Drug Class Description
Selective immunosuppressive agents

Generic Name
Adalimumab

Drug Description
Solution for injection in pre-filled syringe.

Presentation
Each 0.8 ml single dose pre-filled syringe contains 40 mg of adalimumab. Adalimumab is a recombinant human monoclonal antibody expressed in Chinese Hamster Ovary cells.

Indications
Rheumatoid arthritis: Humira 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.Psoriatic arthritis Humira is indicated for the treatment of active and progressive psoriatic arthritis in adults when the response to previous disease-modifying antirheumatic drug therapy has been inadequate.

Adult Dosage
Humira treatment should be initiated and supervised by specialist physicians experienced in the diagnosis and treatment of rheumatoid arthritis or psoriatic arthritis. 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. Adults Rheumatoid arthritis The 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 Special Precautions. In monotherapy, some patients who experience a decrease in their response to Humira may benefit from an increase in dose intensity to 40 mg adalimumab every week. 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. Psoriatic arthritis The recommended dose of Humira for patients with psoriatic arthritis is 40 mg adalimumab administered every other week as a single dose via subcutaneous injection. Impaired renal and/or hepatic function Humira has not been studied in these patient populations. No dose recommendations can be made.

Child Dosage
Humira has not been studied in this patient population. Therefore, use of Humira cannot be recommended in patients aged below 18 years until further data become available.

Elderly Dosage
No dose adjustment is required.

Contra Indications
Hypersensitivity to the active substanceor to any of the excipients. Active tuberculosis or other severe infections such as sepsis, and opportunistic infections. Moderate to severe heart failure (NYHA class III/IV).

Special Precautions
Infections Patients must be monitored closely for infections including tuberculosis, before, during and after treatment with Humira. Because the elimination of adalimumab may take up to five months, monitoring should be continued throughout this period. Treatment with Humira should not be initiated in patients with active infections including chronic or localized infections until infections are controlled. Patients who develop a new infection while undergoing treatment with Humira should be monitored closely. Administration of Humira should be discontinued if a patient develops a new serious infection until infections are controlled.Physicians should exercise caution when considering the use of Humira in patients with a history of recurring infection or with underlying conditions which may predispose patients to infections. Serious infections, sepsis, tuberculosis and other opportunistic infections, including fatalities, have been reported with Humira. Before initiation of therapy with Humira, all patients must be eva luated for both active or inactive (latent) tuberculosis infection. This eva luation should include a detailed medical history with a personal history of tuberculosis or possible previous exposure to patients 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 of these tests should be 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 Contraindications). If latent tuberculosis is diagnosed, appropriate anti-tuberculosis prophylaxis in accordance with local recommendations must be initiated before starting treatment with Humira. In this situation, the benefit/risk balance of therapy with Humira should be very carefully considered. Patients should be instructed to seek medical advice if signs/symptoms (eg, persistent cough, wasting/weight loss, low grade fever) suggestive of a tuberculosis infection occur during or after therapy with Humira.Neurological events TNF-antagonists including Humira have been associated in rare cases with new onset or exacerbation of clinical symptoms and/or radiographic evidence of demyelinating disease. Prescribers should exercise caution in considering the use of Humira in patients with pre-existing or recent-onset central nervous system demyelinating disorders. Allergic reactions Serious allergic adverse reactions have not been reported with subcutaneous administration of Humira during clinical trials. Non-serious allergic reactions associated with Humira were uncommon during clinical trials. In postmarketing, serious allergic reactions including anaphylaxis have been reported very rarely following Humira administration. If an anaphylactic reaction or other serious allergic reaction occurs, administration of Humira should be discontinued immediately and appropriate therapy initiated. The needle cover of the syringe contains natural rubber (latex).This may cause severe allergic reactions in patients sensitive to latex. Immunosuppression In 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-and B cells and NK-cells, monocyte/macrophages, and neutrophils. Malignancies and lymphoproliferative disorders In the controlled portions of clinical trials of TNF-antagonists, more cases of lymphoma have been observed among patients receiving a TNF-antagonist compared with control patients. However, the occurrence was rare, and the follow up period of placebo patients was shorter than for patients receiving TNF-antagonist therapy. Furthermore, there is an increased background lymphoma risk 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 or other malignancies in patients treated with a TNF-antagonist cannot be excluded. No studies have been conducted that include patients with a history of malignancy or that continue treatment in patients who develop malignancy while receiving Humira. Thus additional caution should be exercised in considering Humira treatment of these patients (See Adverse Reactions). Haematologic reactions Rare reports of pancytopenia including aplastic anaemia have been reported with TNF blocking agents. Adverse events of the haematologic system, including medically significant cytopenia (eg thrombocytopenia, leukopenia) have been infrequently reported with Humira. All patients should be advised to seek immediate medical attention if they develop signs and symptoms suggestive of blood dyscrasias (eg persistent fever, bruising, bleeding, pallor) while on Humira. Discontinuation of Humira therapy should be considered in patients with confirmed significant haematologic abnormalities.Vaccinations Sixty-one patients with rheumatoid arthritis were given pneumococcal vaccinations against a background of Humira and methotrexate therapy. Most patients receiving Humira were able to mount effective B-cell immune responses to pneumococcal polysaccharide vaccine. Since no data are available, concurrent administration of live vaccines and Humira is not recommended. Congestive heart failure 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 Humira. Humira should be used with caution in patients with mild heart failure (NYHA class I/II). Humira is contraindicated in moderate or severe heart failure (See Contraindications). Treatment with Humira must be discontinued in patients who develop new or worsening symptoms of congestive heart failure.Autoimmune processes Treatment 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. Concurrent administration of TNF-antagonists and anakinra Serious infections were seen in clinical studies with concurrent use of anakinra and another TNFantagonist, 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.Surgery: There 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.

Interactions
Humira has been studied both in rheumatoid arthritis patients taking Humira as monotherapy and those taking concomitant methotrexate. Antibody formation was low (< 1%) when Humira was given together with methotrexate in comparison with use as monotherapy. Administration of Humira without methotrexate resulted in increased formation of antibodies and increased clearance of adalimumab.There is no experience with the efficacy and safety in patients previously treated with other TNF-antagonists. For adalimumab, there is no experience in pregnant women. In a developmental toxicity study conducted in monkeys, there was no indication of maternal toxicity, embryotoxicity or teratogenicity.Preclinical data on postnatal toxicity and fertility effects of adalimumab are not available.Due to its inhibition of TNFa, adalimumab administered during pregnancy could affect normal immune responses in the newborn. Administration of adalimumab is not recommended during pregnancy. Women 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. Use during lactation It 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.

Adverse Reactions
Clinical TrialsHumira was studied in 6,728 patients in controlled and open label trials for up to 60 months. These trials included rheumatoid arthritis patients with short term and long standing disease, polyarticular juvenile idiopathic arthritis as well as psoriatic arthritis, ankylosing spondylitis, Crohn's disease and psoriasis patients. The data in Table 1 is based on the pivotal controlled Studies involving 4,419 patients receiving Humira and 2,552 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 4.5% for patients taking Humira and 4.5% for control treated patients.Undesirable effects in paediatric patients with polyarticular juvenile idiopathic arthritisIn general, the adverse events in paediatric patients were similar in frequency and type to those seen in adult patients.Adverse events at least possibly causally-related to adalimumab, for clinical studies both clinical and laboratory, 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 very rare <1/10,000) in Table 1 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.Approximately 15% of patients can be expected to experience injection site reactions, based on the most common adverse event with adalimumab in controlled clinical studies.Table 1Undesirable Effects in Clinical StudiesSystem Organ Class Frequency Adverse Reaction Infections and infestationsVery commonrespiratory tract infections (including lower and upper respiratory tract infection, pneumonia, sinusitis, pharyngitis, nasopharyngitis and pneumonia herpes viral)Commonsystemic 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 infectionsUncommonopportunistic infections and tuberculosis (including coccidioidomycosis, histoplasmosis and mycobacterium avum complex infection),neurological infections (including viral meningitis),eye infections,bacterial infections,joint infectionsNeoplasms benign, malignant and unspecified (including cysts and polyps)*Commonbenign neoplasm,skin cancer excluding melanoma (including basal cell carcinoma and squamous cell carcinoma)Uncommonlymphoma*,solid organ neoplasm (including breast cancer, lung neoplasm and thyroid neoplasm),melanoma*Blood and the lymphatic system disorders*Very commonleucopaenia (including neutropaenia and agranulocytosis),anaemiaCommonthrombocytopaenia,leucocytosisUncommonidiopathic thrombocytopaenic purpuraRarepancytopaeniaImmune system disordersCommonhypersensitivity,allergies (including seasonal allergy)Metabolism and nutrition disordersVery commonlipids increasedCommonhypokalaemia,uric acid increased,blood sodium abnormal,hypocalcaemiahyperglycemia,hypophosphotemia,blood potassium increasedUncommondehydrationPsychiatric disordersCommonmood alterations (including depression),anxiety, insomniaNervous system disordersVery commonheadacheCommonparaesthesias (including hypoaesthesia),migraine,sciaticaUncommontremorRaremultiple sclerosisEye disordersCommonvisual impairment,conjunctivitisUncommonblepharitis,eye swelling,diplopiaEar and labyrinth disordersCommonvertigoUncommondeafness,tinnitusCardiac disordersCommontachycardiaUncommonarrhythmia,congestive heart failureRarecardiac arrestVascular disordersCommonhypertension,flushing,haematomaRarevascular arterial occlusion,thrombophlebitis,aortic aneurysmRespiratory, thoracic and mediastinal disorders*Commoncough,asthma,dyspnoeaUncommonchronic obstructive pulmonary disease,interstitial lung disease,pneumonitisGastrointestinal disordersVery commonabdominal pain,nausea and vomitingCommonGI haemorrhage,dyspepsia,gastroesophageal reflux disease,sicca syndromeUncommonpancreatitis,dysphagia,face oedemaHepato-biliary disordersVery Commonelevated liver enzymesUncommoncholecystitis and cholelithiasis,bilirubin increased,hepatic steatosisSkin and subcutaneous tissue disordersVery Commonrash (including exfoliative rash),Commonpruritus,urticaria,bruising (including purpura),dermatitis (including eczema),onychoclasis,hyperhydrosisUncommonnight sweats,scarMusculoskeletal, connective tissue and bone disordersVery commonmusculoskeletal painCommonmuscle spasms (including blood creatine phosphokinase increased)UncommonrhabdomyolysisRaresystemic lupus erythematosusRenal and urinary disordersCommonhaematuria,renal impairmentUncommonnocturiaReproductive system and breast disordersUncommonerectile dysfunctionGeneral disorders and administration site conditionsVery Commoninjection site reaction (including injection site erythema)Commonchest pain,oedemaUncommoninflammationInvestigationsCommoncoagulation and bleeding disorders (including activated partial thromboplastin time prolonged),autoantibody test positive (including double stranded DNA antibody),blood lactate dehydrogenase increasedInjury and poisoningCommonimpaired healing* including open label extension studiesInjection site reactions In the pivotal controlled trials, 15% of patients treated with Humira developed injection site reactions (erythema and/or itching, haemorrhage, pain or swelling), compared to 9% of patients receiving placebo or active control. Injection site reactions generally did not necessitate discontinuation of the medicinal product.Infections In the pivotal controlled trials, the rate of infection was 1.50 per patient year in the Humira treated patients and 1.42 per patient year in the placebo and active controltreated patients. The infections consisted primarily nasopharyngitis, upper respiratory tract infection, and sinusitis. Most patients continued on Humira after the infection resolved.The incidence of serious infections was 0.043 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 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 171 patients with an exposure of 192.5 patient years during a Humira trial in juvenile idiopathic arthritis patients.During the controlled portions of pivotal Humira trials at least 12 weeks in duration in patients with moderately to severely active rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn's disease or psoriasis, malignancies, other than lymphoma and non-melanoma skin cancer, were observed at a rate (95% confidence interval) of 6.6 (4.0, 10.8) per 1,000 patient-years among 3,917 Humira treated patients versus a rate of 4.2 (1.8, 10.41) per 1,000 patient-years among 2,247 control patients (median duration of treatment was 5.6 months for Humira and 4.0 months for control-treated patients). The rate (95% confidence interval) of non-melanoma skin cancers was 9.9 (6.6, 14.8) per 1,000 patient-years among Humira-treated patients and 2.5 (0.8, 7.9) per 1,000 patient-years among control patients. Of these skin cancers, squamous cell carcinomas occurred at rates (95% confidence interval) of 2.5 (1.1, 5.5) per 1,000 patient-years among Humira-treated patients and 0.8 (0.1, 6.0) per 1,000 patient-years among control patients. The rate (95% confidence interval) of lymphomas was 0.8 (0.2, 3.3) per 1,000 patient-years among Humira-treated patients and 0.8 (0.1, 6.0) per 1,000 patient-years among control patients.When combining controlled portions of these trials and ongoing open label extension studies with a median duration of approximately 3.4 years including 4,912 patients and over 19,640 patient-years of therapy, the observed rate of malignancies, other than lymphoma and non-melanoma skin cancers is approximately 9.2 per 1,000 patient years. The observed rate of non-melanoma skin cancers is approximately 9.9 per 1,000 patient years, and the observed rate of lymphomas is approximately 1.2 per 1,000 patient years.In post-marketing experience from January 2003, predominately in patients with rheumatoid arthritis, the reported rate of malignancies other than lymphomas and non-melanoma skin cancers is approximately 1.7 per 1,000 patient years. The reported rates for non-melanoma skin cancers and lymphomas are approximately 0.2 and 0.4 per 1,000 patient years, respectively.Rare post-marketing cases of hepatosplenic T-cell lymphoma have been reported in patients treated with adalimumab.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.Liver Enzyme ElevationsRheumatoid arthritis clinical trials: in controlled rheumatoid arthritis clinical trials (RA studies I − IV), elevations of ALT were similar in patients receiving adalimumab or placebo. In patients with early rheumatoid arthritis (disease duration of less than 3 years) (RA study V), elevations of ALT were more common in the combination arm (Humira /methotrexate) compared to the methotrexate monotherapy arm or the Humira monotherapy arm. In the JIA trial the few transaminase elevations were small and similar in the placebo and adalimumab exposed patients, and mostly occurred in combination with methotrexate.Psoriatic arthritis clinical trials: elevations in ALT were more common in psoriatic arthritis patients (PsA studies I - II) compared with patients in rheumatoid arthritis clinical studies.In all rheumatoid arthritis, polyarticular juvenile idiopathic arthritis and psoriatic arthritis studies, patients with raised ALT were asymptomatic and in most cases elevations were transient and resolved on continued treatment.Crohn's disease clinical trials: in controlled clinical trials, elevations of ALT were similar in patients receiving adalimumab or placebo.Psoriasis clinical trials: in controlled psoriasis clinical trials, elevations of ALT were similar in patients receiving adalimumab or placebo.Additional Adverse Reactions from Postmarketing Surveillance or Phase IV Clinical TrialsThe additional adverse reactions in Table 2 have been reported from postmarketing surveillance or Phase IV clinical trials:Table 2Undesirable Effects in Postmarketing Surveillance and Phase IV Clinical StudiesSystem Organ ClassAdverse ReactionInfections and InfestationsdiverticulitisNeoplasm benign, malignant and unspecified (including cysts and polyps)hepatosplenic T-cell lymphoma, leukemiaImmune system disordersanaphylaxisNervous system disordersdemyelinating disorders (e.g. optic neuritis, Guillain-Barré syndrome); cerebrovascular accidentRespiratory, thoracic and mediastinal disorderspulmonary embolismpleural effusionGastrointestinal disordersintestinal perforationHepatobiliary disordersreactivation of hepatitis BSkin and subcutaneous tissue disorderscutaneous vasculitis, Stevens-Johnson syndrome, angioedema, new onset or worsening of psoriasis (including palmoplantar pustular psoriasis), erythema multiforme, alopeciaMusculoskeletal and connective tissue disorderslupus-like syndromeCardiac disordersmyocardial infarction

Manufacturer
Abbott Laboratories

Drug Availability
(POM)

Updated
10 September 2010