult patients when the response to disease-modifying anti-rheumatic drugs including methotrexate has been inadequate. • the treatment of severe, active and progressive rheumatoid arthritis in adults not previously treated with methotrexate.Humira can be given as monotherapy in case of intolerance to methotrexate or when continued treatment with methotrexate is inappropriate.Humira has been shown to reduce the rate of progression of joint damage as measured by X-ray and to improve physical function, when given in combination with methotrexate.
Juvenile idiopathic arthritis
Polyarticular juvenile idiopathic arthritisHumira in combination with methotrexate is indicated for the treatment of active polyarticular juvenile idiopathic arthritis, in patients from the age of 2 years who have had an inadequate response to one or more disease-modifying anti-rheumatic drugs (DMARDs). Humira can be given as monotherapy in case of intolerance to methotrexate or when continued treatment with methotrexate is inappropriate (for the efficacy in monotherapy see section 5.1). Humira has not been studied in patients aged less than 2 years.
Enthesitis-related arthritisHumira is indicated for the treatment of active enthesitis-related arthritis in patients, 6 years of age and older, who have had an inadequate response to, or who are intolerant of, conventional therapy (see section 5.1).
Ankylosing spondylitis (AS)Humira is indicated for the treatment of adults with severe active ankylosing spondylitis who have had an inadequate response to conventional therapy.
Axial spondyloarthritis without radiographic evidence of ASHumira is indicated for the treatment of adults with severe axial spondyloarthritis without radiographic evidence of AS but with objective signs of inflammation by elevated CRP and / or MRI, who have had an inadequate response to, or are intolerant to nonsteroidal anti-inflammatory drugs.
Psoriatic arthritisHumira is indicated for the treatment of active and progressive psoriatic arthritis in adults when the response to previous disease-modifying anti-rheumatic drug therapy has been inadequate. Humira has been shown to reduce the rate of progression of peripheral joint damage as measured by X-ray in patients with polyarticular symmetrical subtypes of the disease (see Section 5.1) and to improve physical function.
PsoriasisHumira is indicated for the treatment of moderate to severe chronic plaque psoriasis in adult patients who failed to respond to or who have a contraindication to, or are intolerant to other systemic therapy including cyclosporine, methotrexate or PUVA.
Paediatric plaque psoriasisHumira is indicated for the treatment of severe chronic plaque psoriasis in children and adolescents from 4 years of age who have had an inadequate response to or are inappropriate candidates for topical therapy and phototherapies.
Crohn's diseaseHumira is indicated for treatment of moderately to severely active Crohn's disease, in adult patients who have not responded despite a full and adequate course of therapy with a corticosteroid and/or an immunosuppressant; or who are intolerant to or have medical contraindications for such therapies.
Paediatric Crohn's diseaseHumira is indicated for the treatment of severe active Crohn's disease in paediatric patients (from 6 years of age) who have had an inadequate response to conventional therapy including primary nutrition therapy, a corticosteroid, and an immunomodulator, or who are intolerant to or have contraindications for such therapies.
Ulcerative colitisHumira is indicated for treatment of moderately to severely active ulcerative colitis in adult patients who have had an inadequate response to conventional therapy including corticosteroids and 6-mercaptopurine (6-MP) or azathioprine (AZA), or who are intolerant to or have medical contraindications for such therapies.
PosologyHumira treatment should be initiated and supervised by specialist physicians experienced in the diagnosis and treatment of conditions for which Humira is indicated. Patients treated with Humira should be given the special alert card.After proper training in injection technique, patients may self-inject with Humira if their physician determines that it is appropriate and with medical follow-up as necessary. During treatment with Humira, other concomitant therapies (e.g., corticosteroids and/or immunomodulatory agents) should be optimised.
Rheumatoid arthritisThe recommended dose of Humira for adult patients with rheumatoid arthritis is 40 mg adalimumab administered every other week as a single dose via subcutaneous injection. Methotrexate should be continued during treatment with Humira.Glucocorticoids, salicylates, nonsteroidal anti-inflammatory drugs, or analgesics can be continued during treatment with Humira. Regarding combination with disease modifying anti-rheumatic drugs other than methotrexate see sections 4.4 and 5.1.In monotherapy, some patients who experience a decrease in their response may benefit from an increase in dose intensity to 40 mg adalimumab every week.
Dose InterruptionThere may be a need for dose interruption, for instance before surgery or if a serious infection occurs.Available data suggest that re-introduction of Humira after discontinuation for 70 days or longer resulted in the same magnitudes of clinical response and similar safety profile as before dose interruption.Ankylosing spondylitis, axial spondyloarthritis without radiographic evidence of AS and psoriatic arthritisThe recommended dose of Humira for patients with ankylosing spondylitis, axial spondyloarthritis without radiographic evidence of AS and for patients with psoriatic arthritis is 40 mg adalimumab administered every other week as a single dose via subcutaneous injection.For all of the above indications, available data suggest that the clinical response is usually achieved within 12 weeks of treatment. Continued therapy should be carefully reconsidered in a patient not responding within this time period.
PsoriasisThe recommended dose of Humira for adult patients is an initial dose of 80 mg administered subcutaneously, followed by 40 mg subcutaneously given every other week starting one week after the initial dose.Continued therapy beyond 16 weeks should be carefully reconsidered in a patient not responding within this time period.
Crohn's diseaseThe recommended Humira induction dose regimen for adult patients with moderately to severely active Crohn's disease is 80 mg at Week 0 followed by 40 mg at Week 2. In case there is a need for a more rapid response to therapy, the regimen 160 mg at Week 0 (dose can be administered as four injections in one day or as two injections per day for two consecutive days), 80 mg at Week 2, can be used with the awareness that the risk for adverse events is higher during induction.After induction treatment, the recommended dose is 40 mg every other week via subcutaneous injection. Alternatively, if a patient has stopped Humira and signs and symptoms of disease recur, Humira may be re-administered. There is little experience from re-administration after more than 8 weeks since the previous dose.During maintenance treatment, corticosteroids may be tapered in accordance with clinical practice guidelines.Some patients who experience decrease in their response may benefit from an increase in dosing frequency to 40 mg Humira every week.Some patients who have not responded by Week 4 may benefit from continued maintenance therapy through Week 12. Continued therapy should be carefully reconsidered in a patient not responding within this time period.
Ulcerative colitisThe recommended Humira induction dose regimen for adult patients with moderate to severe ulcerative colitis is 160 mg at Week 0 (dose can be administered as four injections in one day or as two injections per day for two consecutive days) and 80 mg at Week 2. After induction treatment, the recommended dose is 40 mg every other week via subcutaneous injection. During maintenance treatment, corticosteroids may be tapered in accordance with clinical practice guidelines. Some patients who experience decrease in their response may benefit from an increase in dosing frequency to 40 mg Humira every week.Available data suggest that clinical response is usually achieved within 2-8 weeks of treatment. Humira therapy should not be continued in patients failing to respond within this time period.Older peopleNo dose adjustment is required.
Impaired renal and/or hepatic functionHumira has not been studied in these patient populations. No dose recommendations can be made.
Juvenile idiopathic arthritisPolyarticular juvenile idiopathic arthritis from 2 to 12 years of ageThe recommended dose of Humira for patients with polyarticular juvenile idiopathic arthritis, aged 2-12 years, is 24 mg/m² body surface area up to a maximum single dose of 20 mg adalimumab (for patients aged 2-<4) and up to a maximum single dose of 40 mg adalimumab (for patients aged 4-12) administered every other week via subcutaneous injection. The volume for injection is selected based on the patients' height and weight (Table 1). A 40 mg paediatric vial is available for patients who need to administer less than the full 40 mg dose.
Humira Dose in Millilitres (ml) by Height and Weight of Patients for Polyarticular Juvenile Idiopathic Arthritis and Enthesitis-Related Arthritis
|Height (cm)||Total Body Weight (kg)|
Paediatric plaque psoriasisThe recommended Humira dose is 0.8 mg per kg body weight (up to a maximum of 40 mg per dose) administered subcutaneously weekly for the first two doses and every other week thereafter. Continued therapy beyond 16 weeks should be carefully considered in a patient not responding within this time period.If retreatment with Humira is indicated, the above guidance on dose and treatment duration should be followed.The safety of Humira in paediatric patients with plaque psoriasis has been assessed for a mean of 13 months.There is no relevant use of Humira in children aged less than 4 years in this indication.The volume for injection is selected based on the patients' weight (Table 2).Table 2: Humira Dose in Milliliters (ml) by Weight for Patients with Pediatric Psoriasis
|Body Weight (kg)||Paediatric Psoriasis Dose|
|13 16||0.2 ml (10 mg)|
|17 22||0.3 ml (15 mg)|
|23 28||0.4 ml (20 mg)|
|29 34||0.5 ml (25 mg)|
|35 40||0.6 ml (30 mg)|
|41 46||0.7 ml (35 mg)|
|47+||0.8 ml (40 mg)|
Paediatric Crohn's diseasePaediatric Crohn's disease patients < 40 kg: The recommended Humira induction dose regimen for paediatric subjects with severe Crohn's disease is 40 mg at Week 0 followed by 20 mg at Week 2. In case there is a need for a more rapid response to therapy, the regimen 80 mg at Week 0 (dose can be administered as two injections in one day), 40 mg at Week 2 can be used, with the awareness that the risk for adverse events may be higher with use of the higher induction dose.After induction treatment, the recommended dose is 20 mg every other week via subcutaneous injection. Some subjects who experience insufficient response may benefit from an increase in dosing frequency to 20 mg Humira every week. Paediatric Crohn's disease patients ≥ 40 kg: The recommended Humira induction dose regimen for paediatric subjects with severe Crohn's disease is 80 mg at Week 0 followed by 40 mg at Week 2. In case there is a need for a more rapid response to therapy, the regimen 160 mg at Week 0 (dose can be administered as four injections in one day or as two injections per day for two consecutive days), 80 mg at Week 2 can be used, with the awareness that the risk for adverse events may be higher with use of the higher induction dose.After induction treatment, the recommended dose is 40 mg every other week via subcutaneous injection. Some subjects who experience insufficient response may benefit from an increase in dosing frequency to 40 mg Humira every week. Continued therapy should be carefully considered in a subject not responding by Week 12.There is no relevant use of Humira in children aged less than 6 years in this indication.
Paediatric ulcerative colitisThe safety and efficacy of Humira in children aged 4-17 years have not yet been established. No data are available. There is no relevant use of Humira in children aged <4 years in this indication.
Psoriatic arthritis and axial spondyloarthritis including ankylosing spondylitisThere is no relevant use of Humira in the paediatric population in the indications, ankylosing spondylitis and psoriatric arthritis.
Method of administrationHumira is administered by subcutaneous injection. Full instructions for use are provided in the package leaflet.A 40 mg pen and a 40 mg prefilled syringe are available for patients to administer a full 40 mg dose. A 40 mg paediatric vial is available for patients who need to administer less than the full 40 mg dose.
Tuberculosis:Tuberculosis, including reactivation and new onset of tuberculosis, has been reported in patients receiving Humira. Reports included cases of pulmonary and extra-pulmonary (i.e. disseminated) tuberculosis. Before initiation of therapy with Humira, all patients must be evaluated for both active or inactive (latent) tuberculosis infection. This evaluation should include a detailed medical assessment of patient history of tuberculosis or possible previous exposure to people with active tuberculosis and previous and/or current immunosuppressive therapy. Appropriate screening tests (i.e. tuberculin skin test and chest X-ray) should be performed in all patients (local recommendations may apply). It is recommended that the conduct and results of these tests are recorded in the patient alert card. Prescribers are reminded of the risk of false negative tuberculin skin test results, especially in patients who are severely ill or immunocompromised. If active tuberculosis is diagnosed, Humira therapy must not be initiated (see section 4.3). In all situations described below, the benefit/risk balance of therapy should be very carefully considered.If latent tuberculosis is suspected, a physician with expertise in the treatment of tuberculosis should be consulted. If latent tuberculosis is diagnosed, appropriate treatment must be started with anti-tuberculosis prophylaxistreatment before the initiation of Humira, and in accordance with local recommendations. Use of anti-tuberculosis prophylaxis treatment should also be considered before the initiation of Humira in patients with several or significant risk factors for tuberculosis despite a negative test for tuberculosis and in patients with a past history of latent or active tuberculosis in whom an adequate course of treatment cannot be confirmed. Despite prophylactic treatment for tuberculosis, cases of reactivated tuberculosis have occurred in patients treated with Humira. Some patients who have been successfully treated for active tuberculosis have redeveloped tuberculosis while being treated with Humira.Patients should be instructed to seek medical advice if signs/symptoms suggestive of a tuberculosis infection (e.g., persistent cough, wasting/weight loss, low grade fever, listlessness) occur during or after therapy with Humira.
Other opportunistic infections:Opportunistic infections, including invasive fungal infections have been observed in patients receiving Humira. These infections have not consistently been recognised in patients taking TNF-antagonists and this resulted in delays in appropriate treatment, sometimes resulting in fatal outcomes. For patients who develop the signs and symptoms such as fever, malaise, weight loss, sweats, cough, dyspnea, and/or pulmonary infiltrates or other serious systemic illness with or without concomitant shock an invasive fungal infection should be suspected and administration of Humira should be promptly discontinued. Diagnosis and administration of empiric antifungal therapy in these patients should be made in consultation with a physician with expertise in the care of patients with invasive fungal infections. Hepatitis B reactivationReactivation of hepatitis B has occurred in patients receiving a TNF-antagonist including Humira, who are chronic carriers of this virus (i.e. surface antigen positive). Some cases have had a fatal outcome. Patients should be tested forHBV infection before initiating treatment with Humira. 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 Humira 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, Humira should be stopped and effective anti-viral therapy with appropriate supportive treatment should be initiated. Neurological eventsTNF-antagonists including Humira have been associated in rare instances with new onset or exacerbation of clinical symptoms and/or radiographic evidence of central nervous system, demyelinating disease including multiple sclerosis, optic neuritis and peripheral demyelinating disease, including Guillain-Barré syndrome. Prescribers should exercise caution in considering the use of Humira in patients with pre-existing or recent-onset central or peripheral nervous system demyelinating disorders. Allergic reactionsSerious allergic reactions associated with Humira were rare during clinical trials. Non-serious allergic reactions associated with Humira were uncommon during clinical trials. Reports of serious allergic reactions including anaphylaxis have been received following Humira administration. If an anaphylactic reaction or other serious allergic reaction occurs, administration of Humira should be discontinued immediately and appropriate therapy initiated. ImmunosuppressionIn a study of 64 patients with rheumatoid arthritis that were treated with Humira, there was no evidence of depression of delayed-type hypersensitivity, depression of immunoglobulin levels, or change in enumeration of effector T-, B, - NK-cells, monocyte/macrophages, and neutrophils.Malignancies and lymphoproliferative disordersIn the controlled portions of clinical trials of TNF-antagonists, more cases of malignancies including lymphoma have been observed among patients receiving a TNF-antagonist compared with control patients. However, the occurrence was rare. In the post marketing setting, cases of leukemia have been reported in patients treated with a TNF-antagonist. There is an increased background risk for lymphoma and leukemia in rheumatoid arthritis patients with long-standing highly active, inflammatory disease, which complicates the risk estimation. With the current knowledge, a possible risk for the development of lymphomas, leukemia, and other malignancies in patients treated with a TNF-antagonist cannot be excluded.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), including adalimumab 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. Rare postmarketing cases of hepatosplenic T-cell lymphoma have been identified in patients treated with adalimumab. This rare type of T-cell lymphoma has a very aggressive disease course and is usually fatal. Some of these hepatosplenic T-cell lymphomas with Humira have occurred in young adult patients on concomitant treatment with azathioprine or 6-mercaptopurine used for inflammatory bowel disease. The potential risk with the combination of azathioprine or 6-mercaptopurine and Humira should be carefully considered. A risk for the development of hepatosplenic T-cell lymphoma in patients treated with Humira cannot be excluded (see section 4.8).No studies have been conducted that include patients with a history of malignancy or in whom treatment with Humira is continued following development of malignancy. Thus additional caution should be exercised in considering Humira treatment of these patients (see section 4.8).All patients, and in particular patients with a medical history of extensive immunosuppressant therapy or psoriasis patients with a history of PUVA treatment should be examined for the presence of non-melanoma skin cancer prior to and during treatment with Humira. Melanoma and Merkel cell carcinoma have also been reported in patients treated with TNF-antagonists including adalimumab (see section 4.8).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.With current data it is not known if adalimumab treatment influences the risk for developing dysplasia or colon cancer. All patients with ulcerative colitis who are at increased risk for dysplasia or colon carcinoma (for example, patients with long-standing ulcerative colitis or primary sclerosing cholangitis), or who had a prior history of dysplasia or colon carcinoma should be screened for dysplasia at regular intervals before therapy and throughout their disease course. This evaluation should include colonoscopy and biopsies per local recommendations.Haematologic reactionsRare reports of pancytopaenia including aplastic anaemia have been reported with TNF-antagonists. Adverse events of the haematologic system, including medically significant cytopoenia (e.g. thrombocytopaenia, leucopaenia) have been reported with Humira. All patients should be advised to seek immediate medical attention if they develop signs and symptoms suggestive of blood dyscrasias (e.g. persistent fever, bruising, bleeding, pallor) while on Humira. Discontinuation of Humira therapy should be considered in patients with confirmed significant haematologic abnormalities.Vaccinations 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 Humira. It is recommended thatpaediatric patients, if possible, be brought up to date with all immunisations in agreement with current immunisation guidelines prior to initiating Humira therapy.Patients on Humira may receive concurrent vaccinations, except for live vaccines. Administration of live vaccines to infants exposed to adalimumab in utero is not recommended for 5 months following the mother's last adalimumab injection during pregnancy.Congestive heart failureIn 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 Humira. Humira should be used with caution in patients with mild heart failure (NYHA class I/II). Humira is contraindicated in moderate to severe heart failure (see section 4.3). Treatment with Humira must be discontinued in patients who develop new or worsening symptoms of congestive heart failure.Autoimmune processesTreatment with Humira may result in the formation of autoimmune antibodies. The impact of long-term treatment with Humira on the development of autoimmune diseases is unknown. If a patient develops symptoms suggestive of a lupus-like syndrome following treatment with Humira and is positive for antibodies against double-stranded DNA, further treatment with Humira should not be given (see section 4.8).Concurrent administration of biologic DMARDS or TNF-antagonistsSerious infections were seen in clinical studies with concurrent use of anakinra and another TNF-antagonist, etanercept, with no added clinical benefit compared to etanercept alone. Because of the nature of the adverse events seen with the combination of etanercept and anakinra therapy, similar toxicities may also result from the combination of anakinra and other TNF-antagonists. Therefore, the combination of adalimumab and anakinra is not recommended. (See section 4.5).Concomitant administration of adalimumab with other biologic DMARDS (e.g, anakinra and abatacept) or other TNF-antagonists is not recommended based upon the possible increased risk for infections, including serious infections and other potential pharmacological interactions. (See section 4.5).SurgeryThere is limited safety experience of surgical procedures in patients treated with Humira. The long half-life of adalimumab should be taken into consideration if a surgical procedure is planned. A patient who requires surgery while on Humira should be closely monitored for infections, and appropriate actions should be taken. There is limited safety experience in patients undergoing arthroplasty while receiving Humira. Small bowel obstructionFailure to respond to treatment for Crohn's disease may indicate the presence of fixed fibrotic stricture that may require surgical treatment. Available data suggest that Humira does not worsen or cause strictures.
Older peopleThe frequency of serious infections among Humira treated subjects over 65 years of age (3.5%) was higher than for those under 65 years of age (1.45%). Some of those had a fatal outcome. Particular attention regarding the risk for infection should be paid when treating the elderly.
Paediatric populationSee Vaccinations above.
PregnancyFor Humira, limited clinical data on exposed pregnancies are available.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 (see section 5.3).Due to its inhibition of TNFα, adalimumab administered during pregnancy could affect normal immune responses in the newborn. Administration of adalimumab is not recommended during pregnancy.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 to infants exposed to adalimumab in utero is not recommended for 5 months following the mother's last adalimumab injection during pregnancy.
Breast feedingIt is not known whether adalimumab is excreted in human milk or absorbed systemically after ingestion. However, because human immunoglobulins are excreted in milk, women must not breast-feed for at least five months after the last Humira treatment.
FertilityPreclinical data on fertility effects of adalimumab are not available.
Women of child bearing potential, Contraception in males and femalesWomen of childbearing potential are strongly recommended to use adequate contraception to prevent pregnancy and continue its use for at least five months after the last Humira treatment.
Summary of the safety profileThe 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 Humira. TNF-antagonists, such as Humira affect the immune system and their use may affect the body's defense 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 Humira.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.
Undesirable effects in paediatric patientsIn general, the adverse events in paediatric patients were similar in frequency and type to those seen in adult patients.Tabulated list of adverse reactionsThe following list of adverse reactions is based on experience from clinical trials and on postmarketing experience and is 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) in Table 3 below. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. The highest frequency seen among the various indications has been included. An asterisk (*) appears in the SOC column if further information is found elsewhere in sections 4.3, 4.4 and 4.8.
|System Organ Class||Frequency||Adverse Reaction|
|Infections and infestations*||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 infection|
|Uncommon||neurological infections (including viral meningitis), opportunistic infections and tuberculosis (including coccidioidomycosis, histoplasmosis and mycobacterium aviumcomplex infection), eye infections, diverticulitis1)|
|Neoplasms benign, malignant and unspecified (including cysts and polyps)*||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**|
|Not Known||hepatosplenic T-cell lymphoma1)Merkel cell carcinoma (neuroendocrine carcinoma of the skin)1)|
|Blood and the lymphatic system disorders*||Very common||leucopaenia (including neutropaenia and agranulocytosis), anaemia|
|Uncommon||idiopathic thrombocytopaenic purpura|
|Immune system disorders*||Common||hypersensitivity, allergies (including seasonal allergy)|
|Metabolism and nutrition disorders||Very common||lipids increased|
|Common||hypokalaemia, uric acid increased, blood sodium abnormal, hypocalcaemia, hyperglycaemia, hypophosphataemia, dehydration|
|Psychiatric disorders||Common||mood alterations (including depression), anxiety, insomnia|
|Nervous system disorders*||Very common||headache|
|Common||paraesthesias (including hypoaesthesia), migraine, nerve root compression|
|Uncommon||cerebrovascular accident 1), tremor, neuropathy|
|Rare||multiple sclerosis, demyelinating disorder (e.g. optic neuritis, Guillain-Barré syndrome) 1)|
|Eye disorders||Common||visual impairment, conjunctivitis, blepharitis, eye swelling,|
|Ear and labyrinth disorders||Common||vertigo|
|Uncommon||myocardial infarction1), arrhythmia, congestive heart failure|
|Vascular disorders||Common||hypertension, flushing, haematoma|
|Uncommon||aortic aneurysm vascular arterial occlusion, thrombophlebitis|
|Respiratory, thoracic and mediastinal disorders*||Common||asthma, dyspnoea, cough|
|Uncommon||pulmonary embolism1), interstitial lung disease, chronic obstructive pulmonary disease, pneumonitis pleural effusion1)|
|Gastrointestinal disorders||Very common||abdominal pain, nausea and vomiting|
|Common||GI haemorrhage, dyspepsia, gastroesophageal reflux disease, sicca syndrome|
|Uncommon||pancreatitis, dysphagia, face oedema|
|Hepato-biliary disorders*||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)|
|Skin and subcutaneous tissue disorders||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, hyperhydrosis, alopecia 1), pruritus|
|Uncommon||night sweats, scar|
|Rare||erythema multiforme1)Stevens-Johnson syndrome1), angioedema1), cutaneous vasculitis1)|
|Not known||worsening of symptoms of dermatomyositis1)|
|Musculoskeletal and, connective tissue disorders||Very common||musculoskeletal pain|
|Common||muscle spasms (including blood creatine phosphokinase increased)|
|Uncommon||rhabdomyolysis, systemic lupus erythematosus|
|Renal and urinary disorders||Common||renal impairment, haematuria|
|Reproductive system and breast disorders||Uncommon||erectile dysfunction|
|General disorders and administration site conditions*||Very Common||injection site reaction (including injection site erythema)|
|Common||chest pain, oedema, pyrexia1)|
|Investigations*||Common||coagulation and bleeding disorders (including activated partial thromboplastin time prolonged), autoantibody test positive (including double stranded DNA antibody), blood lactate dehydrogenase increased|
|Injury, poisoning and procedural complications||Common||impaired healing|
Description of selected adverse reactionsInjection site reactionsIn the pivotal controlled trials in adults and children, 13.5 % of patients treated with Humira developed injection site reactions (erythema and/or itching, haemorrhage, pain or swelling), compared to 7.6% of patients receiving placebo or active control. Injection site reactions generally did not necessitate discontinuation of the medicinal product. InfectionsIn the pivotal controlled trials in adults and children, the rate of infection was 1.51 per patient year in the Humira treated patients and 1.44 per patient year in the placebo and active control-treated patients. The infections consisted primarily of nasopharyngitis, upper respiratory tract infection, and urinary tract infection. Most patients continued on Humira after the infection resolved. The incidence of serious infections was 0.04 per patient year in Humira 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 Humira, 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.Malignancies and lymphoproliferative disordersNo malignancies were observed in 249 paediatric patients with an exposure of 655.6 patient years during Humira 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 258.9 patient years during a Humira trial 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 Humira trial in paediatric patients with chronic plaque psoriasis.During the controlled portions of pivotal Humira 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, Crohn's disease and ulcerative colitis malignancies, other than lymphoma and non-melanoma skin cancer, were observed at a rate (95% confidence interval) of 6.0 (3.7, 9.8) per 1,000 patient-years among 4,622 Humira treated patients versus a rate of 5.1 (2.4, 10.7) per 1,000 patient-years among 2,828 control patients (median duration of treatment was 5.1 months for Humira and 4.0 months for control-treated patients). The rate (95% confidence interval) of non-melanoma skin cancers was 9.7 (6.6, 14.3) per 1,000 patient-years among Humira-treated patients and 5.1 (2.4, 10.7) per 1,000 patient-years among control patients. Of these skin cancers, squamous cell carcinomas occurred at rates (95% confidence interval) of 2.6 (1.2, 5.5) per 1,000 patient-years among Humira-treated patients and 0.7 (0.1, 5.2) per 1,000 patient-years among control patients. The rate (95% confidence interval) of lymphomas was 0.7 (0.2, 3.0) per 1,000 patient-years among Humira-treated patients and 1.5 (0.4, 5.8) 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 3.4 years including 5,727 patients and over 24,568 patient-years of therapy, the observed rate of malignancies, other than lymphoma and non-melanoma skin cancers is approximately 8.8 per 1,000 patient years. The observed rate of non-melanoma skin cancers is approximately 10.3 per 1,000 patient years, and the observed rate of lymphomas is approximately 1.4 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 (see section 4.4).Rare post-marketing cases of hepatosplenic T-cell lymphoma have been reported in patients treated with adalimumab (see section 4.4).Autoantibodies 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 Humira 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 Humira 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.
Hepato-biliary eventsIn controlled Phase 3 trials of Humira 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 Humira-treated patients and 1.6% of control-treated patients. In controlled Phase 3 trials of Humira 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 Humira-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 Humira in patients with polyarticular juvenile idiopathic arthritis who were 2 to <4 years.In controlled Phase 3 trials of Humira 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 Humira-treated patients and 0.9% of controlled-treated patients. In the Phase 3 trial of Humira 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% of patients all of whom were exposed to concomitant immunosuppressants at baseline.In controlled Phase 3 trials of Humira 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 Humira-treated patients and 1.8% of control-treated patients. No ALT elevations ≥3 X ULN occurred in the Phase 3 trial of Humira in paediatric patients with plaque psoriasis.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.
Concurrent treatment with azathioprine/6-mercaptopurineIn adult Crohn's disease studies, higher incidences of malignant and serious infection-related adverse events were seen with the combination of Humira and azathioprine/6-mercaptopurine compared with Humira alone.
Reporting of suspected adverse reactionsReporting 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 Yellow Card Scheme:Website: www.mhra.gov.uk/yellowcard
Adults with rheumatoid arthritisHumira was evaluated in over 3000 patients in all rheumatoid arthritis clinical trials. The efficacy and safety of Humira were assessed in five randomised, double-blind and well-controlled studies. Some patients were treated for up to 120 months duration. RA study I evaluated 271 patients with moderately to severely active rheumatoid arthritis who were ≥ 18 years old, had failed therapy with at least one disease-modifying, anti rheumatic drug and had insufficient efficacy with methotrexate at doses of 12.5 to 25 mg (10 mg if methotrexate-intolerant) every week and whose methotrexate dose remained constant at 10 to 25 mg every week. Doses of 20, 40 or 80 mg of Humira or placebo were given every other week for 24 weeks. RA study II evaluated 544 patients with moderately to severely active rheumatoid arthritis who were ≥ 18 years old and had failed therapy with at least one disease-modifying, anti-rheumatic drugs. Doses of 20 or 40 mg of Humira were given by subcutaneous injection every other week with placebo on alternative weeks or every week for 26 weeks; placebo was given every week for the same duration. No other disease-modifying anti-rheumatic drugs were allowed.RA study III evaluated 619 patients with moderately to severely active rheumatoid arthritis who were ≥ 18 years old, and who had an ineffective response to methotrexate at doses of 12.5 to 25 mg or have been intolerant to 10 mg of methotrexate every week. There were three groups in this study. The first received placebo injections every week for 52 weeks. The second received 20 mg of Humira every week for 52 weeks. The third group received 40 mg of Humira every other week with placebo injections on alternate weeks. Upon completion of the first 52 weeks, 457 patients enrolled in an open-label extension phase in which 40 mg of Humira/MTX was administered every other week up to 10 years.RA study IV primarily assessed safety in 636 patients with moderately to severely active rheumatoid arthritis who were ≥ 18 years old. Patients were permitted to be either disease-modifying, anti-rheumatic drug-naïve or to remain on their pre-existing rheumatologic therapy provided that therapy was stable for a minimum of 28 days. These therapies include methotrexate, leflunomide, hydroxychloroquine, sulfasalazine and/or gold salts. Patients were randomised to 40 mg of Humira or placebo every other week for 24 weeks. RA study V evaluated 799 methotrexate-naïve, adult patients with moderate to severely active early rheumatoid arthritis (mean disease duration less than 9 months). This study evaluated the efficacy of Humira 40 mg every other week/methotrexate combination therapy, Humira 40 mg every other week monotherapy and methotrexate monotherapy in reducing the signs and symptoms and rate of progression of joint damage in rheumatoid arthritis for 104 weeks.The primary end point in RA studies I, II and III and the secondary endpoint in RA study IV was the percent of patients who achieved an ACR 20 response at Week 24 or 26. The primary endpoint in RA study V was the percent of patients who achieved an ACR 50 response at Week 52. RA studies III and V had an additional primary endpoint at 52 weeks of retardation of disease progression (as detected by X-ray results). RA study III also had a primary endpoint of changes in quality of life.ACR responseThe percent of Humira-treated patients achieving ACR 20, 50 and 70 responses was consistent across RA studies I, II and III. The results for the 40 mg every other week dose are summarised in Table 4. Table 4 ACR Responses in Placebo-Controlled Trials(Percent of Patients)
|Response||RA Study Ia**||RA Study IIa**||RA Study IIIa**|
|Placebo/ MTXc||Humirab/ MTXc||Placebo||Humirab||Placebo/ MTXc||Humirab/ MTXc|
|a RA study I at 24 weeks, RA study II at 26 weeks , and RA study III at 24 and 52 weeks b 40 mg Humira administered every other week c MTX = methotrexate **p < 0.01, Humira versus placebo|
|Week 52||62.6%||54.4%||72.8%||0.013||< 0.001||0.043|
|Week 104||56.0%||49.3%||69.4%||0.002||< 0.001||0.140|
|Week 52||45.9%||41.2%||61.6%||< 0.001||< 0.001||0.317|
|Week 104||42.8%||36.9%||59.0%||< 0.001||< 0.001||0.162|
|Week 52||27.2%||25.9%||45.5%||< 0.001||< 0.001||0.656|
|Week 104||28.4%||28.1%||46.6%||< 0.001||< 0.001||0.864|
|a. p-value is from the pairwise comparison of methotrexate monotherapy and Humira/methotrexate combination therapy using the Mann-Whitney U test. b. p-value is from the pairwise comparison of Humira monotherapy and Humira/methotrexate combination therapy using the Mann-Whitney U test c. p-value is from the pairwise comparison of Humira monotherapy and methotrexate monotherapy using the Mann-Whitney U test|
|Placebo/MTXa||Humira/MTX 40 mg every other week||Placebo/MTX-Humira/MTX (95% Confidence Intervalb)||p-value|
|Total Sharp Score||2.7||0.1||2.6 (1.4, 3.8)||< 0.001c|
|Erosion score||1.6||0.0||1.6 (0.9, 2.2)||< 0.001|
|JSNd score||1.0||0.1||0.9 (0.3, 1.4)||0.002|
|MTX n=257 (95% confidence interval)||Humira n=274 (95% confidence interval)||Humira/MTX n=268 (95% confidence interval)||p-valuea||p-valueb||p-valuec|
|Total Sharp Score||5.7 (4.2-7.3)||3.0 (1.7-4.3)||1.3 (0.5-2.1)||< 0.001||0.0020||< 0.001|
|Erosion score||3.7 (2.7-4.7)||1.7 (1.0-2.4)||0.8 (0.4-1.2)||< 0.001||0.0082||< 0.001|
|JSN score||2.0 (1.2-2.8)||1.3 (0.5-2.1)||0.5 (0-1.0)||< 0.001||0.0037||0.151|
Juvenile idiopathric arthritis (JIA)
Polyarticular juvenile idiopathic arthritis (pJIA)The safety and efficacy of Humira was assessed in two studies (pJIA I and II) in children with active polyarticular or polyarticular course juvenile idiopathic arthritis, who had a variety of JIA onset types (most frequently rheumatoid-factor negative or positive polyarthritis and extended oligoarthritis).pJIA IThe safety and efficacy of Humira were assessed in a multicentre, randomised, double-blind, parallel − group study in 171 children (4-17 years old) with polyarticular JIA. In the open-label lead in phase (OL LI) patients were stratified into two groups, MTX (methotrexate)-treated or non-MTX-treated. Patients who were in the non-MTX stratum were either naïve to or had been withdrawn from MTX at least two weeks prior to study drug administration. Patients remained on stable doses of NSAIDs and or prednisone (≤ 0.2 mg /kg/day or 10 mg/day maximum). In the OL LI phase all patients received 24 mg/m2 up to a maximum of 40 mg Humira every other week for 16 weeks. The distribution of patients by age and minimum, median and maximum dose received during the OL LI phase is presented in Table 8.Table 8Distribution of patients by age and adalimumab dose received during the OL LI phase
|Age Group||Number of patients at Baseline n (%)||Minimum, median and maximum dose|
|4 to 7 years||31 (18.1)||10, 20 and 25 mg|
|8 to 12 years||71 (41.5)||20, 25 and 40 mg|
|13 to 17 years||69 (40.4)||25, 40 and 40 mg|
|OL-LI 16 weeks|
|Ped ACR 30 response (n/N)||94.1% (80/85)||74.4% (64/86)|
|Double Blind 32 week||Humira /MTX (N = 38)||Placebo/ MTX (N = 37)||Humira (N = 30)||Placebo (N = 28)|
|Disease flares at the end of 32 weeksa (n/N)||36.8% (14/38)||64.9% (24/37)b||43.3% (13/30)||71.4% (20/28)c|
|Median time to disease flare||>32 weeks||20 weeks||>32 weeks||14 weeks|
Enthesitis-related arthritisThe safety and efficacy of Humira were assessed in a multicenter, randomised, double-blind study in 46 paediatric patients (6 to 17 years old) with moderate enthesitis-related arthritis. Patients were randomised to receive either 24 mg/m2 body surface area (BSA) of Humira up to a maximum of 40 mg, or placebo every other week for 12 weeks. The double-blind period is followed by an open-label (OL) period during which patients received 24 mg/m2 BSA of Humira up to a maximum of 40 mg every other week subcutaneously for up to an additional 192 weeks. The primary endpoint was the percent change from Baseline to Week 12 in the number of active joints with arthritis (swelling not due to deformity or joints with loss of motion plus pain and/or tenderness), which was achieved with mean percent decrease of -62.6% (median percent change -88.9%) in patients in the Humira group compared to -11.6% (median percent change -50.0%) in patients in the placebo group. Improvement in number of active joints with arthritis was maintained during the OL period through Week 52 of the study. Although not statistically significant, the majority of patients demonstrated clinical improvement in secondary endpoints such as number of sites of enthesitis, tender joint count (TJC), swollen joint count (SJC), Pediatric ACR 50 response, and Pediatric ACR 70 response.
Axial spondyloarthritisAnkylosing spondylitis (AS)Humira 40 mg every other week was assessed in 393 patients in two randomised, 24 week double − blind, placebo − controlled studies in patients with active ankylosing spondylitis (mean baseline score of disease activity [Bath Ankylosing Spondylitis Disease Activity Index (BASDAI)] was 6.3 in all groups) who have had an inadequate response to conventional therapy. Seventy-nine (20.1%) patients were treated concomitantly with disease modifying anti − rheumatic drugs, and 37 (9.4%) patients with glucocorticoids. The blinded period was followed by an open − label period during which patients received Humira 40 mg every other week subcutaneously for up to an additional 28 weeks. Subjects (n=215, 54.7%) who failed to achieve ASAS 20 at Weeks 12, or 16 or 20 received early escape open-label adalimumab 40 mg every other week subcutaneously and were subsequently treated as non-responders in the double-blind statistical analyses.In the larger AS study I with 315 patients, results showed statistically significant improvement of the signs and symptoms of ankylosing spondylitis in patients treated with Humira compared to placebo. Significant response was first observed at Week 2 and maintained through 24 weeks (Table 10).
Efficacy Responses in Placebo-Controlled AS Study Study I
Reduction of Signs and Symptoms
Axial spondyloarthritis without radiographic evidence of ASHumira 40mg every other week was assessed in 185 patients in one randomised, 12 week double - blind, placebo - controlled study in patients with active non-radiographic axial spondyloarthitis (mean baseline score of disease activity [Bath Ankylosing Spondylitis Disease Activity Index (BASDAI)] was 6.4 for patients treated with Humira and 6.5 for those on placebo) who have had an inadequate response to or intolerance to ≥ 1 NSAIDs, or a contraindication for NSAIDs.Thirty-three (18%) of patients were treated concomitantly with disease modifying anti-rheumatic drugs, and 145 (78%) patients with NSAIDs at baseline. The double-blind period was followed by an open-label period during which patients receive Humira 40 mg every other week subcutaneously for up to an additional 144 weeks. Week 12 results showed statistically significant improvement of the signs and symptoms of active non-radiographic axial spondyloarthritis in patients treated with Humira compared to placebo (Table 11).
Efficacy Response in Placebo-Controlled Axial SpA Study - Reduction of signs and symptoms
|Double-BlindResponse at Week 12||PlaceboN=94||HumiraN=91|
|ASAS partial remission||5%||16%*|
Psoriatic arthritisHumira, 40 mg every other week, was studied in patients with moderately to severely active psoriatic arthritis in two placebo-controlled studies, PsA studies I and II. PsA study I with 24 week duration, treated 313 adult patients who had an inadequate response to non-steroidal anti-inflammatory drug therapy and of these, approximately 50% were taking methotrexate. PsA study II with 12-week duration, treated 100 patients who had an inadequate response to DMARD therapy. Upon completion of both studies, 383 patients enrolled in an open-label extension study, in which 40 mg Humira was administered eow.There is insufficient evidence of the efficacy of Humira in patients with ankylosing spondylitis-like psoriatic arthropathy due to the small number of patients studied. Table 12 ACR Response in Placebo-Controlled Psoriatic Arthritis Studies(Percent of Patients)
|PsA Study I||PsA Study II|
|Response||Placebo N=162||Humira N=151||Placebo N=49||Humira N=51|
|Week 12||1%||20%***||0%||14% *|
PsoriasisThe safety and efficacy of Humira were studied in adult patients with chronic plaque psoriasis (≥ 10% BSA involvement and Psoriasis Area and Severity Index (PASI) ≥ 12 or ≥ 10) who were candidates for systemic therapy or phototherapy in randomised, double-blind studies. 73% of patients enrolled in Psoriasis Studies I and II had received prior systemic therapy or phototherapy. The safety and efficacy of Humira were also studied in adult patients with moderate to severe chronic plaque psoriasis with concomitant hand and/or foot psoriasis who were candidates for systemic therapy in a randomised double-blind study (Psoriasis Study III).Psoriasis Study I (REVEAL) evaluated 1,212 patients within three treatment periods. In period A, patients received placebo or Humira at an initial dose of 80 mg followed by 40 mg every other week starting one week after the initial dose. After 16 weeks of therapy, patients who achieved at least a PASI 75 response (PASI score improvement of at least 75% relative to baseline), entered period B and received open-label 40 mg Humira every other week. Patients who maintained ≥PASI 75 response at Week 33 and were originally randomised to active therapy in Period A, were re-randomised in period C to receive 40 mg Humira every other week or placebo for an additional 19 weeks. Across all treatment groups, the mean baseline PASI score was 18.9 and the baseline Physician's Global Assessment (PGA) score ranged from moderate (53% of subjects included) to severe (41%) to very severe (6%).Psoriasis Study II (CHAMPION) compared the efficacy and safety of Humira versus methotrexate and placebo in 271 patients. Patients received placebo, an initial dose of MTX 7.5 mg and thereafter dose increases up to Week 12, with a maximum dose of 25 mg or an initial dose of 80 mg Humira followed by 40 mg every other week (starting one week after the initial dose) for 16 weeks. There are no data available comparing Humira and MTX beyond 16 weeks of therapy. Patients receiving MTX who achieved a ≥PASI 50 response at Week 8 and/or 12 did not receive further dose increases. Across all treatment groups, the mean baseline PASI score was 19.7 and the baseline PGA score ranged from mild (<1%) to moderate (48%) to severe (46%) to very severe (6%).Patients participating in all Phase 2 and Phase 3 psoriasis studies were eligible to enroll into an open-label extension trial, where Humira was given for at least an additional 108 weeks.In Psoriasis Studies I and II, a primary endpoint was the proportion of patients who achieved a PASI 75 response from baseline at Week 16 (see Tables 13 and 14).Table 13Ps Study I (REVEAL) - Efficacy Results at 16 Weeks
|PlaceboN=398n (%)||Humira 40 mg eowN=814n (%)|
|≥PASI 75a||26 (6.5)||578 (70.9)b|
|PASI 100||3 (0.8)||163 (20.0)b|
|PGA: Clear/minimal||17 (4.3)||506 (62.2)b|
|a Percent of patients achieving PASI75 response was calculated as center-adjusted rate b p<0.001, Humira vs. placebo|
|PlaceboN=53n (%)||MTXN=110n (%)||Humira 40 mg eowN=108n (%)|
|≥PASI 75||10 (18.9)||39 (35.5)||86 (79.6) a, b|
|PASI 100||1 (1.9)||8 (7.3)||18 (16.7) c, d|
|PGA: Clear/minimal||6 (11.3)||33 (30.0)||79 (73.1) a, b|
|a p<0.001 Humira vs. placebo b p<0.001 Humira vs. methotrexate c p<0.01 Humira vs. placebo d p<0.05 Humira vs. methotrexate|
Paediatric plaque psoriasisThe efficacy of Humira was assessed in a randomised, double-blind, controlled study of 114 paediatric patients from 4 years of age with severe chronic plaque psoriasis (as defined by a PGA ≥ 4 or > 20% BSA involvement or > 10% BSA involvement with very thick lesions or PASI ≥ 20 or ≥ 10 with clinically relevant facial, genital, or hand/ foot involvement) who were inadequately controlled with topical therapy and heliotherapy or phototherapy. Patients received Humira 0.8mg/kg eow (up to 40 mg), 0.4 mg/kg eow (up to 20 mg), or methotrexate 0.1 0.4 mg/kg weekly (up to 25 mg). At week 16, more patients randomised to Humira 0.8 mg/kg had positive efficacy responses (e.g., PASI 75) than those randomised to 0.4mg/kg eow or MTX.
|Table 15: Paediatric Plaque Psoriasis Efficacy Results at 16 Weeks|
|MTXa N=37||Humira 0.8mg/kg eow N=38|
|PASI 75b||12 (32.4%)||22 (57.9%)|
|PGA: Clear/minimalc||15 (40.5%)||23 (60.5%)|
|a MTX = methotrexate b P=0.027, Humira 0.8 mg/kg versus MTX c P=0.083, Humira 0.8 mg/kg versus MTX|
|CDStudy I: Infliximab Naive Patients||CD Study II: Infliximab Experienced Patients|
|PlaceboN=74||Humira80/40 mgN = 75||Humira 160/80 mgN=76||PlaceboN=166||Humira 160/80 mgN=159|
|Clinical response (CR-100)||24%||37%||49%**||25%||38%**|
|Placebo||40 mg Humira every other week||40 mg Humira every week|
|Clinical response (CR-100)||27%||52%*||52%*|
|Patients in steroid-free remission for >=90 daysa||3% (2/66)||19% (11/58)**||15% (11/74)**|
|Clinical response (CR-100)||17%||41%*||48%*|
|Patients in steroid-free remission for >=90 daysa||5% (3/66)||29% (17/58)*||20% (15/74)**|
Paediatric Crohn's diseaseHumira was assessed in a multicenter, randomised, double-blind clinical trial designed to evaluate the efficacy and safety of induction and maintenance treatment with doses dependent on body weight (< 40 kg or ≥ 40 kg) in 192 paediatric subjects between the ages of 6 and 17 (inclusive) years, with moderate to severe Crohn´s disease (CD) defined as Paediatric Crohn's Disease Activity Index (PCDAI) score > 30. Subjects had to have failed conventional therapy (including a corticosteroid and/or an immunomodulator) for CD. Subjects may also have previously lost response or been intolerant to infliximab. All subjects received open-label induction therapy at a dose based on their Baseline body weight: 160 mg at Week 0 and 80 mg at Week 2 for subjects ≥ 40 kg, and 80 mg and 40 mg, respectively, for subjects < 40 kg.At Week 4, subjects were randomised 1:1 based on their body weight at the time to either the Low Dose or Standard Dose maintenance regimens as shown in Table 18.
|Table 18Maintenance regimen|
|Patient Weight||Low dose||Standard dose|
|< 40 kg||10 mg eow||20 mg eow|
|≥ 40 kg||20 mg eow||40 mg eow|
Efficacy ResultsThe primary endpoint of the study was clinical remission at Week 26, defined as PCDAI score ≤ 10.Clinical remission and clinical response (defined as reduction in PCDAI score of at least 15 points from Baseline) rates are presented in Table 19. Rates of discontinuation of corticosteroids or immunomodulators are presented in Table 20.
|Table 19Paediatric CD StudyPCDAI Clinical Remission and Response|
|Standard Dose40/20 mg eow N = 93||Low Dose20/10 mg eow N = 95||P value*|
|* p value for Standard Dose versus Low Dose comparison.|
|Table 20Paediatric CD StudyDiscontinuation of Corticosteroids or Immunomodulators and Fistula Remission|
|Standard Dose40/20 mg eow||Low Dose20/10 mg eow||P value1|
|Discontinued corticosteroids||N= 33||N=38|
|Discontinuation of Immunomodulators2||N=60||N=57|
Ulcerative ColitisThe safety and efficacy of multiple doses of Humira were assessed in adult patients with moderately to severely active ulcerative colitis (Mayo score 6 to 12 with endoscopy subscore of 2 to 3) in randomised, double-blind, placebo-controlled studies. In study UC-I, 390 TNF-antagonist naïve patients were randomised to receive either placebo at Weeks 0 and 2, 160 mg Humira at Week 0 followed by 80 mg at Week 2, or 80 mg Humira at Week 0 followed by 40 mg at Week 2. After Week 2, patients in both adalimumab arms received 40 mg eow. Clinical remission (defined as Mayo score ≤ 2 with no subscore > 1) was assessed at Week 8. In study UC-II, 248 patients received 160 mg of Humira at Week 0, 80 mg at Week 2 and 40 mg eow thereafter, and 246 patients received placebo. Clinical results were assessed for induction of remission at Week 8 and for maintenance of remission at Week 52. Patients induced with 160/80 mg Humira achieved clinical remission versus placebo at Week 8 in statistically significantly greater percentages in study UC-I (18% vs. 9% respectively, p=0.031) and study UC-II (17% vs. 9% respectively, p=0.019). In study UC-II, among those treated with Humira who were in remission at Week 8, 21/41 (51%) were in remission at Week 52.Results from the overall UC-II study population are shown in Table 21.
Response, Remission and Mucosal Healing in Study UC-II
(Percent of Patients)
|Placebo||Humira 40 mg eow|
|Steroid-free remission for ≥ 90 days a||6% (N=140)||13% * (N=150)|
|Week 8 and 52|
|Sustained Mucosal Healing||11%||19%*|
Hospitalisation ratesDuring 52 weeks of studies UC-I and UC-II, lower rates of all-cause hospitalisations and UC-related hospitalisations were observed for the adalimumab-treated arm compared to the placebo arm. The number of all cause hospitalisations in the adalimumab treatment group was 0.18 per patient year vs. 0.26 per patient year in the placebo group and the corresponding figures for UC-related hospitalisations were 0.12 per patient year vs. 0.22 per patient year.
Quality of LifeIn study UC-II, treatment with adalimumab resulted in improvements in the Inflammatory Bowel Disease Questionnaire (IBDQ) score.Immunogenicity Formation of anti-adalimumab antibodies is associated with increased clearance and reduced efficacy of adalimumab. There is no apparent correlation between the presence of anti-adalimumab antibodies and the occurrence of adverse events.Patients in rheumatoid arthritis studies I, II and III were tested at multiple time points for anti-adalimumab antibodies during the 6 to 12 month period. In the pivotal trials, anti-adalimumab antibodies were identified in 5.5% (58/1053) of patients treated with adalimumab, compared to 0.5% (2/370) on placebo. In patients not given concomitant methotrexate, the incidence was 12.4%, compared to 0.6% when adalimumab was used as add-on to methotrexate. In patients with polyarticular juvenile idiopathic arthritis who were 4 to 17 years, anti-adalimumab antibodies were identified in 15.8% (27/171) of patients treated with adalimumab. In patients not given concomitant methotrexate, the incidence was 25.6% (22/86), compared to 5.9% (5/85) when adalimumab was used as add-on to methotrexate.In patients with enthesitis-related arthritis, anti-adalimumab antibodies were identified in 10.9% (5/46) of patients treated with adalimumab. In patients not given concomitant methotrexate, the incidence was 13.6% (3/22), compared to 8.3% (2/24) when adalimumab was used as add-on to methotrexate.In patients with psoriatic arthritis, anti-adalimumab antibodies were identified in 38/376 subjects (10%) treated with adalimumab. In patients not given concomitant methotrexate, the incidence was 13.5% (24/178 subjects), compared to 7% (14 of 198 subjects) when adalimumab was used as add-on to methotrexate.In patients with ankylosing spondylitis anti-adalimumab antibodies were identified in 17/204 subjects (8.3%) treated with adalimumab. In patients not given concomitant methotrexate, the incidence was 16/185 (8.6%), compared to 1/19 (5.3%) when adalimumab was used as add-on to methotrexate.In patients with Crohn's disease, anti-adalimumab antibodies were identified in 7/269 subjects (2.6%) and in 19/487 subjects (3.9%) with ulcerative colitis.In adult patients with psoriasis, anti-adalimumab antibodies were identified in 77/920 subjects (8.4%) treated with adalimumab monotherapy.In adult plaque psoriasis patients on long term adalimumab monotherapy who participated in a withdrawal and retreatment study, the rate of antibodies to adalimumab after retreatment (11 of 482 subjects, 2.3%) was similar to the rate observed prior to withdrawal (11 of 590 subjects, 1.9%).In patients with paediatric psoriasis, anti-adalimumab antibodies were identified in 5/38 subjects (13%) treated with 0.8mg/kg adalimumab monotherapy.Because immunogenicity analyses are product-specific, comparison of antibody rates with those from other products is not appropriate.
Paediatric populationThe European Medicines Agency has waived the obligation to submit the results of studies with Humira in all subsets of the paediatric population rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis, see section 4.2 for information on paediatric use.The European Medicines Agency has deferred the obligation to submit the results of the studies with Humira in one or more subsets of the paediatric population in ulcerative colitis, see section 4.2 for information on paediatric use.
Absorption and distributionAfter subcutaneous administration of a single 40 mg dose, absorption and distribution of adalimumab was slow, with peak serum concentrations being reached about 5 days after administration. The average absolute bioavailability of adalimumab estimated from three studies following a single 40 mg subcutaneous dose was 64%. After single intravenous doses ranging from 0.25 to 10 mg/kg, concentrations were dose proportional. After doses of 0.5 mg/kg (~40 mg), clearances ranged from 11 to 15 ml/hour, the distribution volume (Vss) ranged from 5 to 6 litres and the mean terminal phase half-life was approximately two weeks. Adalimumab concentrations in the synovial fluid from several rheumatoid arthritis patients ranged from 31-96% of those in serum.Following subcutaneous administration of 40 mg of adalimumab every other week in adult rheumatoid arthritis (RA) patients the mean steady-state trough concentrations were approximately 5 μg/ml (without concomitant methotrexate) and 8 to 9 μg/ml (with concomitant methotrexate), respectively. The serum adalimumab trough levels at steady-state increased roughly proportionally with dose following 20, 40 and 80 mg subcutaneous dosing every other week and every week.Following the administration of 24 mg/m2 (up to a maximum of 40 mg) subcutaneously every other week to patients with polyarticular juvenile idiopathic arthritis (JIA) who were 4 to 17 years the mean trough steady-state (values measured from Week 20 to 48) serum adalimumab concentration was 5.6 ± 5.6 µg/mL (102 %CV) for adalimumab without concomitant methotrexate and 10.9 ± 5.2 µg/mL (47.7% CV) with concomitant methotrexate.In patients with polyarticular JIA who were 2 to <4 years old or aged 4 and above weighing <15 kg dosed with adalimumab 24 mg/m2, the mean trough steady-state serum adalimumab concentrations was 6.0 ± 6.1 µg/ml (101% CV) for adalimumab without concomitant methotrexate and 7.9 ± 5.6 µg/ml (71.2% CV) with concomitant methotrexate.Following the administration of 24 mg/m2 (up to a maximum of 40 mg) subcutaneously every other week to patients with enthesitis-related arthritis who were 6 to 17 years, the mean trough steady-state (values measured at Week 24) serum adalimumab concentrations were 8.8 ± 6.6 μg/mL for adalimumab without concomitant methotrexate and 11.8 ± 4.3 μg/mL with concomitant methotrexate.In adult patients with psoriasis, the mean steady-state trough concentration was 5 μg/mL during adalimumab 40 mg every other week monotherapy treatment.Following the administration of 0.8 mg/kg (up to a maximum of 40 mg) subcutaneously every other week to paediatric patients with chronic plaque psoriasis, the mean ± SD steady-state adalimumab trough concentration was approximately 7.4 ± 5.8 µg/mL (79% CV).In patients with Crohn's disease, the loading dose of 80 mg Humira on Week 0 followed by 40 mg Humira on Week 2 achieves serum adalimumab trough concentrations of approximately 5.5 μg/ml during the induction period. A loading dose of 160 mg Humira on Week 0 followed by 80 mg Humira on Week 2 achieves serum adalimumab trough concentrations of approximately 12 μg/ml during the induction period. Mean steady-state trough levels of approximately 7 μg/ml were observed in Crohn's disease patients who received a maintenance dose of 40 mg Humira every other week.In paediatric patients with moderate to severe CD, the open-label adalimumab induction dose was 160/80 mg or 80/40 mg at Weeks 0 and 2, respectively, dependent on a body weight cut-off of 40 kg. At Week 4, patients were randomised 1:1 to either the Standard Dose (40/20 mg eow) or Low Dose (20/10 mg eow) maintenance treatment groups based on their body weight. The mean (±SD) serum adalimumab trough concentrations achieved at Week 4 were 15.7±6.6 μg/mL for patients ≥ 40 kg (160/80 mg) and 10.6±6.1 μg/mL for patients < 40 kg (80/40 mg). For patients who stayed on their randomised therapy, the mean (±SD) adalimumab trough concentrations at Week 52 were 9.5±5.6μg/mL for the Standard Dose group and 3.5±2.2 μg/mL for the Low Dose group. The mean trough concentrations were maintained in patients who continued to receive adalimumab treatment eow for 52 weeks. For patients who dose escalated from eow to weekly regimen, the mean (±SD) serum concentrations of adalimumab at Week 52 were 15.3±11.4 μg/mL (40/20 mg, weekly) and 6.7±3.5 μg/mL (20/10 mg, weekly).In patients with ulcerative colitis, a loading dose of 160 mg Humira on Week 0 followed by 80 mg Humira on Week 2 achieves serum adalimumab trough concentrations of approximately 12 μg/ml during the induction period. Mean steady-state trough levels of approximately 8 μg/ml were observed in ulcerative colitis patients who received a maintenance dose of 40 mg Humira every other week.
EliminationPopulation pharmacokinetic analyses with data from over 1,300 RA patients revealed a trend toward higher apparent clearance of adalimumab with increasing body weight. After adjustment for weight differences, gender and age appeared to have a minimal effect on adalimumab clearance. The serum levels of free adalimumab (not bound to anti-adalimumab antibodies, AAA) were observed to be lower in patients with measurable AAA.
Hepatic or renal impairmentHumira has not been studied in patients with hepatic or renal impairment.
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