Aspose.Words.Document doc = new Aspose.Words.Document();
Aspose.Words.DocumentBuilder builder = new Aspose.Words.DocumentBuilder(doc);
builder.PageSetup.PageWidth =pageWidth;
builder.PageSetup.PageHeight =pageHeight;
builder.PageSetup.BottomMargin = 10;
builder.PageSetup.TopMargin = 10;
builder.PageSetup.LeftMargin = 20;
builder.PageSetup.RightMargin = 10;
builder.InsertHtml(sHtml);
doc.ResourceLoadingCallback = new HandleResourceLoading();
doc.PageColor = System.Drawing.Color.White;
Aspose.Words.Saving.PdfSaveOptions saveOptions = new Aspose.Words.Saving.PdfSaveOptions();
saveOptions.JpegQuality = 100;
saveOptions.SaveFormat = Aspose.Words.SaveFormat.Pdf;
saveOptions.DownsampleOptions.Resolution = 200;
MemoryStream docStream = new MemoryStream();
doc.Save(docStream, saveOptions);
@ravina As I can see resolution is already specified in saveOptions.DownsampleOptions.Resolution = 200;. Could you please let us know what else is required to specify? If possible, please attach your input, output and expected output documents here for our reference or elaborate the issue in more details.
I get this type of pdf file as output.(Image.png)
But i want pdf in full size of page. like this
@ravina Could you please attach your source HTML document here for testing/ We will check it and provide you more information.
sHtml="<html><head><style type='text/css'></style> <div class='table-responsive' id='divTableResponsive'> <table id ='tableComparediff' class='table'><tr class='clsRow'><td><b>Section</b></td><td><b><a target='_blank' href=''> Humira 20 mg solution for injection in pre-filled syringe </a></b></td><td><i>Merged Documents</i></td><td><b><a target='_blank' href='> Humira 40 mg solution for injection in pre-filled syringe Humira 40 mg solution for injection in pre-filled pen [1] </a><b></td></tr><tr class='clsRow'><td><b>Highlights</b></td><td><b>Identical</b></td><td><b>Identical</b></td><td><b>Identical</b></td></tr><tr class='clsRow'><td><b>Abuse Section</b></td><td><b>Identical</b></td><td><b>Identical</b></td><td><b>Identical</b></td></tr><tr class='clsRow'><td><b>Adverse Reactions</b></td><td><br/><b>Adverse Reactions</b><br/><div ids='section-UNDESIRABLE_EFFECTS' class='Section'><h3 class='sectionNameHeader' sectionnameid='sectionName-UNDESIRABLE_EFFECTS'>4.8 Undesirable effects</h3> <p class='p_style8'><span class='style2'>Summary of the safety profile</span></p><p class='p_style3'><span class='style1'>Humira was studied in 9,506 patients in pivotal controlled and open label trials for up to 60 months or more. These trials included rheumatoid arthritis patients with short term and long standing disease, juvenile idiopathic arthritis (polyarticular juvenile idiopathic arthritis and enthesitis-related arthritis) as well as axial spondyloarthritis (ankylosing spondylitis and axial spondyloarthritis without radiographic evidence of AS), psoriatic arthritis, Crohn’s disease, ulcerative colitis, psoriasis, hidradenitis suppurativa and uveitis patients. The pivotal controlled studies involved 6,089 patients receiving Humira and 3,801 patients receiving placebo or active comparator during the controlled period.</span></p><p class='p_style30'><span class='style1'>The proportion of patients who discontinued treatment due to adverse events during the double-blind, controlled portion of pivotal studies was 5.9% for patients taking Humira and 5.4% for control treated patients.</span></p><p class='p_style6'><span class='style1'>The most commonly reported adverse reactions are infections (such as nasopharyngitis, upper respiratory tract infection and sinusitis), injection site reactions (erythema, itching, haemorrhage, pain or swelling), headache and musculoskeletal pain.</span></p><p class='p_style8'><span class='style1'>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 defence against infection and cancer.</span></p><p class='p_style31'><span class='style1'>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.</span></p><p class='p_style6'><span class='style1'>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.</span></p><p class='p_style6'><span class='style2'>Paediatric population</span></p><p class='p_style28'><span class='style1'>In general, the adverse events in paediatric patients were similar in frequency and type to those seen in adult patients.</span></p><p class='p_style28'><span class='style2'>Tabulated list of adverse reactions</span></p><p class='p_style9'><span class='style1'>The following list of adverse reactions is based on experience from clinical trials and on postmarketing experience and are displayed by system organ class and frequency in Table 6 below: very common</span></p><p class='p_style3'><span class='style1'>(</span><span class='style5'></span> <span class='style1'> 1/10); common (</span><span class='style5'></span> <span class='style1'> 1/100 to < 1/10); uncommon (</span><span class='style5'></span> <span class='style1'> 1/1,000 to < 1/100); rare (</span><span class='style5'></span> <span class='style1'> 1/10,000 to < 1/1,000); and not known (cannot be estimated from the available data). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. The highest frequency seen among the various indications has been included. An asterisk (*) appears in the SOC column if further information is found elsewhere in sections 4.3, 4.4 and 4.8.</span></p><p class='p_style32'><span class='style0'>Table 6</span></p><p class='p_style33'><span class='style0'>Undesirable Effects</span></p><table class='clsChildTable'> <tr><td><p class='p_style34'><span class='style0'>System Organ Class</span></p></td><td><p class='p_style35'><span class='style0'>Frequency</span></p></td><td><p class='p_style36'><span class='style0'>Adverse Reaction</span></p></td></tr> <tr><td rowspan='2'><p class='p_style37'><span class='style1'>Infections and </span><br><span class='style1'>infestations*</span></p></td><td><p class='p_style37'><span class='style1'>Very common</span></p></td><td><p class='p_style37'><span class='style1'>Respiratory tract infections (including lower and upper respiratory tract infection, pneumonia, sinusitis, pharyngitis, nasopharyngitis and pneumonia herpes viral)</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Common</span></p></td><td><p class='p_style37'><span class='style1'>Systemic infections (including sepsis, candidiasis and influenza),</span></p><p class='p_style37'><span class='style1'>intestinal infections (including gastroenteritis viral),</span></p><p class='p_style37'><span class='style1'>skin and soft tissue infections (including paronychia, cellulitis, impetigo, necrotising fasciitis and herpes zoster),</span></p><p class='p_style37'><span class='style1'>ear infections, </span><br><span class='style1'>oral infections (including herpes simplex, oral herpes and tooth infections),</span></p><p class='p_style37'><span class='style1'>reproductive tract infections (including vulvovaginal mycotic infection), urinary tract infections (including pyelonephritis),</span></p><p class='p_style37'><span class='style1'>fungal infections, </span><br><span class='style1'>joint infections</span></p></td></tr> <tr><td><p class='p_style34'><span class='style0'>System Organ Class</span></p></td><td><p class='p_style35'><span class='style0'>Frequency</span></p></td><td><p class='p_style36'><span class='style0'>Adverse Reaction</span></p></td></tr> <tr> <td><p class='p_style37'><span class='style1'>Uncommon</span></p></td><td><p class='p_style37'><span class='style1'>Neurological infections (including viral meningitis),</span></p><p class='p_style37'><span class='style1'>opportunistic infections and tuberculosis (including coccidioidomycosis, histoplasmosis and mycobacterium avium complex infection), bacterial infections, </span><br><span class='style1'>eye infections, </span><br><span class='style1'>diverticulitis</span><span class='style6'>1)</span></p></td></tr> <tr><td rowspan='4'><p class='p_style37'><span class='style1'>Neoplasms benign, malignant and unspecified (including cysts and polyps)*</span></p></td><td><p class='p_style37'><span class='style1'>Common</span></p></td><td><p class='p_style37'><span class='style1'>Skin cancer excluding melanoma (including basal cell carcinoma and squamous cell carcinoma),</span></p><p class='p_style37'><span class='style1'>benign neoplasm</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Uncommon</span></p></td><td><p class='p_style37'><span class='style1'>Lymphoma**, </span><br><span class='style1'>solid organ neoplasm (including breast cancer, lung neoplasm and thyroid neoplasm), melanoma**</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Rare</span></p></td><td><p class='p_style37'><span class='style1'>Leukaemia</span><span class='style6'>1)</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Not known</span></p></td><td><p class='p_style37'><span class='style1'>Hepatosplenic T-cell lymphoma</span><span class='style7'>1)</span> <span class='style1'> Merkel cell carcinoma (neuroendocrine carcinoma of the skin)</span><span class='style7'>1)</span><span class='style1'>,</span></p><p class='p_style37'><span class='style1'>Kaposi’s sarcoma</span></p></td></tr> <tr><td rowspan='4'><p class='p_style37'><span class='style1'>Blood and the lymphatic system disorders*</span></p></td><td><p class='p_style37'><span class='style1'>Very common</span></p></td><td><p class='p_style37'><span class='style1'>Leukopenia (including neutropenia and agranulocytosis),</span></p><p class='p_style37'><span class='style1'>anaemia</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Common</span></p></td><td><p class='p_style37'><span class='style1'>Leucocytosis, </span><br><span class='style1'>thrombocytopenia</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Uncommon</span></p></td><td><p class='p_style37'><span class='style1'>Idiopathic thrombocytopenic purpura</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Rare</span></p></td><td><p class='p_style37'><span class='style1'>Pancytopenia</span></p></td></tr> <tr><td rowspan='3'><p class='p_style37'><span class='style1'>Immune system disorders*</span></p></td><td><p class='p_style37'><span class='style1'>Common</span></p></td><td><p class='p_style37'><span class='style1'>Hypersensitivity, </span><br><span class='style1'>allergies (including seasonal allergy)</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Uncommon</span></p></td><td><p class='p_style37'><span class='style1'>Sarcoidosis</span><span class='style6'>1)</span><span class='style1'>, </span><br><span class='style1'>vasculitis</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Rare</span></p></td><td><p class='p_style37'><span class='style1'>Anaphylaxis</span><span class='style6'>1)</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Very common</span></p></td><td><p class='p_style37'><span class='style1'>Lipids increased</span></p></td></tr> <tr><td><p class='p_style34'><span class='style0'>System Organ Class</span></p></td><td><p class='p_style35'><span class='style0'>Frequency</span></p></td><td><p class='p_style36'><span class='style0'>Adverse Reaction</span></p></td></tr> <tr><td rowspan='2'><p class='p_style37'><span class='style1'>disorders</span></p></td> </tr> <tr><td><p class='p_style37'><span class='style1'>Common</span></p></td><td><p class='p_style37'><span class='style1'>Hypokalaemia, </span><br><span class='style1'>uric acid increased, </span><br><span class='style1'>blood sodium abnormal, </span><br><span class='style1'>hypocalcaemia, </span><br><span class='style1'>hyperglycaemia, </span><br><span class='style1'>hypophosphatemia, </span><br><span class='style1'>dehydration</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Psychiatric disorders</span></p></td><td><p class='p_style37'><span class='style1'>Common</span></p></td><td><p class='p_style37'><span class='style1'>Mood alterations (including depression), anxiety, </span><br><span class='style1'>insomnia</span></p></td></tr> <tr><td rowspan='4'><p class='p_style37'><span class='style1'>Nervous system disorders*</span></p></td><td><p class='p_style37'><span class='style1'>Very common</span></p></td><td><p class='p_style37'><span class='style1'>Headache</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Common</span></p></td><td><p class='p_style37'><span class='style1'>Paraesthesias (including hypoesthesia), migraine, </span><br><span class='style1'>nerve root compression</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Uncommon</span></p></td><td><p class='p_style37'><span class='style1'>Cerebrovascular accident</span><span class='style7'>1)</span><span class='style1'>, tremor, </span><br><span class='style1'>neuropathy</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Rare</span></p></td><td><p class='p_style37'><span class='style1'>Multiple sclerosis, </span><br><span class='style1'>demyelinating disorders (e.g. optic neuritis, Guillain-Barr syndrome)</span> <span class='style7'> 1)</span></p></td></tr> <tr><td rowspan='2'><p class='p_style37'><span class='style1'>Eye disorders</span></p></td><td><p class='p_style37'><span class='style1'>Common</span></p></td><td><p class='p_style37'><span class='style1'>Visual impairment, </span><br><span class='style1'>conjunctivitis, </span><br><span class='style1'>blepharitis, </span><br><span class='style1'>eye swelling</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Uncommon</span></p></td><td><p class='p_style37'><span class='style1'>Diplopia</span></p></td></tr> <tr><td rowspan='2'><p class='p_style37'><span class='style1'>Ear and labyrinth disorders</span></p></td><td><p class='p_style37'><span class='style1'>Common</span></p></td><td><p class='p_style37'><span class='style1'>Vertigo</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Uncommon</span></p></td><td><p class='p_style37'><span class='style1'>Deafness, </span><br><span class='style1'>tinnitus</span></p></td></tr> <tr><td rowspan='2'><p class='p_style37'><span class='style1'>Cardiac disorders*</span></p></td><td><p class='p_style37'><span class='style1'>Common</span></p></td><td><p class='p_style37'><span class='style1'>Tachycardia</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Uncommon</span></p></td><td><p class='p_style37'><span class='style1'>Myocardial infarction</span><span class='style6'>1)</span><span class='style1'>,</span></p></td></tr> <tr><td><p class='p_style34'><span class='style0'>System Organ Class</span></p></td><td><p class='p_style35'><span class='style0'>Frequency</span></p></td><td><p class='p_style36'><span class='style0'>Adverse Reaction</span></p></td></tr> <tr> <td><p class='p_style37'><span class='style1'>arrhythmia, </span><br><span class='style1'>congestive heart failure</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Rare</span></p></td><td><p class='p_style37'><span class='style1'>Cardiac arrest</span></p></td></tr> <tr><td rowspan='2'><p class='p_style37'><span class='style1'>Vascular disorders</span></p></td><td><p class='p_style37'><span class='style1'>Common</span></p></td><td><p class='p_style37'><span class='style1'>Hypertension, </span><br><span class='style1'>flushing, </span><br><span class='style1'>haematoma</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Uncommon</span></p></td><td><p class='p_style37'><span class='style1'>Aortic aneurysm, </span><br><span class='style1'>vascular arterial occlusion, thrombophlebitis</span></p></td></tr> <tr><td rowspan='3'><p class='p_style37'><span class='style1'>Respiratory, thoracic and mediastinal disorders*</span></p></td><td><p class='p_style37'><span class='style1'>Common</span></p></td><td><p class='p_style37'><span class='style1'>Asthma, </span><br><span class='style1'>dyspnoea, </span><br><span class='style1'>cough</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Uncommon</span></p></td><td><p class='p_style37'><span class='style1'>Pulmonary embolism</span><span class='style6'>1)</span><span class='style1'>, </span><br><span class='style1'>interstitial lung disease, </span><br><span class='style1'>chronic obstructive pulmonary disease, pneumonitis, </span><br><span class='style1'>pleural effusion</span><span class='style6'>1)</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Rare</span></p></td><td><p class='p_style37'><span class='style1'>Pulmonary fibrosis</span><span class='style6'>1)</span></p></td></tr> <tr><td rowspan='4'><p class='p_style37'><span class='style1'>Gastrointestinal disorders</span></p></td><td><p class='p_style37'><span class='style1'>Very common</span></p></td><td><p class='p_style37'><span class='style1'>Abdominal pain, </span><br><span class='style1'>nausea and vomiting</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Common</span></p></td><td><p class='p_style37'><span class='style1'>GI haemorrhage, </span><br><span class='style1'>dyspepsia, </span><br><span class='style1'>gastroesophageal reflux disease, sicca syndrome</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Uncommon</span></p></td><td><p class='p_style37'><span class='style1'>Pancreatitis, </span><br><span class='style1'>dysphagia, </span><br><span class='style1'>face oedema</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Rare</span></p></td><td><p class='p_style37'><span class='style1'>Intestinal perforation</span><span class='style6'>1)</span></p></td></tr> <tr><td rowspan='3'><p class='p_style37'><span class='style1'>Hepato-biliary disorders*</span></p></td><td><p class='p_style37'><span class='style1'>Very Common</span></p></td><td><p class='p_style37'><span class='style1'>Elevated liver enzymes</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Uncommon</span></p></td><td><p class='p_style37'><span class='style1'>Cholecystitis and cholelithiasis, hepatic steatosis, </span><br><span class='style1'>bilirubin increased</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Rare</span></p></td><td><p class='p_style37'><span class='style1'>Hepatitis</span></p></td></tr> <tr><td><p class='p_style34'><span class='style0'>System Organ Class</span></p></td><td><p class='p_style35'><span class='style0'>Frequency</span></p></td><td><p class='p_style36'><span class='style0'>Adverse Reaction</span></p></td></tr> <tr> <td><p class='p_style37'><span class='style1'>reactivation of hepatitis B</span><span class='style7'>1)</span> <span class='style1'> autoimmune hepatitis</span><span class='style6'>1)</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Not known</span></p></td><td><p class='p_style37'><span class='style1'>Liver failure</span><span class='style6'>1)</span></p></td></tr> <tr><td rowspan='5'><p class='p_style37'><span class='style1'>Skin and subcutaneous tissue disorders</span></p></td><td><p class='p_style37'><span class='style1'>Very Common</span></p></td><td><p class='p_style37'><span class='style1'>Rash (including exfoliative rash)</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Common</span></p></td><td><p class='p_style37'><span class='style1'>Worsening or new onset of psoriasis(including palmoplantar pustular psoriasis)</span><span class='style7'>1)</span><span class='style1'>,</span></p><p class='p_style37'><span class='style1'>urticaria, </span><br><span class='style1'>bruising (including purpura), dermatitis (including eczema), onychoclasis, </span><br><span class='style1'>hyperhidrosis, </span><br><span class='style1'>alopecia</span><span class='style6'>1)</span><span class='style1'>, </span><br><span class='style1'>pruritus</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Uncommon</span></p></td><td><p class='p_style37'><span class='style1'>Night sweats, </span><br><span class='style1'>scar</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Rare</span></p></td><td><p class='p_style37'><span class='style1'>Erythema multiforme</span><span class='style6'>1)</span><span class='style1'>, </span><br><span class='style1'>Stevens-Johnson syndrome</span><span class='style7'>1)</span><span class='style1'>, angioedema</span><span class='style6'>1)</span><span class='style1'>,</span></p><p class='p_style37'><span class='style1'>cutaneous vasculitis</span><span class='style6'>1) </span><br> <span class='style1'>lichenoid skin reaction</span><span class='style7'>1)</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Not known</span></p></td><td><p class='p_style37'><span class='style1'>Worsening of symptoms of dermatomyositis</span><span class='style7'>1)</span></p></td></tr> <tr><td rowspan='4'><p class='p_style37'><span class='style1'>Musculoskeletal and connective tissue disorders</span></p></td><td><p class='p_style37'><span class='style1'>Very common</span></p></td><td><p class='p_style37'><span class='style1'>Musculoskeletal pain</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Common</span></p></td><td><p class='p_style37'><span class='style1'>Muscle spasms (including blood creatine phosphokinase increased)</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Uncommon</span></p></td><td><p class='p_style37'><span class='style1'>Rhabdomyolysis, </span><br><span class='style1'>systemic lupus erythematosus</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Rare</span></p></td><td><p class='p_style37'><span class='style1'>Lupus-like syndrome</span><span class='style6'>1)</span></p></td></tr> <tr><td rowspan='2'><p class='p_style37'><span class='style1'>Renal and urinary disorders</span></p></td><td><p class='p_style37'><span class='style1'>Common</span></p></td><td><p class='p_style37'><span class='style1'>Renal impairment, </span><br><span class='style1'>haematuria</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Uncommon</span></p></td><td><p class='p_style37'><span class='style1'>Nocturia</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Reproductive system and breast disorders</span></p></td><td><p class='p_style37'><span class='style1'>Uncommon</span></p></td><td><p class='p_style37'><span class='style1'>Erectile dysfunction</span></p></td></tr> <tr><td><p class='p_style34'><span class='style0'>System Organ Class</span></p></td><td><p class='p_style35'><span class='style0'>Frequency</span></p></td><td><p class='p_style36'><span class='style0'>Adverse Reaction</span></p></td></tr> <tr><td rowspan='3'><p class='p_style37'><span class='style1'>General disorders and administration site conditions*</span></p></td><td><p class='p_style37'><span class='style1'>Very Common</span></p></td><td><p class='p_style37'><span class='style1'>Injection site reaction (including injection site erythema)</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Common</span></p></td><td><p class='p_style37'><span class='style1'>Chest pain, </span><br><span class='style1'>oedema, </span><br><span class='style1'>pyrexia</span><span class='style6'>1)</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Uncommon</span></p></td><td><p class='p_style37'><span class='style1'>Inflammation</span></p></td></tr> <tr><td rowspan='2'><p class='p_style37'><span class='style1'>Investigations*</span></p></td><td><p class='p_style37'><span class='style1'>Common</span></p></td><td><p class='p_style37'><span class='style1'>Coagulation and bleeding disorders (including activated partial thromboplastin time prolonged), autoantibody test positive (including double stranded DNA antibody),</span></p><p class='p_style37'><span class='style1'>blood lactate dehydrogenase increased</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Not known</span></p></td><td><p class='p_style37'><span class='style1'>Weight increased</span><span class='style6'>2)</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Injury, poisoning and procedural complications</span></p></td><td><p class='p_style37'><span class='style1'>Common</span></p></td><td><p class='p_style37'><span class='style1'>Impaired healing</span></p></td></tr> </table><p class='p_style3'><span class='style1'>* further information is found elsewhere in sections 4.3, 4.4 and 4.8 ** including open label extension studies</span></p><ul> <li> 1) including spontaneous reporting data </li> <li> 2) The mean weight change from baseline for adalimumab ranged from 0.3 kg to 1.0 kg across adult indications compared to (minus) -0.4 kg to 0.4 kg for placebo over a treatment period of 4-6 months. Weight increase of 5-6 kg has also been observed in long-term extension studies with mean exposures of approximately 1-2 years without control group, particularly in patients with Crohn’s disease and Ulcerative colitis. The mechanism behind this effect is unclear but could be associated with the anti-inflammatory effect of adalimumab. </li> </ul><p class='p_style3'><span class='style2'>Uveitis</span></p><p class='p_style9'><span class='style1'>The safety profile for patients with uveitis treated with Humira every other week was consistent with the known safety profile of Humira.</span></p><p class='p_style9'><span class='style2'>Description of selected adverse reactions</span></p><p class='p_style9'><span class='style3'>Injection site reactions</span></p><p class='p_style3'><span class='style1'>In the pivotal controlled trials in adults and children, 12.9% of patients treated with Humira developed injection site reactions (erythema and/or itching, haemorrhage, pain or swelling), compared to 7.2% of patients receiving placebo or active control. Injection site reactions generally did not necessitate discontinuation of the medicinal product.</span></p><p class='p_style3'><span class='style3'>Infections</span></p><p class='p_style38'><span class='style1'>In the pivotal controlled trials in adults and children, the rate of infection was 1.51 per patient year in the Humira treated patients and 1.46 per patient year in the placebo and active control-treated patients. The infections consisted primarily of nasopharyngitis, upper respiratory tract infection, and sinusitis. Most patients continued on Humira after the infection resolved.</span></p><p class='p_style3'><span class='style1'>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.</span></p><p class='p_style6'><span class='style1'>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.</span></p><p class='p_style6'><span class='style3'>Malignancies and lymphoproliferative disorders</span></p><p class='p_style3'><span class='style1'>No 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 498.1 patient years during Humira trials in paediatric patients with Crohn’s disease. No malignancies were observed in 77 paediatric patients with an exposure of 80.0 patient years during a Humira trial in paediatric patients with chronic plaque psoriasis. No malignancies were observed in 60 paediatric patients with an exposure of 58.4 patient years during a Humira trial in paediatric patients with uveitis.</span></p><p class='p_style3'><span class='style1'>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, hidradenitis suppurativa, Crohn’s disease, ulcerative colitis and uveitis, malignancies, other than lymphoma and non-melanoma skin cancer, were observed at a rate (95% confidence interval) of 6.8 (4.4, 10.5) per 1,000 patient-years among 5,291 Humira treated patients</span> <span class='style3'> versus</span> <span class='style1'> a rate of 6.3 (3.4, 11.8) per 1,000 patient-years among 3,444 control patients (median duration of treatment was 4.0 months for Humira and 3.8 months for control-treated patients). The rate (95% confidence interval) of non-melanoma skin cancers was 8.8 (6.0, 13.0) per 1,000 patient-years among Humira-treated patients and 3.2 (1.3, 7.6) per 1,000 patient-years among control patients. Of these skin cancers, squamous cell carcinomas occurred at rates (95% confidence interval) of 2.7 (1.4, 5.4) per 1,000 patient-years among Humira-treated patients and 0.6 (0.1, 4.5) per 1,000 patient-years among control patients. The rate (95% confidence interval) of lymphomas was 0.7 (0.2, 2.7) per 1,000 patient-years among Humira-treated patients and 0.6 (0.1, 4.5) per 1,000 patient-years among control patients.</span></p><p class='p_style3'><span class='style1'>When combining controlled portions of these trials and ongoing and completed open label extension studies with a median duration of approximately 3.3 years including 6,427 patients and over 26,439 patient-years of therapy, the observed rate of malignancies, other than lymphoma and non-melanoma skin cancers is approximately 8.5 per 1,000 patient years. The observed rate of non-melanoma skin cancers is approximately 9.6 per 1,000 patient years, and the observed rate of lymphomas is approximately 1.3 per 1,000 patient years.</span></p><p class='p_style38'><span class='style1'>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).</span></p><p class='p_style3'><span class='style1'>Rare post-marketing cases of hepatosplenic T-cell lymphoma have been reported in patients treated with adalimumab (see section 4.4).</span></p><p class='p_style3'><span class='style3'>Autoantibodies</span></p><p class='p_style3'><span class='style1'>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.</span></p><p class='p_style3'><span class='style3'>Hepato-biliary events</span></p><p class='p_style4'><span class='style1'>In 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.</span></p><p class='p_style3'><span class='style1'>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.</span></p><p class='p_style6'><span class='style1'>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.</span></p><p class='p_style3'><span class='style1'>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% (5/192) of patients of whom 4 were receiving concomitant immunosuppressants at baseline.</span></p><p class='p_style6'><span class='style1'>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.</span></p><p class='p_style9'><span class='style1'>No ALT elevations ≥ 3 x ULN occurred in the Phase 3 trial of Humira in paediatric patients with plaque psoriasis.</span></p><p class='p_style7'><span class='style1'>In controlled trials of Humira (initial doses of 80 mg at Week 0 followed by 40 mg every other week starting at Week 1) in adult patients with uveitis up to 80 weeks with a median exposure of 166.5 days and 105.0 days in Humira-treated and control-treated patients, respectively, ALT elevations ≥ 3 x ULN occurred in 2.4% of Humira-treated patients and 2.4% of control-treated patients.</span></p><p class='p_style38'><span class='style1'>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.</span></p><p class='p_style38'><span class='style2'>Concurrent treatment with azathioprine/6-mercaptopurine</span></p><p class='p_style30'><span class='style1'>In 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.</span></p><p class='p_style2'><span class='style2'>Reporting of suspected adverse reactions</span></p><p class='p_style29'><span class='style1'>Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via</span> <span class='style8'> the national reporting system listed in</span> <span class='style9'><a href='http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc'> Appendix V</a></span><span class='style10'><a href='http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc'>.</a></span></p></div><br/></td><td><br/><b>Adverse Reactions</b><br/><div ids='section-UNDESIRABLE_EFFECTS' class='Section'><h3 class='sectionNameHeader' sectionnameid='sectionName-UNDESIRABLE_EFFECTS'>4.8 Undesirable effects</h3> <p class='p_style8'><span class='style2'><del class='diffdel'>Summary of the safety profile</del></span></p><p class='p_style3'><span class='style1'><del class='diffdel'>Humira was studied in 9,506 patients in pivotal controlled and open label trials for up to 60 months or more. These trials included rheumatoid arthritis patients with short term and long standing disease, juvenile idiopathic arthritis (polyarticular juvenile idiopathic arthritis and enthesitis-related arthritis) as well as axial spondyloarthritis (ankylosing spondylitis and axial spondyloarthritis without radiographic evidence of AS), psoriatic arthritis, Crohn’s disease, ulcerative colitis, psoriasis, hidradenitis suppurativa and uveitis patients. The pivotal controlled studies involved 6,089 patients receiving Humira and 3,801 patients receiving placebo or active comparator during the controlled period.</del></span></p><p class='p_style30'><span class='style1'><del class='diffdel'>The proportion of patients who discontinued treatment due to adverse events during the double-blind, controlled portion of pivotal studies was 5.9% for patients taking Humira and 5.4% for control treated patients.</del></span></p><p class='p_style6'><span class='style1'><del class='diffdel'>The most commonly reported adverse reactions are infections (such as nasopharyngitis, upper respiratory tract infection and sinusitis), injection site reactions (erythema, itching, haemorrhage, pain or swelling), headache and musculoskeletal pain.</del></span></p><p class='p_style8'><span class='style1'><del class='diffdel'>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 defence against infection and cancer.</del></span></p><p class='p_style31'><span class='style1'><del class='diffdel'>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.</del></span></p><p class='p_style6'><span class='style1'><del class='diffdel'>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.</del></span></p><p class='p_style6'><span class='style2'><del class='diffdel'>Paediatric population</del></span></p><p class='p_style28'><span class='style1'><del class='diffdel'>In general, the adverse events in paediatric patients were similar in frequency and type to those seen in adult patients.</del></span></p><p class='p_style28'><span class='style2'><del class='diffdel'>Tabulated list of adverse reactions</del></span></p><p class='p_style9'><span class='style1'><del class='diffdel'>The following list of adverse reactions is based on experience from clinical trials and on postmarketing experience and are displayed by system organ class and frequency in Table 6 below: very common</del></span></p><p class='p_style3'><span class='style1'><del class='diffdel'>(</del></span><span class='style5'><del class='diffdel'></del></span><del class='diffdel'> </del><span class='style1'><del class='diffdel'> 1/10); common (</del></span><span class='style5'><del class='diffdel'></del></span><del class='diffdel'> </del><span class='style1'><del class='diffdel'> 1/100 to < 1/10); uncommon (</del></span><span class='style5'><del class='diffdel'></del></span><del class='diffdel'> </del><span class='style1'><del class='diffdel'> 1/1,000 to < 1/100); rare (</del></span><span class='style5'><del class='diffdel'></del></span><del class='diffdel'> </del><span class='style1'><del class='diffdel'> 1/10,000 to < 1/1,000); and not known (cannot be estimated from the available data). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. The highest frequency seen among the various indications has been included. An asterisk (*) appears in the SOC column if further information is found elsewhere in sections 4.3, 4.4 and 4.8.</del></span></p><p class='p_style32'><span class='style0'><del class='diffdel'>Table 6</del></span></p><p class='p_style33'><span class='style0'><del class='diffdel'>Undesirable Effects</del></span></p><table class='clsChildTable'> <tr><td><p class='p_style34'><span class='style0'>System Organ Class</span></p></td><td><p class='p_style35'><span class='style0'>Frequency</span></p></td><td><p class='p_style36'><span class='style0'>Adverse Reaction</span></p></td></tr> <tr><td rowspan='3'><p class='p_style37'><span class='style1'>Infections and </span><br><span class='style1'>infestations*</span></p></td><td><p class='p_style37'><span class='style1'>Very common</span></p></td><td><p class='p_style37'><span class='style1'>Respiratory tract infections (including lower and upper respiratory tract infection, pneumonia, sinusitis, pharyngitis, nasopharyngitis and pneumonia herpes viral)</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Common</span></p></td><td><p class='p_style37'><span class='style1'>Systemic infections (including sepsis, candidiasis and influenza),</span></p><p class='p_style37'><span class='style1'>intestinal infections (including gastroenteritis viral),</span></p><p class='p_style37'><span class='style1'>skin and soft tissue infections (including paronychia, cellulitis, impetigo, necrotising fasciitis and herpes zoster),</span></p><p class='p_style37'><span class='style1'>ear infections, </span><br><span class='style1'>oral infections (including herpes simplex, oral herpes and tooth infections),</span></p><p class='p_style37'><span class='style1'>reproductive tract infections (including vulvovaginal mycotic infection), urinary tract infections (including pyelonephritis),</span></p><p class='p_style37'><span class='style1'>fungal infections, </span><br><span class='style1'>joint infections</span></p></td></tr><del class='diffdel'> </del><tr><td><p class='p_style34'><span class='style0'><del class='diffdel'>System Organ Class</del></span></p></td><td><p class='p_style35'><span class='style0'><del class='diffdel'>Frequency</del></span></p></td><td><p class='p_style36'><span class='style0'><del class='diffdel'>Adverse Reaction</del></span></p></td></tr> <tr><del class='diffdel'> </del><td><p class='p_style37'><span class='style1'>Uncommon</span></p></td><td><p class='p_style37'><span class='style1'>Neurological infections (including viral meningitis),</span></p><p class='p_style37'><span class='style1'>opportunistic infections and tuberculosis (including coccidioidomycosis, histoplasmosis and mycobacterium avium complex infection), bacterial infections, </span><br><span class='style1'>eye infections, </span><br><span class='style1'>diverticulitis</span><span class='style6'>1)</span></p></td></tr> <tr><td rowspan='2'><p class='p_style37'><span class='style1'>Neoplasms benign, malignant and unspecified (including cysts and polyps)*</span></p></td><td><p class='p_style37'><span class='style1'>Common</span></p></td><td><p class='p_style37'><span class='style1'>Skin cancer excluding melanoma (including basal cell carcinoma and squamous cell carcinoma),</span></p><p class='p_style37'><span class='style1'>benign neoplasm</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Uncommon</span></p></td><td><p class='p_style37'><span class='style1'>Lymphoma**, </span><br><span class='style1'>solid organ neoplasm (including breast cancer, lung neoplasm and thyroid neoplasm), melanoma**</span></p></td></tr> <tr><ins class='diffins'> </ins><td><p class='p_style37'><span class='style1'>Rare</span></p></td><td><p class='p_style37'><span class='style1'>Leukaemia</span><span class='style6'>1)</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Not known</span></p></td><td><p class='p_style37'><span class='style1'>Hepatosplenic T-cell lymphoma</span><span class='style7'>1)</span><span class='style1'><ins class='diffins'>,</ins></span></p></td></tr><ins class='diffins'> </ins><tr><td><p class='p_style34'><span class='style0'><ins class='diffins'>System</ins> <ins class='diffins'>Organ Class</ins></span></p></td><td><p class='p_style35'><span class='style0'><ins class='diffins'>Frequency</ins></span></p></td><td><p class='p_style36'><span class='style0'><ins class='diffins'>Adverse</ins> <ins class='diffins'>Reaction</ins></span></p></td></tr><ins class='diffins'> </ins><tr><ins class='diffins'> </ins><td><p class='p_style37'><span class='style1'>Merkel cell carcinoma (neuroendocrine carcinoma of the skin)</span><span class='style7'>1)</span><span class='style1'>,</span></p><p class='p_style37'><span class='style1'>Kaposi’s sarcoma</span></p></td></tr> <tr><td rowspan='4'><p class='p_style37'><span class='style1'>Blood and the lymphatic system disorders*</span></p></td><td><p class='p_style37'><span class='style1'>Very common</span></p></td><td><p class='p_style37'><span class='style1'>Leukopenia (including neutropenia and agranulocytosis),</span></p><p class='p_style37'><span class='style1'>anaemia</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Common</span></p></td><td><p class='p_style37'><span class='style1'>Leucocytosis, </span><br><span class='style1'>thrombocytopenia</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Uncommon</span></p></td><td><p class='p_style37'><span class='style1'>Idiopathic thrombocytopenic purpura</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Rare</span></p></td><td><p class='p_style37'><span class='style1'>Pancytopenia</span></p></td></tr> <tr><td rowspan='3'><p class='p_style37'><span class='style1'>Immune system disorders*</span></p></td><td><p class='p_style37'><span class='style1'>Common</span></p></td><td><p class='p_style37'><span class='style1'>Hypersensitivity, </span><br><span class='style1'>allergies (including seasonal allergy)</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Uncommon</span></p></td><td><p class='p_style37'><span class='style1'>Sarcoidosis</span><span class='style6'>1)</span><span class='style1'>, </span><br><span class='style1'>vasculitis</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Rare</span></p></td><td><p class='p_style37'><span class='style1'>Anaphylaxis</span><span class='style6'>1)</span></p></td></tr> <tr><td rowspan='2'><p class='p_style37'><span class='style1'><ins class='diffins'>Metabolism and nutrition disorders</ins></span></p></td><td><p class='p_style37'><span class='style1'>Very common</span></p></td><td><p class='p_style37'><span class='style1'>Lipids increased</span></p></td></tr><del class='diffdel'> </del><tr><td><p class='p_style34'><span class='style0'><del class='diffdel'>System Organ Class</del></span></p></td><td><p class='p_style35'><span class='style0'><del class='diffdel'>Frequency</del></span></p></td><td><p class='p_style36'><span class='style0'><del class='diffdel'>Adverse Reaction</del></span></p></td></tr><del class='diffdel'> </del><tr><td rowspan='2'><p class='p_style37'><span class='style1'><del class='diffdel'>disorders</del></span></p></td><del class='diffdel'> </del></tr> <tr><td><p class='p_style37'><span class='style1'>Common</span></p></td><td><p class='p_style37'><span class='style1'>Hypokalaemia, </span><br><span class='style1'>uric acid increased, </span><br><span class='style1'>blood sodium abnormal, </span><br><span class='style1'>hypocalcaemia, </span><br><span class='style1'>hyperglycaemia, </span><br><span class='style1'>hypophosphatemia, </span><br><span class='style1'>dehydration</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Psychiatric disorders</span></p></td><td><p class='p_style37'><span class='style1'>Common</span></p></td><td><p class='p_style37'><span class='style1'>Mood alterations (including depression), anxiety, </span><br><span class='style1'>insomnia</span></p></td></tr> <tr><td rowspan='2'><p class='p_style37'><span class='style1'>Nervous system disorders*</span></p></td><td><p class='p_style37'><span class='style1'>Very common</span></p></td><td><p class='p_style37'><span class='style1'>Headache</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Common</span></p></td><td><p class='p_style37'><span class='style1'>Paraesthesias (including hypoesthesia), migraine, </span><br><span class='style1'>nerve root compression</span></p></td></tr><ins class='diffins'> </ins><tr><td><p class='p_style34'><span class='style0'><ins class='diffins'>System Organ Class</ins></span></p></td><td><p class='p_style35'><span class='style0'><ins class='diffins'>Frequency</ins></span></p></td><td><p class='p_style36'><span class='style0'><ins class='diffins'>Adverse Reaction</ins></span></p></td></tr> <tr><ins class='diffins'> </ins><td><p class='p_style37'><span class='style1'>Uncommon</span></p></td><td><p class='p_style37'><span class='style1'>Cerebrovascular accident</span><span class='style7'>1)</span><span class='style1'>, tremor, </span><br><span class='style1'>neuropathy</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Rare</span></p></td><td><p class='p_style37'><span class='style1'>Multiple sclerosis, </span><br><span class='style1'>demyelinating disorders (e.g. optic neuritis, Guillain-Barr syndrome)</span> <span class='style7'> 1)</span></p></td></tr> <tr><td rowspan='2'><p class='p_style37'><span class='style1'>Eye disorders</span></p></td><td><p class='p_style37'><span class='style1'>Common</span></p></td><td><p class='p_style37'><span class='style1'>Visual impairment, </span><br><span class='style1'>conjunctivitis, </span><br><span class='style1'>blepharitis, </span><br><span class='style1'>eye swelling</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Uncommon</span></p></td><td><p class='p_style37'><span class='style1'>Diplopia</span></p></td></tr> <tr><td rowspan='2'><p class='p_style37'><span class='style1'>Ear and labyrinth disorders</span></p></td><td><p class='p_style37'><span class='style1'>Common</span></p></td><td><p class='p_style37'><span class='style1'>Vertigo</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Uncommon</span></p></td><td><p class='p_style37'><span class='style1'>Deafness, </span><br><span class='style1'>tinnitus</span></p></td></tr> <tr><td rowspan='3'><p class='p_style37'><span class='style1'>Cardiac disorders*</span></p></td><td><p class='p_style37'><span class='style1'>Common</span></p></td><td><p class='p_style37'><span class='style1'>Tachycardia</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Uncommon</span></p></td><td><p class='p_style37'><span class='style1'>Myocardial infarction</span><span class='style6'>1)</span><span class='style1'>,<ins class='diffins'> </ins></span></p></td></tr><del class='diffmod'> </del><tr><td><p class='p_style34'><span class='style0'><del class='diffmod'>System Organ Class</del></span></p></td><td><p class='p_style35'><span class='style0'><del class='diffmod'>Frequency</del></span></p></td><td><p class='p_style36'><span class='style0'><del class='diffmod'>Adverse Reaction</del></span></p></td></tr><del class='diffmod'> </del><tr><del class='diffmod'> </del><td><p class='p_style37'><br><span class='style1'>arrhythmia, </span><br><span class='style1'>congestive heart failure</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Rare</span></p></td><td><p class='p_style37'><span class='style1'>Cardiac arrest</span></p></td></tr> <tr><td rowspan='2'><p class='p_style37'><span class='style1'>Vascular disorders</span></p></td><td><p class='p_style37'><span class='style1'>Common</span></p></td><td><p class='p_style37'><span class='style1'>Hypertension, </span><br><span class='style1'>flushing, </span><br><span class='style1'>haematoma</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Uncommon</span></p></td><td><p class='p_style37'><span class='style1'>Aortic aneurysm, </span><br><span class='style1'>vascular arterial occlusion, thrombophlebitis</span></p></td></tr> <tr><td rowspan='2'><p class='p_style37'><span class='style1'>Respiratory, thoracic and mediastinal disorders*</span></p></td><td><p class='p_style37'><span class='style1'>Common</span></p></td><td><p class='p_style37'><span class='style1'>Asthma, </span><br><span class='style1'>dyspnoea, </span><br><span class='style1'>cough</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Uncommon</span></p></td><td><p class='p_style37'><span class='style1'>Pulmonary embolism</span><span class='style6'>1)</span><span class='style1'>, </span><br><span class='style1'>interstitial lung disease, </span><br><span class='style1'>chronic obstructive pulmonary disease, pneumonitis,</span></p></td></tr><ins class='diffins'> </ins><tr><td><p class='p_style34'><span class='style0'><ins class='diffins'>System</ins> <ins class='diffins'>Organ Class</ins></span><br></p></td><td><p class='p_style35'><span class='style0'><ins class='diffmod'>Frequency</ins></span></p></td><td><p class='p_style36'><span class='style0'><ins class='diffmod'>Adverse Reaction</ins></span></p></td></tr><ins class='diffmod'> </ins><tr><ins class='diffmod'> </ins><td><p class='p_style37'><span class='style1'>pleural effusion</span><span class='style6'>1)</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Rare</span></p></td><td><p class='p_style37'><span class='style1'>Pulmonary fibrosis</span><span class='style6'>1)</span></p></td></tr> <tr><td rowspan='4'><p class='p_style37'><span class='style1'>Gastrointestinal disorders</span></p></td><td><p class='p_style37'><span class='style1'>Very common</span></p></td><td><p class='p_style37'><span class='style1'>Abdominal pain, </span><br><span class='style1'>nausea and vomiting</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Common</span></p></td><td><p class='p_style37'><span class='style1'>GI haemorrhage, </span><br><span class='style1'>dyspepsia, </span><br><span class='style1'>gastroesophageal reflux disease, sicca syndrome</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Uncommon</span></p></td><td><p class='p_style37'><span class='style1'>Pancreatitis, </span><br><span class='style1'>dysphagia, </span><br><span class='style1'>face oedema</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Rare</span></p></td><td><p class='p_style37'><span class='style1'>Intestinal perforation</span><span class='style6'>1)</span></p></td></tr> <tr><td rowspan='4'><p class='p_style37'><span class='style1'>Hepato-biliary disorders*</span></p></td><td><p class='p_style37'><span class='style1'>Very Common</span></p></td><td><p class='p_style37'><span class='style1'>Elevated liver enzymes</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Uncommon</span></p></td><td><p class='p_style37'><span class='style1'>Cholecystitis and cholelithiasis, hepatic steatosis, </span><br><span class='style1'>bilirubin increased</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Rare</span></p></td><td><p class='p_style37'><span class='style1'>Hepatitis<ins class='diffins'> </ins></span></p></td></tr><del class='diffmod'> </del><tr><td><p class='p_style34'><span class='style0'><del class='diffmod'>System Organ Class</del></span></p></td><td><p class='p_style35'><span class='style0'><del class='diffmod'>Frequency</del></span></p></td><td><p class='p_style36'><span class='style0'><del class='diffmod'>Adverse Reaction</del></span></p></td></tr><del class='diffmod'> </del><tr><del class='diffmod'> </del><td><p class='p_style37'><br><span class='style1'>reactivation of hepatitis B</span><span class='style7'>1)</span> <span class='style1'> autoimmune hepatitis</span><span class='style6'>1)</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Not known</span></p></td><td><p class='p_style37'><span class='style1'>Liver failure</span><span class='style6'>1)</span></p></td></tr> <tr><td rowspan='3'><p class='p_style37'><span class='style1'>Skin and subcutaneous tissue disorders</span></p></td><td><p class='p_style37'><span class='style1'>Very Common</span></p></td><td><p class='p_style37'><span class='style1'>Rash (including exfoliative rash)</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Common</span></p></td><td><p class='p_style37'><span class='style1'>Worsening or new onset of psoriasis(including palmoplantar pustular psoriasis)</span><span class='style7'>1)</span><span class='style1'>,</span></p><p class='p_style37'><span class='style1'>urticaria, </span><br><span class='style1'>bruising (including purpura), dermatitis (including eczema), onychoclasis, </span><br><span class='style1'>hyperhidrosis, </span><br><span class='style1'>alopecia</span><span class='style6'>1)</span><span class='style1'>, </span><br><span class='style1'>pruritus</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Uncommon</span></p></td><td><p class='p_style37'><span class='style1'>Night sweats, </span><br><span class='style1'>scar</span></p></td></tr><ins class='diffins'> </ins><tr><td><p class='p_style34'><span class='style0'><ins class='diffins'>System Organ Class</ins></span></p></td><td><p class='p_style35'><span class='style0'><ins class='diffins'>Frequency</ins></span></p></td><td><p class='p_style36'><span class='style0'><ins class='diffins'>Adverse Reaction</ins></span></p></td></tr> <tr><ins class='diffins'> </ins><td><p class='p_style37'><span class='style1'>Rare</span></p></td><td><p class='p_style37'><span class='style1'>Erythema multiforme</span><span class='style6'>1)</span><span class='style1'>, </span><br><span class='style1'>Stevens-Johnson syndrome</span><span class='style7'>1)</span><span class='style1'>, angioedema</span><span class='style6'>1)</span><span class='style1'>,</span></p><p class='p_style37'><span class='style1'>cutaneous vasculitis</span><span class='style6'>1) </span><br> <span class='style1'>lichenoid skin reaction</span><span class='style7'>1)</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Not known</span></p></td><td><p class='p_style37'><span class='style1'>Worsening of symptoms of dermatomyositis</span><span class='style7'>1)</span></p></td></tr> <tr><td rowspan='4'><p class='p_style37'><span class='style1'>Musculoskeletal and connective tissue disorders</span></p></td><td><p class='p_style37'><span class='style1'>Very common</span></p></td><td><p class='p_style37'><span class='style1'>Musculoskeletal pain</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Common</span></p></td><td><p class='p_style37'><span class='style1'>Muscle spasms (including blood creatine phosphokinase increased)</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Uncommon</span></p></td><td><p class='p_style37'><span class='style1'>Rhabdomyolysis, </span><br><span class='style1'>systemic lupus erythematosus</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Rare</span></p></td><td><p class='p_style37'><span class='style1'>Lupus-like syndrome</span><span class='style6'>1)</span></p></td></tr> <tr><td rowspan='2'><p class='p_style37'><span class='style1'>Renal and urinary disorders</span></p></td><td><p class='p_style37'><span class='style1'>Common</span></p></td><td><p class='p_style37'><span class='style1'>Renal impairment, </span><br><span class='style1'>haematuria</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Uncommon</span></p></td><td><p class='p_style37'><span class='style1'>Nocturia</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Reproductive system and breast disorders</span></p></td><td><p class='p_style37'><span class='style1'>Uncommon</span></p></td><td><p class='p_style37'><span class='style1'>Erectile dysfunction</span></p></td></tr><del class='diffdel'> </del><tr><td><p class='p_style34'><span class='style0'><del class='diffdel'>System Organ Class</del></span></p></td><td><p class='p_style35'><span class='style0'><del class='diffdel'>Frequency</del></span></p></td><td><p class='p_style36'><span class='style0'><del class='diffdel'>Adverse Reaction</del></span></p></td></tr> <tr><td rowspan='3'><p class='p_style37'><span class='style1'>General disorders and administration site conditions*</span></p></td><td><p class='p_style37'><span class='style1'>Very Common</span></p></td><td><p class='p_style37'><span class='style1'>Injection site reaction (including injection site erythema)</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Common</span></p></td><td><p class='p_style37'><span class='style1'>Chest pain, </span><br><span class='style1'>oedema, </span><br><span class='style1'>pyrexia</span><span class='style6'>1)</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Uncommon</span></p></td><td><p class='p_style37'><span class='style1'>Inflammation</span></p></td></tr> <tr><td rowspan='2'><p class='p_style37'><span class='style1'>Investigations*</span></p></td><td><p class='p_style37'><span class='style1'>Common</span></p></td><td><p class='p_style37'><span class='style1'>Coagulation and bleeding disorders (including activated partial thromboplastin time prolonged), autoantibody test positive (including double stranded DNA antibody),</span></p><p class='p_style37'><span class='style1'>blood lactate dehydrogenase increased</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Not known</span></p></td><td><p class='p_style37'><span class='style1'>Weight increased</span><span class='style6'>2)</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Injury, poisoning and procedural complications</span></p></td><td><p class='p_style37'><span class='style1'>Common</span></p></td><td><p class='p_style37'><span class='style1'>Impaired healing</span></p></td></tr> </table><p class='p_style8'><span class='style1'>* further information is found elsewhere in sections 4.3, 4.4 and 4.8 ** including open label extension studies</span></p><ul> <li> 1) including spontaneous reporting data </li> <li> 2) The mean weight change from baseline for adalimumab ranged from 0.3 kg to 1.0 kg across adult indications compared to (minus) -0.4 kg to 0.4 kg for placebo over a treatment period of 4-6 months. Weight increase of 5-6 kg has also been observed in long-term extension studies with mean exposures of approximately 1-2 years without control group, particularly in patients with Crohn’s disease and Ulcerative colitis. The mechanism behind this effect is unclear but could be associated with the anti-inflammatory effect of adalimumab. </li> </ul><p class='p_style6'><span class='style2'><ins class='diffins'>Hidradenitis suppurativa</ins></span></p><p class='p_style28'><span class='style1'><ins class='diffins'>The safety profile for patients with HS treated with Humira weekly was consistent with the known safety profile of Humira.</ins></span></p><p class='p_style28'><span class='style2'>Uveitis</span></p><p class='p_style9'><span class='style1'>The safety profile for patients with uveitis treated with Humira every other week was consistent with the known safety profile of Humira.</span></p><p class='p_style9'><span class='style2'>Description of selected adverse reactions</span></p><p class='p_style9'><span class='style3'>Injection site reactions</span></p><p class='p_style3'><span class='style1'>In the pivotal controlled trials in adults and children, 12.9% of patients treated with Humira developed injection site reactions (erythema and/or itching, haemorrhage, pain or swelling), compared to 7.2% of patients receiving placebo or active control. Injection site reactions generally did not necessitate discontinuation of the medicinal product.</span></p><p class='p_style3'><span class='style3'>Infections</span></p><p class='p_style3'><span class='style1'>In the pivotal controlled trials in adults and children, the rate of infection was 1.51 per patient year in the Humira treated patients and 1.46 per patient year in the placebo and active control-treated patients. The infections consisted primarily of nasopharyngitis, upper respiratory tract infection, and sinusitis. Most patients continued on Humira after the infection resolved.</span></p><p class='p_style3'><span class='style1'>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.</span></p><p class='p_style3'><span class='style1'>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.</span></p><p class='p_style3'><span class='style3'>Malignancies and lymphoproliferative disorders</span></p><p class='p_style3'><span class='style1'>No 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 498.1 patient years during Humira trials in paediatric patients with Crohn’s disease. No malignancies were observed in 77 paediatric patients with an exposure of 80.0 patient years during a</span> <span class='style1'>Humira trial in paediatric patients with chronic plaque psoriasis.</span><ins class='diffins'> </ins><span class='style21'><ins class='diffins'> No malignancies were observed in 93 paediatric patients with an exposure of 65.3 patient years during a Humira trial in paediatric patients with ulcerative colitis.</ins></span><ins class='diffins'> </ins><span class='style1'> No malignancies were observed in 60 paediatric patients with an exposure of 58.4 patient years during a Humira trial in paediatric patients with uveitis.</span></p><p class='p_style3'><span class='style1'>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, hidradenitis suppurativa, Crohn’s disease, ulcerative colitis and uveitis, malignancies, other than lymphoma and non-melanoma skin cancer, were observed at a rate (95% confidence interval) of 6.8 (4.4, 10.5) per 1,000 patient-years among 5,291 Humira treated patients</span> <span class='style3'> versus</span> <span class='style1'> a rate of 6.3 (3.4, 11.8) per 1,000 patient-years among 3,444 control patients (median duration of treatment was 4.0 months for Humira and 3.8 months for control-treated patients). The rate (95% confidence interval) of non-melanoma skin cancers was 8.8 (6.0, 13.0) per 1,000 patient-years among Humira-treated patients and 3.2 (1.3, 7.6) per 1,000 patient-years among control patients. Of these skin cancers, squamous cell carcinomas occurred at rates (95% confidence interval) of 2.7 (1.4, 5.4) per 1,000 patient-years among Humira-treated patients and 0.6 (0.1, 4.5) per 1,000 patient-years among control patients. The rate (95% confidence interval) of lymphomas was 0.7 (0.2, 2.7) per 1,000 patient-years among Humira-treated patients and 0.6 (0.1, 4.5) per 1,000 patient-years among control patients.</span></p><p class='p_style3'><span class='style1'>When combining controlled portions of these trials and ongoing and completed open label extension studies with a median duration of approximately 3.3 years including 6,427 patients and over 26,439 patient-years of therapy, the observed rate of malignancies, other than lymphoma and non-melanoma skin cancers is approximately 8.5 per 1,000 patient years. The observed rate of non-melanoma skin cancers is approximately 9.6 per 1,000 patient years, and the observed rate of lymphomas is approximately 1.3 per 1,000 patient years.</span></p><p class='p_style3'><span class='style1'>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).</span></p><p class='p_style3'><span class='style1'>Rare post-marketing cases of hepatosplenic T-cell lymphoma have been reported in patients treated with adalimumab (see section 4.4).</span></p><p class='p_style3'><span class='style3'>Autoantibodies</span></p><p class='p_style29'><span class='style1'>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.</span></p><p class='p_style29'><span class='style3'>Hepato-biliary events</span></p><p class='p_style6'><span class='style1'>In 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.</span></p><p class='p_style9'><span class='style1'>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</span> <span class='style1'>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 <<del class='diffmod'>; 4</del><ins class='diffmod'>;4</ins> years.</span></p><p class='p_style4'><span class='style1'>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.</span></p><p class='p_style3'><span class='style1'>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% (5/192) of patients of whom 4 were receiving concomitant immunosuppressants at baseline.</span></p><p class='p_style6'><span class='style1'>In controlled Phase 3 trials of Humira in patients with plaque <del class='diffmod'>psoriasis</del><ins class='diffmod'>Psoriasis</ins> 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.</span></p><p class='p_style9'><span class='style1'>No ALT elevations &ge<del class='diffmod'>;</del><ins class='diffmod'>;3</ins> <del class='diffmod'>3 x</del><ins class='diffmod'>X</ins> ULN occurred in the Phase 3 trial of Humira in paediatric patients with plaque psoriasis<ins class='diffins'>.</ins></span></p><p class='p_style3'><span class='style1'><ins class='diffins'>In controlled trials of Humira (initial doses of 160 mg at Week 0 and 80 mg at Week 2, followed by 40 mg every week starting at Week 4), in patients with hidradenitis suppurativa with a control period duration ranging from 12 to 16 weeks, ALT elevations ≥ 3 x ULN occurred in 0.3% of Humira-treated patients and 0.6% of control-treated patients</ins>.</span></p><p class='p_style3'><span class='style1'>In controlled trials of Humira (initial doses of 80 mg at Week 0 followed by 40 mg every other week starting at Week 1) in adult patients with uveitis up to 80 weeks with a median exposure of 166.5 days and 105.0 days in Humira-treated and control-treated patients, respectively, ALT elevations ≥ 3 x ULN occurred in 2.4% of Humira-treated patients and 2.4% of control-treated<ins class='diffins'> patients.</ins></span></p><p class='p_style3'><span class='style21'><ins class='diffins'>In the controlled Phase 3 trial of Humira in patients with paediatric ulcerative colitis (N=93) which evaluated efficacy and safety of a maintenance dose of 0.6 mg/kg (maximum of 40 mg) every other week (N=31) and a maintenance dose of 0.6 mg/kg (maximum of 40 mg) every Week (N=32), following body weight adjusted induction dosing of 2.4 mg/kg (maximum of 160 mg) at Week 0 and Week 1, and 1.2 mg/kg (maximum of 80 mg) at Week 2 (N=63), or an induction dose of 2.4 mg/kg (maximum of 160 mg) at Week 0, placebo at Week 1, and 1.2 mg/kg (maximum of 80 mg) at Week 2 (N=30), ALT elevations ≥ 3 X ULN occurred in 1.1% (1/93) of</ins> patients.</span></p><p class='p_style3'><span class='style1'>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.</span></p><p class='p_style3'><span class='style2'>Concurrent treatment with azathioprine/6-mercaptopurine</span></p><p class='p_style31'><span class='style1'>In 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<del class='diffmod'>-mercaptopurine</del></span><span class='style2'><ins class='diffmod'>-</ins></span><span class='style1'><ins class='diffmod'>mercaptopurine</ins> compared with Humira alone.</span></p><p class='p_style29'><span class='style2'>Reporting of suspected adverse reactions</span></p><p class='p_style6'><span class='style1'>Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via</span> <span class='style8'> the national reporting system listed in</span> <span class='style9'><a href='http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc'> Appendix V</a></span><span class='style10'><a href='http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc'>.</a></span></p></div><br/></td><td><br/><b>Adverse Reactions</b><br/><div ids='section-UNDESIRABLE_EFFECTS' class='Section'><h3 class='sectionNameHeader' sectionnameid='sectionName-UNDESIRABLE_EFFECTS'>4.8 Undesirable effects</h3> <table class='clsChildTable'> <tr><td><p class='p_style34'><span class='style0'>System Organ Class</span></p></td><td><p class='p_style35'><span class='style0'>Frequency</span></p></td><td><p class='p_style36'><span class='style0'>Adverse Reaction</span></p></td></tr> <tr><td rowspan='3'><p class='p_style37'><span class='style1'>Infections and </span><br><span class='style1'>infestations*</span></p></td><td><p class='p_style37'><span class='style1'>Very common</span></p></td><td><p class='p_style37'><span class='style1'>Respiratory tract infections (including lower and upper respiratory tract infection, pneumonia, sinusitis, pharyngitis, nasopharyngitis and pneumonia herpes viral)</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Common</span></p></td><td><p class='p_style37'><span class='style1'>Systemic infections (including sepsis, candidiasis and influenza),</span></p><p class='p_style37'><span class='style1'>intestinal infections (including gastroenteritis viral),</span></p><p class='p_style37'><span class='style1'>skin and soft tissue infections (including paronychia, cellulitis, impetigo, necrotising fasciitis and herpes zoster),</span></p><p class='p_style37'><span class='style1'>ear infections, </span><br><span class='style1'>oral infections (including herpes simplex, oral herpes and tooth infections),</span></p><p class='p_style37'><span class='style1'>reproductive tract infections (including vulvovaginal mycotic infection), urinary tract infections (including pyelonephritis),</span></p><p class='p_style37'><span class='style1'>fungal infections, </span><br><span class='style1'>joint infections</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Uncommon</span></p></td><td><p class='p_style37'><span class='style1'>Neurological infections (including viral meningitis),</span></p><p class='p_style37'><span class='style1'>opportunistic infections and tuberculosis (including coccidioidomycosis, histoplasmosis and mycobacterium avium complex infection), bacterial infections, </span><br><span class='style1'>eye infections, </span><br><span class='style1'>diverticulitis</span><span class='style6'>1)</span></p></td></tr> <tr><td rowspan='2'><p class='p_style37'><span class='style1'>Neoplasms benign, malignant and unspecified (including cysts and polyps)*</span></p></td><td><p class='p_style37'><span class='style1'>Common</span></p></td><td><p class='p_style37'><span class='style1'>Skin cancer excluding melanoma (including basal cell carcinoma and squamous cell carcinoma),</span></p><p class='p_style37'><span class='style1'>benign neoplasm</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Uncommon</span></p></td><td><p class='p_style37'><span class='style1'>Lymphoma**, </span><br><span class='style1'>solid organ neoplasm (including breast cancer, lung neoplasm and thyroid neoplasm), melanoma**</span></p></td></tr> <tr> <td><p class='p_style37'><span class='style1'>Rare</span></p></td><td><p class='p_style37'><span class='style1'>Leukaemia</span><span class='style6'>1)</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Not known</span></p></td><td><p class='p_style37'><span class='style1'>Hepatosplenic T-cell lymphoma</span><span class='style7'>1)</span><span class='style1'>,</span></p></td></tr> <tr><td><p class='p_style34'><span class='style0'>System Organ Class</span></p></td><td><p class='p_style35'><span class='style0'>Frequency</span></p></td><td><p class='p_style36'><span class='style0'>Adverse Reaction</span></p></td></tr> <tr> <td><p class='p_style37'><span class='style1'>Merkel cell carcinoma (neuroendocrine carcinoma of the skin)</span><span class='style7'>1)</span><span class='style1'>,</span></p><p class='p_style37'><span class='style1'>Kaposi’s sarcoma</span></p></td></tr> <tr><td rowspan='4'><p class='p_style37'><span class='style1'>Blood and the lymphatic system disorders*</span></p></td><td><p class='p_style37'><span class='style1'>Very common</span></p></td><td><p class='p_style37'><span class='style1'>Leukopenia (including neutropenia and agranulocytosis),</span></p><p class='p_style37'><span class='style1'>anaemia</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Common</span></p></td><td><p class='p_style37'><span class='style1'>Leucocytosis, </span><br><span class='style1'>thrombocytopenia</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Uncommon</span></p></td><td><p class='p_style37'><span class='style1'>Idiopathic thrombocytopenic purpura</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Rare</span></p></td><td><p class='p_style37'><span class='style1'>Pancytopenia</span></p></td></tr> <tr><td rowspan='3'><p class='p_style37'><span class='style1'>Immune system disorders*</span></p></td><td><p class='p_style37'><span class='style1'>Common</span></p></td><td><p class='p_style37'><span class='style1'>Hypersensitivity, </span><br><span class='style1'>allergies (including seasonal allergy)</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Uncommon</span></p></td><td><p class='p_style37'><span class='style1'>Sarcoidosis</span><span class='style6'>1)</span><span class='style1'>, </span><br><span class='style1'>vasculitis</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Rare</span></p></td><td><p class='p_style37'><span class='style1'>Anaphylaxis</span><span class='style6'>1)</span></p></td></tr> <tr><td rowspan='2'><p class='p_style37'><span class='style1'>Metabolism and nutrition disorders</span></p></td><td><p class='p_style37'><span class='style1'>Very common</span></p></td><td><p class='p_style37'><span class='style1'>Lipids increased</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Common</span></p></td><td><p class='p_style37'><span class='style1'>Hypokalaemia, </span><br><span class='style1'>uric acid increased, </span><br><span class='style1'>blood sodium abnormal, </span><br><span class='style1'>hypocalcaemia, </span><br><span class='style1'>hyperglycaemia, </span><br><span class='style1'>hypophosphatemia, </span><br><span class='style1'>dehydration</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Psychiatric disorders</span></p></td><td><p class='p_style37'><span class='style1'>Common</span></p></td><td><p class='p_style37'><span class='style1'>Mood alterations (including depression), anxiety, </span><br><span class='style1'>insomnia</span></p></td></tr> <tr><td rowspan='2'><p class='p_style37'><span class='style1'>Nervous system disorders*</span></p></td><td><p class='p_style37'><span class='style1'>Very common</span></p></td><td><p class='p_style37'><span class='style1'>Headache</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Common</span></p></td><td><p class='p_style37'><span class='style1'>Paraesthesias (including hypoesthesia), migraine, </span><br><span class='style1'>nerve root compression</span></p></td></tr> <tr><td><p class='p_style34'><span class='style0'>System Organ Class</span></p></td><td><p class='p_style35'><span class='style0'>Frequency</span></p></td><td><p class='p_style36'><span class='style0'>Adverse Reaction</span></p></td></tr> <tr> <td><p class='p_style37'><span class='style1'>Uncommon</span></p></td><td><p class='p_style37'><span class='style1'>Cerebrovascular accident</span><span class='style7'>1)</span><span class='style1'>, tremor, </span><br><span class='style1'>neuropathy</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Rare</span></p></td><td><p class='p_style37'><span class='style1'>Multiple sclerosis, </span><br><span class='style1'>demyelinating disorders (e.g. optic neuritis, Guillain-Barr syndrome)</span> <span class='style7'> 1)</span></p></td></tr> <tr><td rowspan='2'><p class='p_style37'><span class='style1'>Eye disorders</span></p></td><td><p class='p_style37'><span class='style1'>Common</span></p></td><td><p class='p_style37'><span class='style1'>Visual impairment, </span><br><span class='style1'>conjunctivitis, </span><br><span class='style1'>blepharitis, </span><br><span class='style1'>eye swelling</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Uncommon</span></p></td><td><p class='p_style37'><span class='style1'>Diplopia</span></p></td></tr> <tr><td rowspan='2'><p class='p_style37'><span class='style1'>Ear and labyrinth disorders</span></p></td><td><p class='p_style37'><span class='style1'>Common</span></p></td><td><p class='p_style37'><span class='style1'>Vertigo</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Uncommon</span></p></td><td><p class='p_style37'><span class='style1'>Deafness, </span><br><span class='style1'>tinnitus</span></p></td></tr> <tr><td rowspan='3'><p class='p_style37'><span class='style1'>Cardiac disorders*</span></p></td><td><p class='p_style37'><span class='style1'>Common</span></p></td><td><p class='p_style37'><span class='style1'>Tachycardia</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Uncommon</span></p></td><td><p class='p_style37'><span class='style1'>Myocardial infarction</span><span class='style6'>1)</span><span class='style1'>, </span><br><span class='style1'>arrhythmia, </span><br><span class='style1'>congestive heart failure</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Rare</span></p></td><td><p class='p_style37'><span class='style1'>Cardiac arrest</span></p></td></tr> <tr><td rowspan='2'><p class='p_style37'><span class='style1'>Vascular disorders</span></p></td><td><p class='p_style37'><span class='style1'>Common</span></p></td><td><p class='p_style37'><span class='style1'>Hypertension, </span><br><span class='style1'>flushing, </span><br><span class='style1'>haematoma</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Uncommon</span></p></td><td><p class='p_style37'><span class='style1'>Aortic aneurysm, </span><br><span class='style1'>vascular arterial occlusion, thrombophlebitis</span></p></td></tr> <tr><td rowspan='2'><p class='p_style37'><span class='style1'>Respiratory, thoracic and mediastinal disorders*</span></p></td><td><p class='p_style37'><span class='style1'>Common</span></p></td><td><p class='p_style37'><span class='style1'>Asthma, </span><br><span class='style1'>dyspnoea, </span><br><span class='style1'>cough</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Uncommon</span></p></td><td><p class='p_style37'><span class='style1'>Pulmonary embolism</span><span class='style6'>1)</span><span class='style1'>, </span><br><span class='style1'>interstitial lung disease, </span><br><span class='style1'>chronic obstructive pulmonary disease, pneumonitis,</span></p></td></tr> <tr><td><p class='p_style34'><span class='style0'>System Organ Class</span></p></td><td><p class='p_style35'><span class='style0'>Frequency</span></p></td><td><p class='p_style36'><span class='style0'>Adverse Reaction</span></p></td></tr> <tr> <td><p class='p_style37'><span class='style1'>pleural effusion</span><span class='style6'>1)</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Rare</span></p></td><td><p class='p_style37'><span class='style1'>Pulmonary fibrosis</span><span class='style6'>1)</span></p></td></tr> <tr><td rowspan='4'><p class='p_style37'><span class='style1'>Gastrointestinal disorders</span></p></td><td><p class='p_style37'><span class='style1'>Very common</span></p></td><td><p class='p_style37'><span class='style1'>Abdominal pain, </span><br><span class='style1'>nausea and vomiting</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Common</span></p></td><td><p class='p_style37'><span class='style1'>GI haemorrhage, </span><br><span class='style1'>dyspepsia, </span><br><span class='style1'>gastroesophageal reflux disease, sicca syndrome</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Uncommon</span></p></td><td><p class='p_style37'><span class='style1'>Pancreatitis, </span><br><span class='style1'>dysphagia, </span><br><span class='style1'>face oedema</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Rare</span></p></td><td><p class='p_style37'><span class='style1'>Intestinal perforation</span><span class='style6'>1)</span></p></td></tr> <tr><td rowspan='4'><p class='p_style37'><span class='style1'>Hepato-biliary disorders*</span></p></td><td><p class='p_style37'><span class='style1'>Very Common</span></p></td><td><p class='p_style37'><span class='style1'>Elevated liver enzymes</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Uncommon</span></p></td><td><p class='p_style37'><span class='style1'>Cholecystitis and cholelithiasis, hepatic steatosis, </span><br><span class='style1'>bilirubin increased</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Rare</span></p></td><td><p class='p_style37'><span class='style1'>Hepatitis </span><br><span class='style1'>reactivation of hepatitis B</span><span class='style7'>1)</span> <span class='style1'> autoimmune hepatitis</span><span class='style6'>1)</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Not known</span></p></td><td><p class='p_style37'><span class='style1'>Liver failure</span><span class='style6'>1)</span></p></td></tr> <tr><td rowspan='3'><p class='p_style37'><span class='style1'>Skin and subcutaneous tissue disorders</span></p></td><td><p class='p_style37'><span class='style1'>Very Common</span></p></td><td><p class='p_style37'><span class='style1'>Rash (including exfoliative rash)</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Common</span></p></td><td><p class='p_style37'><span class='style1'>Worsening or new onset of psoriasis(including palmoplantar pustular psoriasis)</span><span class='style7'>1)</span><span class='style1'>,</span></p><p class='p_style37'><span class='style1'>urticaria, </span><br><span class='style1'>bruising (including purpura), dermatitis (including eczema), onychoclasis, </span><br><span class='style1'>hyperhidrosis, </span><br><span class='style1'>alopecia</span><span class='style6'>1)</span><span class='style1'>, </span><br><span class='style1'>pruritus</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Uncommon</span></p></td><td><p class='p_style37'><span class='style1'>Night sweats, </span><br><span class='style1'>scar</span></p></td></tr> <tr><td><p class='p_style34'><span class='style0'>System Organ Class</span></p></td><td><p class='p_style35'><span class='style0'>Frequency</span></p></td><td><p class='p_style36'><span class='style0'>Adverse Reaction</span></p></td></tr> <tr> <td><p class='p_style37'><span class='style1'>Rare</span></p></td><td><p class='p_style37'><span class='style1'>Erythema multiforme</span><span class='style6'>1)</span><span class='style1'>, </span><br><span class='style1'>Stevens-Johnson syndrome</span><span class='style7'>1)</span><span class='style1'>, angioedema</span><span class='style6'>1)</span><span class='style1'>,</span></p><p class='p_style37'><span class='style1'>cutaneous vasculitis</span><span class='style6'>1) </span><br> <span class='style1'>lichenoid skin reaction</span><span class='style7'>1)</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Not known</span></p></td><td><p class='p_style37'><span class='style1'>Worsening of symptoms of dermatomyositis</span><span class='style7'>1)</span></p></td></tr> <tr><td rowspan='4'><p class='p_style37'><span class='style1'>Musculoskeletal and connective tissue disorders</span></p></td><td><p class='p_style37'><span class='style1'>Very common</span></p></td><td><p class='p_style37'><span class='style1'>Musculoskeletal pain</span></p></td></tr> <tr><td><p class='p_style37'></html>"
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string sHtml = "<html><head><style type='text/css'></style> <div class='table-responsive' id='divTableResponsive'> <table id ='tableComparediff' class='table'><tr class='clsRow'><td><b>Section</b></td><td><b><a target='_blank' href=''> Humira 20 mg solution for injection in pre-filled syringe </a></b></td><td><i>Merged Documents</i></td><td><b><a target='_blank' href='> Humira 40 mg solution for injection in pre-filled syringe Humira 40 mg solution for injection in pre-filled pen [1] </a><b></td></tr><tr class='clsRow'><td><b>Highlights</b></td><td><b>Identical</b></td><td><b>Identical</b></td><td><b>Identical</b></td></tr><tr class='clsRow'><td><b>Abuse Section</b></td><td><b>Identical</b></td><td><b>Identical</b></td><td><b>Identical</b></td></tr><tr class='clsRow'><td><b>Adverse Reactions</b></td><td><br/><b>Adverse Reactions</b><br/><div ids='section-UNDESIRABLE_EFFECTS' class='Section'><h3 class='sectionNameHeader' sectionnameid='sectionName-UNDESIRABLE_EFFECTS'>4.8 Undesirable effects</h3> <p class='p_style8'><span class='style2'>Summary of the safety profile</span></p><p class='p_style3'><span class='style1'>Humira was studied in 9,506 patients in pivotal controlled and open label trials for up to 60 months or more. These trials included rheumatoid arthritis patients with short term and long standing disease, juvenile idiopathic arthritis (polyarticular juvenile idiopathic arthritis and enthesitis-related arthritis) as well as axial spondyloarthritis (ankylosing spondylitis and axial spondyloarthritis without radiographic evidence of AS), psoriatic arthritis, Crohn’s disease, ulcerative colitis, psoriasis, hidradenitis suppurativa and uveitis patients. The pivotal controlled studies involved 6,089 patients receiving Humira and 3,801 patients receiving placebo or active comparator during the controlled period.</span></p><p class='p_style30'><span class='style1'>The proportion of patients who discontinued treatment due to adverse events during the double-blind, controlled portion of pivotal studies was 5.9% for patients taking Humira and 5.4% for control treated patients.</span></p><p class='p_style6'><span class='style1'>The most commonly reported adverse reactions are infections (such as nasopharyngitis, upper respiratory tract infection and sinusitis), injection site reactions (erythema, itching, haemorrhage, pain or swelling), headache and musculoskeletal pain.</span></p><p class='p_style8'><span class='style1'>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 defence against infection and cancer.</span></p><p class='p_style31'><span class='style1'>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.</span></p><p class='p_style6'><span class='style1'>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.</span></p><p class='p_style6'><span class='style2'>Paediatric population</span></p><p class='p_style28'><span class='style1'>In general, the adverse events in paediatric patients were similar in frequency and type to those seen in adult patients.</span></p><p class='p_style28'><span class='style2'>Tabulated list of adverse reactions</span></p><p class='p_style9'><span class='style1'>The following list of adverse reactions is based on experience from clinical trials and on postmarketing experience and are displayed by system organ class and frequency in Table 6 below: very common</span></p><p class='p_style3'><span class='style1'>(</span><span class='style5'></span> <span class='style1'> 1/10); common (</span><span class='style5'></span> <span class='style1'> 1/100 to < 1/10); uncommon (</span><span class='style5'></span> <span class='style1'> 1/1,000 to < 1/100); rare (</span><span class='style5'></span> <span class='style1'> 1/10,000 to < 1/1,000); and not known (cannot be estimated from the available data). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. The highest frequency seen among the various indications has been included. An asterisk (*) appears in the SOC column if further information is found elsewhere in sections 4.3, 4.4 and 4.8.</span></p><p class='p_style32'><span class='style0'>Table 6</span></p><p class='p_style33'><span class='style0'>Undesirable Effects</span></p><table class='clsChildTable'> <tr><td><p class='p_style34'><span class='style0'>System Organ Class</span></p></td><td><p class='p_style35'><span class='style0'>Frequency</span></p></td><td><p class='p_style36'><span class='style0'>Adverse Reaction</span></p></td></tr> <tr><td rowspan='2'><p class='p_style37'><span class='style1'>Infections and </span><br><span class='style1'>infestations*</span></p></td><td><p class='p_style37'><span class='style1'>Very common</span></p></td><td><p class='p_style37'><span class='style1'>Respiratory tract infections (including lower and upper respiratory tract infection, pneumonia, sinusitis, pharyngitis, nasopharyngitis and pneumonia herpes viral)</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Common</span></p></td><td><p class='p_style37'><span class='style1'>Systemic infections (including sepsis, candidiasis and influenza),</span></p><p class='p_style37'><span class='style1'>intestinal infections (including gastroenteritis viral),</span></p><p class='p_style37'><span class='style1'>skin and soft tissue infections (including paronychia, cellulitis, impetigo, necrotising fasciitis and herpes zoster),</span></p><p class='p_style37'><span class='style1'>ear infections, </span><br><span class='style1'>oral infections (including herpes simplex, oral herpes and tooth infections),</span></p><p class='p_style37'><span class='style1'>reproductive tract infections (including vulvovaginal mycotic infection), urinary tract infections (including pyelonephritis),</span></p><p class='p_style37'><span class='style1'>fungal infections, </span><br><span class='style1'>joint infections</span></p></td></tr> <tr><td><p class='p_style34'><span class='style0'>System Organ Class</span></p></td><td><p class='p_style35'><span class='style0'>Frequency</span></p></td><td><p class='p_style36'><span class='style0'>Adverse Reaction</span></p></td></tr> <tr> <td><p class='p_style37'><span class='style1'>Uncommon</span></p></td><td><p class='p_style37'><span class='style1'>Neurological infections (including viral meningitis),</span></p><p class='p_style37'><span class='style1'>opportunistic infections and tuberculosis (including coccidioidomycosis, histoplasmosis and mycobacterium avium complex infection), bacterial infections, </span><br><span class='style1'>eye infections, </span><br><span class='style1'>diverticulitis</span><span class='style6'>1)</span></p></td></tr> <tr><td rowspan='4'><p class='p_style37'><span class='style1'>Neoplasms benign, malignant and unspecified (including cysts and polyps)*</span></p></td><td><p class='p_style37'><span class='style1'>Common</span></p></td><td><p class='p_style37'><span class='style1'>Skin cancer excluding melanoma (including basal cell carcinoma and squamous cell carcinoma),</span></p><p class='p_style37'><span class='style1'>benign neoplasm</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Uncommon</span></p></td><td><p class='p_style37'><span class='style1'>Lymphoma**, </span><br><span class='style1'>solid organ neoplasm (including breast cancer, lung neoplasm and thyroid neoplasm), melanoma**</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Rare</span></p></td><td><p class='p_style37'><span class='style1'>Leukaemia</span><span class='style6'>1)</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Not known</span></p></td><td><p class='p_style37'><span class='style1'>Hepatosplenic T-cell lymphoma</span><span class='style7'>1)</span> <span class='style1'> Merkel cell carcinoma (neuroendocrine carcinoma of the skin)</span><span class='style7'>1)</span><span class='style1'>,</span></p><p class='p_style37'><span class='style1'>Kaposi’s sarcoma</span></p></td></tr> <tr><td rowspan='4'><p class='p_style37'><span class='style1'>Blood and the lymphatic system disorders*</span></p></td><td><p class='p_style37'><span class='style1'>Very common</span></p></td><td><p class='p_style37'><span class='style1'>Leukopenia (including neutropenia and agranulocytosis),</span></p><p class='p_style37'><span class='style1'>anaemia</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Common</span></p></td><td><p class='p_style37'><span class='style1'>Leucocytosis, </span><br><span class='style1'>thrombocytopenia</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Uncommon</span></p></td><td><p class='p_style37'><span class='style1'>Idiopathic thrombocytopenic purpura</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Rare</span></p></td><td><p class='p_style37'><span class='style1'>Pancytopenia</span></p></td></tr> <tr><td rowspan='3'><p class='p_style37'><span class='style1'>Immune system disorders*</span></p></td><td><p class='p_style37'><span class='style1'>Common</span></p></td><td><p class='p_style37'><span class='style1'>Hypersensitivity, </span><br><span class='style1'>allergies (including seasonal allergy)</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Uncommon</span></p></td><td><p class='p_style37'><span class='style1'>Sarcoidosis</span><span class='style6'>1)</span><span class='style1'>, </span><br><span class='style1'>vasculitis</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Rare</span></p></td><td><p class='p_style37'><span class='style1'>Anaphylaxis</span><span class='style6'>1)</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Very common</span></p></td><td><p class='p_style37'><span class='style1'>Lipids increased</span></p></td></tr> <tr><td><p class='p_style34'><span class='style0'>System Organ Class</span></p></td><td><p class='p_style35'><span class='style0'>Frequency</span></p></td><td><p class='p_style36'><span class='style0'>Adverse Reaction</span></p></td></tr> <tr><td rowspan='2'><p class='p_style37'><span class='style1'>disorders</span></p></td> </tr> <tr><td><p class='p_style37'><span class='style1'>Common</span></p></td><td><p class='p_style37'><span class='style1'>Hypokalaemia, </span><br><span class='style1'>uric acid increased, </span><br><span class='style1'>blood sodium abnormal, </span><br><span class='style1'>hypocalcaemia, </span><br><span class='style1'>hyperglycaemia, </span><br><span class='style1'>hypophosphatemia, </span><br><span class='style1'>dehydration</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Psychiatric disorders</span></p></td><td><p class='p_style37'><span class='style1'>Common</span></p></td><td><p class='p_style37'><span class='style1'>Mood alterations (including depression), anxiety, </span><br><span class='style1'>insomnia</span></p></td></tr> <tr><td rowspan='4'><p class='p_style37'><span class='style1'>Nervous system disorders*</span></p></td><td><p class='p_style37'><span class='style1'>Very common</span></p></td><td><p class='p_style37'><span class='style1'>Headache</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Common</span></p></td><td><p class='p_style37'><span class='style1'>Paraesthesias (including hypoesthesia), migraine, </span><br><span class='style1'>nerve root compression</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Uncommon</span></p></td><td><p class='p_style37'><span class='style1'>Cerebrovascular accident</span><span class='style7'>1)</span><span class='style1'>, tremor, </span><br><span class='style1'>neuropathy</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Rare</span></p></td><td><p class='p_style37'><span class='style1'>Multiple sclerosis, </span><br><span class='style1'>demyelinating disorders (e.g. optic neuritis, Guillain-Barr syndrome)</span> <span class='style7'> 1)</span></p></td></tr> <tr><td rowspan='2'><p class='p_style37'><span class='style1'>Eye disorders</span></p></td><td><p class='p_style37'><span class='style1'>Common</span></p></td><td><p class='p_style37'><span class='style1'>Visual impairment, </span><br><span class='style1'>conjunctivitis, </span><br><span class='style1'>blepharitis, </span><br><span class='style1'>eye swelling</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Uncommon</span></p></td><td><p class='p_style37'><span class='style1'>Diplopia</span></p></td></tr> <tr><td rowspan='2'><p class='p_style37'><span class='style1'>Ear and labyrinth disorders</span></p></td><td><p class='p_style37'><span class='style1'>Common</span></p></td><td><p class='p_style37'><span class='style1'>Vertigo</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Uncommon</span></p></td><td><p class='p_style37'><span class='style1'>Deafness, </span><br><span class='style1'>tinnitus</span></p></td></tr> <tr><td rowspan='2'><p class='p_style37'><span class='style1'>Cardiac disorders*</span></p></td><td><p class='p_style37'><span class='style1'>Common</span></p></td><td><p class='p_style37'><span class='style1'>Tachycardia</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Uncommon</span></p></td><td><p class='p_style37'><span class='style1'>Myocardial infarction</span><span class='style6'>1)</span><span class='style1'>,</span></p></td></tr> <tr><td><p class='p_style34'><span class='style0'>System Organ Class</span></p></td><td><p class='p_style35'><span class='style0'>Frequency</span></p></td><td><p class='p_style36'><span class='style0'>Adverse Reaction</span></p></td></tr> <tr> <td><p class='p_style37'><span class='style1'>arrhythmia, </span><br><span class='style1'>congestive heart failure</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Rare</span></p></td><td><p class='p_style37'><span class='style1'>Cardiac arrest</span></p></td></tr> <tr><td rowspan='2'><p class='p_style37'><span class='style1'>Vascular disorders</span></p></td><td><p class='p_style37'><span class='style1'>Common</span></p></td><td><p class='p_style37'><span class='style1'>Hypertension, </span><br><span class='style1'>flushing, </span><br><span class='style1'>haematoma</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Uncommon</span></p></td><td><p class='p_style37'><span class='style1'>Aortic aneurysm, </span><br><span class='style1'>vascular arterial occlusion, thrombophlebitis</span></p></td></tr> <tr><td rowspan='3'><p class='p_style37'><span class='style1'>Respiratory, thoracic and mediastinal disorders*</span></p></td><td><p class='p_style37'><span class='style1'>Common</span></p></td><td><p class='p_style37'><span class='style1'>Asthma, </span><br><span class='style1'>dyspnoea, </span><br><span class='style1'>cough</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Uncommon</span></p></td><td><p class='p_style37'><span class='style1'>Pulmonary embolism</span><span class='style6'>1)</span><span class='style1'>, </span><br><span class='style1'>interstitial lung disease, </span><br><span class='style1'>chronic obstructive pulmonary disease, pneumonitis, </span><br><span class='style1'>pleural effusion</span><span class='style6'>1)</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Rare</span></p></td><td><p class='p_style37'><span class='style1'>Pulmonary fibrosis</span><span class='style6'>1)</span></p></td></tr> <tr><td rowspan='4'><p class='p_style37'><span class='style1'>Gastrointestinal disorders</span></p></td><td><p class='p_style37'><span class='style1'>Very common</span></p></td><td><p class='p_style37'><span class='style1'>Abdominal pain, </span><br><span class='style1'>nausea and vomiting</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Common</span></p></td><td><p class='p_style37'><span class='style1'>GI haemorrhage, </span><br><span class='style1'>dyspepsia, </span><br><span class='style1'>gastroesophageal reflux disease, sicca syndrome</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Uncommon</span></p></td><td><p class='p_style37'><span class='style1'>Pancreatitis, </span><br><span class='style1'>dysphagia, </span><br><span class='style1'>face oedema</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Rare</span></p></td><td><p class='p_style37'><span class='style1'>Intestinal perforation</span><span class='style6'>1)</span></p></td></tr> <tr><td rowspan='3'><p class='p_style37'><span class='style1'>Hepato-biliary disorders*</span></p></td><td><p class='p_style37'><span class='style1'>Very Common</span></p></td><td><p class='p_style37'><span class='style1'>Elevated liver enzymes</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Uncommon</span></p></td><td><p class='p_style37'><span class='style1'>Cholecystitis and cholelithiasis, hepatic steatosis, </span><br><span class='style1'>bilirubin increased</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Rare</span></p></td><td><p class='p_style37'><span class='style1'>Hepatitis</span></p></td></tr> <tr><td><p class='p_style34'><span class='style0'>System Organ Class</span></p></td><td><p class='p_style35'><span class='style0'>Frequency</span></p></td><td><p class='p_style36'><span class='style0'>Adverse Reaction</span></p></td></tr> <tr> <td><p class='p_style37'><span class='style1'>reactivation of hepatitis B</span><span class='style7'>1)</span> <span class='style1'> autoimmune hepatitis</span><span class='style6'>1)</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Not known</span></p></td><td><p class='p_style37'><span class='style1'>Liver failure</span><span class='style6'>1)</span></p></td></tr> <tr><td rowspan='5'><p class='p_style37'><span class='style1'>Skin and subcutaneous tissue disorders</span></p></td><td><p class='p_style37'><span class='style1'>Very Common</span></p></td><td><p class='p_style37'><span class='style1'>Rash (including exfoliative rash)</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Common</span></p></td><td><p class='p_style37'><span class='style1'>Worsening or new onset of psoriasis(including palmoplantar pustular psoriasis)</span><span class='style7'>1)</span><span class='style1'>,</span></p><p class='p_style37'><span class='style1'>urticaria, </span><br><span class='style1'>bruising (including purpura), dermatitis (including eczema), onychoclasis, </span><br><span class='style1'>hyperhidrosis, </span><br><span class='style1'>alopecia</span><span class='style6'>1)</span><span class='style1'>, </span><br><span class='style1'>pruritus</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Uncommon</span></p></td><td><p class='p_style37'><span class='style1'>Night sweats, </span><br><span class='style1'>scar</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Rare</span></p></td><td><p class='p_style37'><span class='style1'>Erythema multiforme</span><span class='style6'>1)</span><span class='style1'>, </span><br><span class='style1'>Stevens-Johnson syndrome</span><span class='style7'>1)</span><span class='style1'>, angioedema</span><span class='style6'>1)</span><span class='style1'>,</span></p><p class='p_style37'><span class='style1'>cutaneous vasculitis</span><span class='style6'>1) </span><br> <span class='style1'>lichenoid skin reaction</span><span class='style7'>1)</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Not known</span></p></td><td><p class='p_style37'><span class='style1'>Worsening of symptoms of dermatomyositis</span><span class='style7'>1)</span></p></td></tr> <tr><td rowspan='4'><p class='p_style37'><span class='style1'>Musculoskeletal and connective tissue disorders</span></p></td><td><p class='p_style37'><span class='style1'>Very common</span></p></td><td><p class='p_style37'><span class='style1'>Musculoskeletal pain</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Common</span></p></td><td><p class='p_style37'><span class='style1'>Muscle spasms (including blood creatine phosphokinase increased)</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Uncommon</span></p></td><td><p class='p_style37'><span class='style1'>Rhabdomyolysis, </span><br><span class='style1'>systemic lupus erythematosus</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Rare</span></p></td><td><p class='p_style37'><span class='style1'>Lupus-like syndrome</span><span class='style6'>1)</span></p></td></tr> <tr><td rowspan='2'><p class='p_style37'><span class='style1'>Renal and urinary disorders</span></p></td><td><p class='p_style37'><span class='style1'>Common</span></p></td><td><p class='p_style37'><span class='style1'>Renal impairment, </span><br><span class='style1'>haematuria</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Uncommon</span></p></td><td><p class='p_style37'><span class='style1'>Nocturia</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Reproductive system and breast disorders</span></p></td><td><p class='p_style37'><span class='style1'>Uncommon</span></p></td><td><p class='p_style37'><span class='style1'>Erectile dysfunction</span></p></td></tr> <tr><td><p class='p_style34'><span class='style0'>System Organ Class</span></p></td><td><p class='p_style35'><span class='style0'>Frequency</span></p></td><td><p class='p_style36'><span class='style0'>Adverse Reaction</span></p></td></tr> <tr><td rowspan='3'><p class='p_style37'><span class='style1'>General disorders and administration site conditions*</span></p></td><td><p class='p_style37'><span class='style1'>Very Common</span></p></td><td><p class='p_style37'><span class='style1'>Injection site reaction (including injection site erythema)</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Common</span></p></td><td><p class='p_style37'><span class='style1'>Chest pain, </span><br><span class='style1'>oedema, </span><br><span class='style1'>pyrexia</span><span class='style6'>1)</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Uncommon</span></p></td><td><p class='p_style37'><span class='style1'>Inflammation</span></p></td></tr> <tr><td rowspan='2'><p class='p_style37'><span class='style1'>Investigations*</span></p></td><td><p class='p_style37'><span class='style1'>Common</span></p></td><td><p class='p_style37'><span class='style1'>Coagulation and bleeding disorders (including activated partial thromboplastin time prolonged), autoantibody test positive (including double stranded DNA antibody),</span></p><p class='p_style37'><span class='style1'>blood lactate dehydrogenase increased</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Not known</span></p></td><td><p class='p_style37'><span class='style1'>Weight increased</span><span class='style6'>2)</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Injury, poisoning and procedural complications</span></p></td><td><p class='p_style37'><span class='style1'>Common</span></p></td><td><p class='p_style37'><span class='style1'>Impaired healing</span></p></td></tr> </table><p class='p_style3'><span class='style1'>* further information is found elsewhere in sections 4.3, 4.4 and 4.8 ** including open label extension studies</span></p><ul> <li> 1) including spontaneous reporting data </li> <li> 2) The mean weight change from baseline for adalimumab ranged from 0.3 kg to 1.0 kg across adult indications compared to (minus) -0.4 kg to 0.4 kg for placebo over a treatment period of 4-6 months. Weight increase of 5-6 kg has also been observed in long-term extension studies with mean exposures of approximately 1-2 years without control group, particularly in patients with Crohn’s disease and Ulcerative colitis. The mechanism behind this effect is unclear but could be associated with the anti-inflammatory effect of adalimumab. </li> </ul><p class='p_style3'><span class='style2'>Uveitis</span></p><p class='p_style9'><span class='style1'>The safety profile for patients with uveitis treated with Humira every other week was consistent with the known safety profile of Humira.</span></p><p class='p_style9'><span class='style2'>Description of selected adverse reactions</span></p><p class='p_style9'><span class='style3'>Injection site reactions</span></p><p class='p_style3'><span class='style1'>In the pivotal controlled trials in adults and children, 12.9% of patients treated with Humira developed injection site reactions (erythema and/or itching, haemorrhage, pain or swelling), compared to 7.2% of patients receiving placebo or active control. Injection site reactions generally did not necessitate discontinuation of the medicinal product.</span></p><p class='p_style3'><span class='style3'>Infections</span></p><p class='p_style38'><span class='style1'>In the pivotal controlled trials in adults and children, the rate of infection was 1.51 per patient year in the Humira treated patients and 1.46 per patient year in the placebo and active control-treated patients. The infections consisted primarily of nasopharyngitis, upper respiratory tract infection, and sinusitis. Most patients continued on Humira after the infection resolved.</span></p><p class='p_style3'><span class='style1'>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.</span></p><p class='p_style6'><span class='style1'>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.</span></p><p class='p_style6'><span class='style3'>Malignancies and lymphoproliferative disorders</span></p><p class='p_style3'><span class='style1'>No 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 498.1 patient years during Humira trials in paediatric patients with Crohn’s disease. No malignancies were observed in 77 paediatric patients with an exposure of 80.0 patient years during a Humira trial in paediatric patients with chronic plaque psoriasis. No malignancies were observed in 60 paediatric patients with an exposure of 58.4 patient years during a Humira trial in paediatric patients with uveitis.</span></p><p class='p_style3'><span class='style1'>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, hidradenitis suppurativa, Crohn’s disease, ulcerative colitis and uveitis, malignancies, other than lymphoma and non-melanoma skin cancer, were observed at a rate (95% confidence interval) of 6.8 (4.4, 10.5) per 1,000 patient-years among 5,291 Humira treated patients</span> <span class='style3'> versus</span> <span class='style1'> a rate of 6.3 (3.4, 11.8) per 1,000 patient-years among 3,444 control patients (median duration of treatment was 4.0 months for Humira and 3.8 months for control-treated patients). The rate (95% confidence interval) of non-melanoma skin cancers was 8.8 (6.0, 13.0) per 1,000 patient-years among Humira-treated patients and 3.2 (1.3, 7.6) per 1,000 patient-years among control patients. Of these skin cancers, squamous cell carcinomas occurred at rates (95% confidence interval) of 2.7 (1.4, 5.4) per 1,000 patient-years among Humira-treated patients and 0.6 (0.1, 4.5) per 1,000 patient-years among control patients. The rate (95% confidence interval) of lymphomas was 0.7 (0.2, 2.7) per 1,000 patient-years among Humira-treated patients and 0.6 (0.1, 4.5) per 1,000 patient-years among control patients.</span></p><p class='p_style3'><span class='style1'>When combining controlled portions of these trials and ongoing and completed open label extension studies with a median duration of approximately 3.3 years including 6,427 patients and over 26,439 patient-years of therapy, the observed rate of malignancies, other than lymphoma and non-melanoma skin cancers is approximately 8.5 per 1,000 patient years. The observed rate of non-melanoma skin cancers is approximately 9.6 per 1,000 patient years, and the observed rate of lymphomas is approximately 1.3 per 1,000 patient years.</span></p><p class='p_style38'><span class='style1'>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).</span></p><p class='p_style3'><span class='style1'>Rare post-marketing cases of hepatosplenic T-cell lymphoma have been reported in patients treated with adalimumab (see section 4.4).</span></p><p class='p_style3'><span class='style3'>Autoantibodies</span></p><p class='p_style3'><span class='style1'>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.</span></p><p class='p_style3'><span class='style3'>Hepato-biliary events</span></p><p class='p_style4'><span class='style1'>In 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.</span></p><p class='p_style3'><span class='style1'>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.</span></p><p class='p_style6'><span class='style1'>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.</span></p><p class='p_style3'><span class='style1'>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% (5/192) of patients of whom 4 were receiving concomitant immunosuppressants at baseline.</span></p><p class='p_style6'><span class='style1'>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.</span></p><p class='p_style9'><span class='style1'>No ALT elevations ≥ 3 x ULN occurred in the Phase 3 trial of Humira in paediatric patients with plaque psoriasis.</span></p><p class='p_style7'><span class='style1'>In controlled trials of Humira (initial doses of 80 mg at Week 0 followed by 40 mg every other week starting at Week 1) in adult patients with uveitis up to 80 weeks with a median exposure of 166.5 days and 105.0 days in Humira-treated and control-treated patients, respectively, ALT elevations ≥ 3 x ULN occurred in 2.4% of Humira-treated patients and 2.4% of control-treated patients.</span></p><p class='p_style38'><span class='style1'>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.</span></p><p class='p_style38'><span class='style2'>Concurrent treatment with azathioprine/6-mercaptopurine</span></p><p class='p_style30'><span class='style1'>In 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.</span></p><p class='p_style2'><span class='style2'>Reporting of suspected adverse reactions</span></p><p class='p_style29'><span class='style1'>Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via</span> <span class='style8'> the national reporting system listed in</span> <span class='style9'><a href='http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc'> Appendix V</a></span><span class='style10'><a href='http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc'>.</a></span></p></div><br/></td><td><br/><b>Adverse Reactions</b><br/><div ids='section-UNDESIRABLE_EFFECTS' class='Section'><h3 class='sectionNameHeader' sectionnameid='sectionName-UNDESIRABLE_EFFECTS'>4.8 Undesirable effects</h3> <p class='p_style8'><span class='style2'><del class='diffdel'>Summary of the safety profile</del></span></p><p class='p_style3'><span class='style1'><del class='diffdel'>Humira was studied in 9,506 patients in pivotal controlled and open label trials for up to 60 months or more. These trials included rheumatoid arthritis patients with short term and long standing disease, juvenile idiopathic arthritis (polyarticular juvenile idiopathic arthritis and enthesitis-related arthritis) as well as axial spondyloarthritis (ankylosing spondylitis and axial spondyloarthritis without radiographic evidence of AS), psoriatic arthritis, Crohn’s disease, ulcerative colitis, psoriasis, hidradenitis suppurativa and uveitis patients. The pivotal controlled studies involved 6,089 patients receiving Humira and 3,801 patients receiving placebo or active comparator during the controlled period.</del></span></p><p class='p_style30'><span class='style1'><del class='diffdel'>The proportion of patients who discontinued treatment due to adverse events during the double-blind, controlled portion of pivotal studies was 5.9% for patients taking Humira and 5.4% for control treated patients.</del></span></p><p class='p_style6'><span class='style1'><del class='diffdel'>The most commonly reported adverse reactions are infections (such as nasopharyngitis, upper respiratory tract infection and sinusitis), injection site reactions (erythema, itching, haemorrhage, pain or swelling), headache and musculoskeletal pain.</del></span></p><p class='p_style8'><span class='style1'><del class='diffdel'>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 defence against infection and cancer.</del></span></p><p class='p_style31'><span class='style1'><del class='diffdel'>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.</del></span></p><p class='p_style6'><span class='style1'><del class='diffdel'>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.</del></span></p><p class='p_style6'><span class='style2'><del class='diffdel'>Paediatric population</del></span></p><p class='p_style28'><span class='style1'><del class='diffdel'>In general, the adverse events in paediatric patients were similar in frequency and type to those seen in adult patients.</del></span></p><p class='p_style28'><span class='style2'><del class='diffdel'>Tabulated list of adverse reactions</del></span></p><p class='p_style9'><span class='style1'><del class='diffdel'>The following list of adverse reactions is based on experience from clinical trials and on postmarketing experience and are displayed by system organ class and frequency in Table 6 below: very common</del></span></p><p class='p_style3'><span class='style1'><del class='diffdel'>(</del></span><span class='style5'><del class='diffdel'></del></span><del class='diffdel'> </del><span class='style1'><del class='diffdel'> 1/10); common (</del></span><span class='style5'><del class='diffdel'></del></span><del class='diffdel'> </del><span class='style1'><del class='diffdel'> 1/100 to < 1/10); uncommon (</del></span><span class='style5'><del class='diffdel'></del></span><del class='diffdel'> </del><span class='style1'><del class='diffdel'> 1/1,000 to < 1/100); rare (</del></span><span class='style5'><del class='diffdel'></del></span><del class='diffdel'> </del><span class='style1'><del class='diffdel'> 1/10,000 to < 1/1,000); and not known (cannot be estimated from the available data). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. The highest frequency seen among the various indications has been included. An asterisk (*) appears in the SOC column if further information is found elsewhere in sections 4.3, 4.4 and 4.8.</del></span></p><p class='p_style32'><span class='style0'><del class='diffdel'>Table 6</del></span></p><p class='p_style33'><span class='style0'><del class='diffdel'>Undesirable Effects</del></span></p><table class='clsChildTable'> <tr><td><p class='p_style34'><span class='style0'>System Organ Class</span></p></td><td><p class='p_style35'><span class='style0'>Frequency</span></p></td><td><p class='p_style36'><span class='style0'>Adverse Reaction</span></p></td></tr> <tr><td rowspan='3'><p class='p_style37'><span class='style1'>Infections and </span><br><span class='style1'>infestations*</span></p></td><td><p class='p_style37'><span class='style1'>Very common</span></p></td><td><p class='p_style37'><span class='style1'>Respiratory tract infections (including lower and upper respiratory tract infection, pneumonia, sinusitis, pharyngitis, nasopharyngitis and pneumonia herpes viral)</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Common</span></p></td><td><p class='p_style37'><span class='style1'>Systemic infections (including sepsis, candidiasis and influenza),</span></p><p class='p_style37'><span class='style1'>intestinal infections (including gastroenteritis viral),</span></p><p class='p_style37'><span class='style1'>skin and soft tissue infections (including paronychia, cellulitis, impetigo, necrotising fasciitis and herpes zoster),</span></p><p class='p_style37'><span class='style1'>ear infections, </span><br><span class='style1'>oral infections (including herpes simplex, oral herpes and tooth infections),</span></p><p class='p_style37'><span class='style1'>reproductive tract infections (including vulvovaginal mycotic infection), urinary tract infections (including pyelonephritis),</span></p><p class='p_style37'><span class='style1'>fungal infections, </span><br><span class='style1'>joint infections</span></p></td></tr><del class='diffdel'> </del><tr><td><p class='p_style34'><span class='style0'><del class='diffdel'>System Organ Class</del></span></p></td><td><p class='p_style35'><span class='style0'><del class='diffdel'>Frequency</del></span></p></td><td><p class='p_style36'><span class='style0'><del class='diffdel'>Adverse Reaction</del></span></p></td></tr> <tr><del class='diffdel'> </del><td><p class='p_style37'><span class='style1'>Uncommon</span></p></td><td><p class='p_style37'><span class='style1'>Neurological infections (including viral meningitis),</span></p><p class='p_style37'><span class='style1'>opportunistic infections and tuberculosis (including coccidioidomycosis, histoplasmosis and mycobacterium avium complex infection), bacterial infections, </span><br><span class='style1'>eye infections, </span><br><span class='style1'>diverticulitis</span><span class='style6'>1)</span></p></td></tr> <tr><td rowspan='2'><p class='p_style37'><span class='style1'>Neoplasms benign, malignant and unspecified (including cysts and polyps)*</span></p></td><td><p class='p_style37'><span class='style1'>Common</span></p></td><td><p class='p_style37'><span class='style1'>Skin cancer excluding melanoma (including basal cell carcinoma and squamous cell carcinoma),</span></p><p class='p_style37'><span class='style1'>benign neoplasm</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Uncommon</span></p></td><td><p class='p_style37'><span class='style1'>Lymphoma**, </span><br><span class='style1'>solid organ neoplasm (including breast cancer, lung neoplasm and thyroid neoplasm), melanoma**</span></p></td></tr> <tr><ins class='diffins'> </ins><td><p class='p_style37'><span class='style1'>Rare</span></p></td><td><p class='p_style37'><span class='style1'>Leukaemia</span><span class='style6'>1)</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Not known</span></p></td><td><p class='p_style37'><span class='style1'>Hepatosplenic T-cell lymphoma</span><span class='style7'>1)</span><span class='style1'><ins class='diffins'>,</ins></span></p></td></tr><ins class='diffins'> </ins><tr><td><p class='p_style34'><span class='style0'><ins class='diffins'>System</ins> <ins class='diffins'>Organ Class</ins></span></p></td><td><p class='p_style35'><span class='style0'><ins class='diffins'>Frequency</ins></span></p></td><td><p class='p_style36'><span class='style0'><ins class='diffins'>Adverse</ins> <ins class='diffins'>Reaction</ins></span></p></td></tr><ins class='diffins'> </ins><tr><ins class='diffins'> </ins><td><p class='p_style37'><span class='style1'>Merkel cell carcinoma (neuroendocrine carcinoma of the skin)</span><span class='style7'>1)</span><span class='style1'>,</span></p><p class='p_style37'><span class='style1'>Kaposi’s sarcoma</span></p></td></tr> <tr><td rowspan='4'><p class='p_style37'><span class='style1'>Blood and the lymphatic system disorders*</span></p></td><td><p class='p_style37'><span class='style1'>Very common</span></p></td><td><p class='p_style37'><span class='style1'>Leukopenia (including neutropenia and agranulocytosis),</span></p><p class='p_style37'><span class='style1'>anaemia</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Common</span></p></td><td><p class='p_style37'><span class='style1'>Leucocytosis, </span><br><span class='style1'>thrombocytopenia</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Uncommon</span></p></td><td><p class='p_style37'><span class='style1'>Idiopathic thrombocytopenic purpura</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Rare</span></p></td><td><p class='p_style37'><span class='style1'>Pancytopenia</span></p></td></tr> <tr><td rowspan='3'><p class='p_style37'><span class='style1'>Immune system disorders*</span></p></td><td><p class='p_style37'><span class='style1'>Common</span></p></td><td><p class='p_style37'><span class='style1'>Hypersensitivity, </span><br><span class='style1'>allergies (including seasonal allergy)</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Uncommon</span></p></td><td><p class='p_style37'><span class='style1'>Sarcoidosis</span><span class='style6'>1)</span><span class='style1'>, </span><br><span class='style1'>vasculitis</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Rare</span></p></td><td><p class='p_style37'><span class='style1'>Anaphylaxis</span><span class='style6'>1)</span></p></td></tr> <tr><td rowspan='2'><p class='p_style37'><span class='style1'><ins class='diffins'>Metabolism and nutrition disorders</ins></span></p></td><td><p class='p_style37'><span class='style1'>Very common</span></p></td><td><p class='p_style37'><span class='style1'>Lipids increased</span></p></td></tr><del class='diffdel'> </del><tr><td><p class='p_style34'><span class='style0'><del class='diffdel'>System Organ Class</del></span></p></td><td><p class='p_style35'><span class='style0'><del class='diffdel'>Frequency</del></span></p></td><td><p class='p_style36'><span class='style0'><del class='diffdel'>Adverse Reaction</del></span></p></td></tr><del class='diffdel'> </del><tr><td rowspan='2'><p class='p_style37'><span class='style1'><del class='diffdel'>disorders</del></span></p></td><del class='diffdel'> </del></tr> <tr><td><p class='p_style37'><span class='style1'>Common</span></p></td><td><p class='p_style37'><span class='style1'>Hypokalaemia, </span><br><span class='style1'>uric acid increased, </span><br><span class='style1'>blood sodium abnormal, </span><br><span class='style1'>hypocalcaemia, </span><br><span class='style1'>hyperglycaemia, </span><br><span class='style1'>hypophosphatemia, </span><br><span class='style1'>dehydration</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Psychiatric disorders</span></p></td><td><p class='p_style37'><span class='style1'>Common</span></p></td><td><p class='p_style37'><span class='style1'>Mood alterations (including depression), anxiety, </span><br><span class='style1'>insomnia</span></p></td></tr> <tr><td rowspan='2'><p class='p_style37'><span class='style1'>Nervous system disorders*</span></p></td><td><p class='p_style37'><span class='style1'>Very common</span></p></td><td><p class='p_style37'><span class='style1'>Headache</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Common</span></p></td><td><p class='p_style37'><span class='style1'>Paraesthesias (including hypoesthesia), migraine, </span><br><span class='style1'>nerve root compression</span></p></td></tr><ins class='diffins'> </ins><tr><td><p class='p_style34'><span class='style0'><ins class='diffins'>System Organ Class</ins></span></p></td><td><p class='p_style35'><span class='style0'><ins class='diffins'>Frequency</ins></span></p></td><td><p class='p_style36'><span class='style0'><ins class='diffins'>Adverse Reaction</ins></span></p></td></tr> <tr><ins class='diffins'> </ins><td><p class='p_style37'><span class='style1'>Uncommon</span></p></td><td><p class='p_style37'><span class='style1'>Cerebrovascular accident</span><span class='style7'>1)</span><span class='style1'>, tremor, </span><br><span class='style1'>neuropathy</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Rare</span></p></td><td><p class='p_style37'><span class='style1'>Multiple sclerosis, </span><br><span class='style1'>demyelinating disorders (e.g. optic neuritis, Guillain-Barr syndrome)</span> <span class='style7'> 1)</span></p></td></tr> <tr><td rowspan='2'><p class='p_style37'><span class='style1'>Eye disorders</span></p></td><td><p class='p_style37'><span class='style1'>Common</span></p></td><td><p class='p_style37'><span class='style1'>Visual impairment, </span><br><span class='style1'>conjunctivitis, </span><br><span class='style1'>blepharitis, </span><br><span class='style1'>eye swelling</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Uncommon</span></p></td><td><p class='p_style37'><span class='style1'>Diplopia</span></p></td></tr> <tr><td rowspan='2'><p class='p_style37'><span class='style1'>Ear and labyrinth disorders</span></p></td><td><p class='p_style37'><span class='style1'>Common</span></p></td><td><p class='p_style37'><span class='style1'>Vertigo</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Uncommon</span></p></td><td><p class='p_style37'><span class='style1'>Deafness, </span><br><span class='style1'>tinnitus</span></p></td></tr> <tr><td rowspan='3'><p class='p_style37'><span class='style1'>Cardiac disorders*</span></p></td><td><p class='p_style37'><span class='style1'>Common</span></p></td><td><p class='p_style37'><span class='style1'>Tachycardia</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Uncommon</span></p></td><td><p class='p_style37'><span class='style1'>Myocardial infarction</span><span class='style6'>1)</span><span class='style1'>,<ins class='diffins'> </ins></span></p></td></tr><del class='diffmod'> </del><tr><td><p class='p_style34'><span class='style0'><del class='diffmod'>System Organ Class</del></span></p></td><td><p class='p_style35'><span class='style0'><del class='diffmod'>Frequency</del></span></p></td><td><p class='p_style36'><span class='style0'><del class='diffmod'>Adverse Reaction</del></span></p></td></tr><del class='diffmod'> </del><tr><del class='diffmod'> </del><td><p class='p_style37'><br><span class='style1'>arrhythmia, </span><br><span class='style1'>congestive heart failure</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Rare</span></p></td><td><p class='p_style37'><span class='style1'>Cardiac arrest</span></p></td></tr> <tr><td rowspan='2'><p class='p_style37'><span class='style1'>Vascular disorders</span></p></td><td><p class='p_style37'><span class='style1'>Common</span></p></td><td><p class='p_style37'><span class='style1'>Hypertension, </span><br><span class='style1'>flushing, </span><br><span class='style1'>haematoma</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Uncommon</span></p></td><td><p class='p_style37'><span class='style1'>Aortic aneurysm, </span><br><span class='style1'>vascular arterial occlusion, thrombophlebitis</span></p></td></tr> <tr><td rowspan='2'><p class='p_style37'><span class='style1'>Respiratory, thoracic and mediastinal disorders*</span></p></td><td><p class='p_style37'><span class='style1'>Common</span></p></td><td><p class='p_style37'><span class='style1'>Asthma, </span><br><span class='style1'>dyspnoea, </span><br><span class='style1'>cough</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Uncommon</span></p></td><td><p class='p_style37'><span class='style1'>Pulmonary embolism</span><span class='style6'>1)</span><span class='style1'>, </span><br><span class='style1'>interstitial lung disease, </span><br><span class='style1'>chronic obstructive pulmonary disease, pneumonitis,</span></p></td></tr><ins class='diffins'> </ins><tr><td><p class='p_style34'><span class='style0'><ins class='diffins'>System</ins> <ins class='diffins'>Organ Class</ins></span><br></p></td><td><p class='p_style35'><span class='style0'><ins class='diffmod'>Frequency</ins></span></p></td><td><p class='p_style36'><span class='style0'><ins class='diffmod'>Adverse Reaction</ins></span></p></td></tr><ins class='diffmod'> </ins><tr><ins class='diffmod'> </ins><td><p class='p_style37'><span class='style1'>pleural effusion</span><span class='style6'>1)</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Rare</span></p></td><td><p class='p_style37'><span class='style1'>Pulmonary fibrosis</span><span class='style6'>1)</span></p></td></tr> <tr><td rowspan='4'><p class='p_style37'><span class='style1'>Gastrointestinal disorders</span></p></td><td><p class='p_style37'><span class='style1'>Very common</span></p></td><td><p class='p_style37'><span class='style1'>Abdominal pain, </span><br><span class='style1'>nausea and vomiting</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Common</span></p></td><td><p class='p_style37'><span class='style1'>GI haemorrhage, </span><br><span class='style1'>dyspepsia, </span><br><span class='style1'>gastroesophageal reflux disease, sicca syndrome</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Uncommon</span></p></td><td><p class='p_style37'><span class='style1'>Pancreatitis, </span><br><span class='style1'>dysphagia, </span><br><span class='style1'>face oedema</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Rare</span></p></td><td><p class='p_style37'><span class='style1'>Intestinal perforation</span><span class='style6'>1)</span></p></td></tr> <tr><td rowspan='4'><p class='p_style37'><span class='style1'>Hepato-biliary disorders*</span></p></td><td><p class='p_style37'><span class='style1'>Very Common</span></p></td><td><p class='p_style37'><span class='style1'>Elevated liver enzymes</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Uncommon</span></p></td><td><p class='p_style37'><span class='style1'>Cholecystitis and cholelithiasis, hepatic steatosis, </span><br><span class='style1'>bilirubin increased</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Rare</span></p></td><td><p class='p_style37'><span class='style1'>Hepatitis<ins class='diffins'> </ins></span></p></td></tr><del class='diffmod'> </del><tr><td><p class='p_style34'><span class='style0'><del class='diffmod'>System Organ Class</del></span></p></td><td><p class='p_style35'><span class='style0'><del class='diffmod'>Frequency</del></span></p></td><td><p class='p_style36'><span class='style0'><del class='diffmod'>Adverse Reaction</del></span></p></td></tr><del class='diffmod'> </del><tr><del class='diffmod'> </del><td><p class='p_style37'><br><span class='style1'>reactivation of hepatitis B</span><span class='style7'>1)</span> <span class='style1'> autoimmune hepatitis</span><span class='style6'>1)</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Not known</span></p></td><td><p class='p_style37'><span class='style1'>Liver failure</span><span class='style6'>1)</span></p></td></tr> <tr><td rowspan='3'><p class='p_style37'><span class='style1'>Skin and subcutaneous tissue disorders</span></p></td><td><p class='p_style37'><span class='style1'>Very Common</span></p></td><td><p class='p_style37'><span class='style1'>Rash (including exfoliative rash)</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Common</span></p></td><td><p class='p_style37'><span class='style1'>Worsening or new onset of psoriasis(including palmoplantar pustular psoriasis)</span><span class='style7'>1)</span><span class='style1'>,</span></p><p class='p_style37'><span class='style1'>urticaria, </span><br><span class='style1'>bruising (including purpura), dermatitis (including eczema), onychoclasis, </span><br><span class='style1'>hyperhidrosis, </span><br><span class='style1'>alopecia</span><span class='style6'>1)</span><span class='style1'>, </span><br><span class='style1'>pruritus</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Uncommon</span></p></td><td><p class='p_style37'><span class='style1'>Night sweats, </span><br><span class='style1'>scar</span></p></td></tr><ins class='diffins'> </ins><tr><td><p class='p_style34'><span class='style0'><ins class='diffins'>System Organ Class</ins></span></p></td><td><p class='p_style35'><span class='style0'><ins class='diffins'>Frequency</ins></span></p></td><td><p class='p_style36'><span class='style0'><ins class='diffins'>Adverse Reaction</ins></span></p></td></tr> <tr><ins class='diffins'> </ins><td><p class='p_style37'><span class='style1'>Rare</span></p></td><td><p class='p_style37'><span class='style1'>Erythema multiforme</span><span class='style6'>1)</span><span class='style1'>, </span><br><span class='style1'>Stevens-Johnson syndrome</span><span class='style7'>1)</span><span class='style1'>, angioedema</span><span class='style6'>1)</span><span class='style1'>,</span></p><p class='p_style37'><span class='style1'>cutaneous vasculitis</span><span class='style6'>1) </span><br> <span class='style1'>lichenoid skin reaction</span><span class='style7'>1)</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Not known</span></p></td><td><p class='p_style37'><span class='style1'>Worsening of symptoms of dermatomyositis</span><span class='style7'>1)</span></p></td></tr> <tr><td rowspan='4'><p class='p_style37'><span class='style1'>Musculoskeletal and connective tissue disorders</span></p></td><td><p class='p_style37'><span class='style1'>Very common</span></p></td><td><p class='p_style37'><span class='style1'>Musculoskeletal pain</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Common</span></p></td><td><p class='p_style37'><span class='style1'>Muscle spasms (including blood creatine phosphokinase increased)</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Uncommon</span></p></td><td><p class='p_style37'><span class='style1'>Rhabdomyolysis, </span><br><span class='style1'>systemic lupus erythematosus</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Rare</span></p></td><td><p class='p_style37'><span class='style1'>Lupus-like syndrome</span><span class='style6'>1)</span></p></td></tr> <tr><td rowspan='2'><p class='p_style37'><span class='style1'>Renal and urinary disorders</span></p></td><td><p class='p_style37'><span class='style1'>Common</span></p></td><td><p class='p_style37'><span class='style1'>Renal impairment, </span><br><span class='style1'>haematuria</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Uncommon</span></p></td><td><p class='p_style37'><span class='style1'>Nocturia</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Reproductive system and breast disorders</span></p></td><td><p class='p_style37'><span class='style1'>Uncommon</span></p></td><td><p class='p_style37'><span class='style1'>Erectile dysfunction</span></p></td></tr><del class='diffdel'> </del><tr><td><p class='p_style34'><span class='style0'><del class='diffdel'>System Organ Class</del></span></p></td><td><p class='p_style35'><span class='style0'><del class='diffdel'>Frequency</del></span></p></td><td><p class='p_style36'><span class='style0'><del class='diffdel'>Adverse Reaction</del></span></p></td></tr> <tr><td rowspan='3'><p class='p_style37'><span class='style1'>General disorders and administration site conditions*</span></p></td><td><p class='p_style37'><span class='style1'>Very Common</span></p></td><td><p class='p_style37'><span class='style1'>Injection site reaction (including injection site erythema)</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Common</span></p></td><td><p class='p_style37'><span class='style1'>Chest pain, </span><br><span class='style1'>oedema, </span><br><span class='style1'>pyrexia</span><span class='style6'>1)</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Uncommon</span></p></td><td><p class='p_style37'><span class='style1'>Inflammation</span></p></td></tr> <tr><td rowspan='2'><p class='p_style37'><span class='style1'>Investigations*</span></p></td><td><p class='p_style37'><span class='style1'>Common</span></p></td><td><p class='p_style37'><span class='style1'>Coagulation and bleeding disorders (including activated partial thromboplastin time prolonged), autoantibody test positive (including double stranded DNA antibody),</span></p><p class='p_style37'><span class='style1'>blood lactate dehydrogenase increased</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Not known</span></p></td><td><p class='p_style37'><span class='style1'>Weight increased</span><span class='style6'>2)</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Injury, poisoning and procedural complications</span></p></td><td><p class='p_style37'><span class='style1'>Common</span></p></td><td><p class='p_style37'><span class='style1'>Impaired healing</span></p></td></tr> </table><p class='p_style8'><span class='style1'>* further information is found elsewhere in sections 4.3, 4.4 and 4.8 ** including open label extension studies</span></p><ul> <li> 1) including spontaneous reporting data </li> <li> 2) The mean weight change from baseline for adalimumab ranged from 0.3 kg to 1.0 kg across adult indications compared to (minus) -0.4 kg to 0.4 kg for placebo over a treatment period of 4-6 months. Weight increase of 5-6 kg has also been observed in long-term extension studies with mean exposures of approximately 1-2 years without control group, particularly in patients with Crohn’s disease and Ulcerative colitis. The mechanism behind this effect is unclear but could be associated with the anti-inflammatory effect of adalimumab. </li> </ul><p class='p_style6'><span class='style2'><ins class='diffins'>Hidradenitis suppurativa</ins></span></p><p class='p_style28'><span class='style1'><ins class='diffins'>The safety profile for patients with HS treated with Humira weekly was consistent with the known safety profile of Humira.</ins></span></p><p class='p_style28'><span class='style2'>Uveitis</span></p><p class='p_style9'><span class='style1'>The safety profile for patients with uveitis treated with Humira every other week was consistent with the known safety profile of Humira.</span></p><p class='p_style9'><span class='style2'>Description of selected adverse reactions</span></p><p class='p_style9'><span class='style3'>Injection site reactions</span></p><p class='p_style3'><span class='style1'>In the pivotal controlled trials in adults and children, 12.9% of patients treated with Humira developed injection site reactions (erythema and/or itching, haemorrhage, pain or swelling), compared to 7.2% of patients receiving placebo or active control. Injection site reactions generally did not necessitate discontinuation of the medicinal product.</span></p><p class='p_style3'><span class='style3'>Infections</span></p><p class='p_style3'><span class='style1'>In the pivotal controlled trials in adults and children, the rate of infection was 1.51 per patient year in the Humira treated patients and 1.46 per patient year in the placebo and active control-treated patients. The infections consisted primarily of nasopharyngitis, upper respiratory tract infection, and sinusitis. Most patients continued on Humira after the infection resolved.</span></p><p class='p_style3'><span class='style1'>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.</span></p><p class='p_style3'><span class='style1'>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.</span></p><p class='p_style3'><span class='style3'>Malignancies and lymphoproliferative disorders</span></p><p class='p_style3'><span class='style1'>No 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 498.1 patient years during Humira trials in paediatric patients with Crohn’s disease. No malignancies were observed in 77 paediatric patients with an exposure of 80.0 patient years during a</span> <span class='style1'>Humira trial in paediatric patients with chronic plaque psoriasis.</span><ins class='diffins'> </ins><span class='style21'><ins class='diffins'> No malignancies were observed in 93 paediatric patients with an exposure of 65.3 patient years during a Humira trial in paediatric patients with ulcerative colitis.</ins></span><ins class='diffins'> </ins><span class='style1'> No malignancies were observed in 60 paediatric patients with an exposure of 58.4 patient years during a Humira trial in paediatric patients with uveitis.</span></p><p class='p_style3'><span class='style1'>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, hidradenitis suppurativa, Crohn’s disease, ulcerative colitis and uveitis, malignancies, other than lymphoma and non-melanoma skin cancer, were observed at a rate (95% confidence interval) of 6.8 (4.4, 10.5) per 1,000 patient-years among 5,291 Humira treated patients</span> <span class='style3'> versus</span> <span class='style1'> a rate of 6.3 (3.4, 11.8) per 1,000 patient-years among 3,444 control patients (median duration of treatment was 4.0 months for Humira and 3.8 months for control-treated patients). The rate (95% confidence interval) of non-melanoma skin cancers was 8.8 (6.0, 13.0) per 1,000 patient-years among Humira-treated patients and 3.2 (1.3, 7.6) per 1,000 patient-years among control patients. Of these skin cancers, squamous cell carcinomas occurred at rates (95% confidence interval) of 2.7 (1.4, 5.4) per 1,000 patient-years among Humira-treated patients and 0.6 (0.1, 4.5) per 1,000 patient-years among control patients. The rate (95% confidence interval) of lymphomas was 0.7 (0.2, 2.7) per 1,000 patient-years among Humira-treated patients and 0.6 (0.1, 4.5) per 1,000 patient-years among control patients.</span></p><p class='p_style3'><span class='style1'>When combining controlled portions of these trials and ongoing and completed open label extension studies with a median duration of approximately 3.3 years including 6,427 patients and over 26,439 patient-years of therapy, the observed rate of malignancies, other than lymphoma and non-melanoma skin cancers is approximately 8.5 per 1,000 patient years. The observed rate of non-melanoma skin cancers is approximately 9.6 per 1,000 patient years, and the observed rate of lymphomas is approximately 1.3 per 1,000 patient years.</span></p><p class='p_style3'><span class='style1'>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).</span></p><p class='p_style3'><span class='style1'>Rare post-marketing cases of hepatosplenic T-cell lymphoma have been reported in patients treated with adalimumab (see section 4.4).</span></p><p class='p_style3'><span class='style3'>Autoantibodies</span></p><p class='p_style29'><span class='style1'>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.</span></p><p class='p_style29'><span class='style3'>Hepato-biliary events</span></p><p class='p_style6'><span class='style1'>In 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.</span></p><p class='p_style9'><span class='style1'>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</span> <span class='style1'>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 <<del class='diffmod'>; 4</del><ins class='diffmod'>;4</ins> years.</span></p><p class='p_style4'><span class='style1'>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.</span></p><p class='p_style3'><span class='style1'>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% (5/192) of patients of whom 4 were receiving concomitant immunosuppressants at baseline.</span></p><p class='p_style6'><span class='style1'>In controlled Phase 3 trials of Humira in patients with plaque <del class='diffmod'>psoriasis</del><ins class='diffmod'>Psoriasis</ins> 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.</span></p><p class='p_style9'><span class='style1'>No ALT elevations &ge<del class='diffmod'>;</del><ins class='diffmod'>;3</ins> <del class='diffmod'>3 x</del><ins class='diffmod'>X</ins> ULN occurred in the Phase 3 trial of Humira in paediatric patients with plaque psoriasis<ins class='diffins'>.</ins></span></p><p class='p_style3'><span class='style1'><ins class='diffins'>In controlled trials of Humira (initial doses of 160 mg at Week 0 and 80 mg at Week 2, followed by 40 mg every week starting at Week 4), in patients with hidradenitis suppurativa with a control period duration ranging from 12 to 16 weeks, ALT elevations ≥ 3 x ULN occurred in 0.3% of Humira-treated patients and 0.6% of control-treated patients</ins>.</span></p><p class='p_style3'><span class='style1'>In controlled trials of Humira (initial doses of 80 mg at Week 0 followed by 40 mg every other week starting at Week 1) in adult patients with uveitis up to 80 weeks with a median exposure of 166.5 days and 105.0 days in Humira-treated and control-treated patients, respectively, ALT elevations ≥ 3 x ULN occurred in 2.4% of Humira-treated patients and 2.4% of control-treated<ins class='diffins'> patients.</ins></span></p><p class='p_style3'><span class='style21'><ins class='diffins'>In the controlled Phase 3 trial of Humira in patients with paediatric ulcerative colitis (N=93) which evaluated efficacy and safety of a maintenance dose of 0.6 mg/kg (maximum of 40 mg) every other week (N=31) and a maintenance dose of 0.6 mg/kg (maximum of 40 mg) every Week (N=32), following body weight adjusted induction dosing of 2.4 mg/kg (maximum of 160 mg) at Week 0 and Week 1, and 1.2 mg/kg (maximum of 80 mg) at Week 2 (N=63), or an induction dose of 2.4 mg/kg (maximum of 160 mg) at Week 0, placebo at Week 1, and 1.2 mg/kg (maximum of 80 mg) at Week 2 (N=30), ALT elevations ≥ 3 X ULN occurred in 1.1% (1/93) of</ins> patients.</span></p><p class='p_style3'><span class='style1'>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.</span></p><p class='p_style3'><span class='style2'>Concurrent treatment with azathioprine/6-mercaptopurine</span></p><p class='p_style31'><span class='style1'>In 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<del class='diffmod'>-mercaptopurine</del></span><span class='style2'><ins class='diffmod'>-</ins></span><span class='style1'><ins class='diffmod'>mercaptopurine</ins> compared with Humira alone.</span></p><p class='p_style29'><span class='style2'>Reporting of suspected adverse reactions</span></p><p class='p_style6'><span class='style1'>Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via</span> <span class='style8'> the national reporting system listed in</span> <span class='style9'><a href='http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc'> Appendix V</a></span><span class='style10'><a href='http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc'>.</a></span></p></div><br/></td><td><br/><b>Adverse Reactions</b><br/><div ids='section-UNDESIRABLE_EFFECTS' class='Section'><h3 class='sectionNameHeader' sectionnameid='sectionName-UNDESIRABLE_EFFECTS'>4.8 Undesirable effects</h3> <table class='clsChildTable'> <tr><td><p class='p_style34'><span class='style0'>System Organ Class</span></p></td><td><p class='p_style35'><span class='style0'>Frequency</span></p></td><td><p class='p_style36'><span class='style0'>Adverse Reaction</span></p></td></tr> <tr><td rowspan='3'><p class='p_style37'><span class='style1'>Infections and </span><br><span class='style1'>infestations*</span></p></td><td><p class='p_style37'><span class='style1'>Very common</span></p></td><td><p class='p_style37'><span class='style1'>Respiratory tract infections (including lower and upper respiratory tract infection, pneumonia, sinusitis, pharyngitis, nasopharyngitis and pneumonia herpes viral)</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Common</span></p></td><td><p class='p_style37'><span class='style1'>Systemic infections (including sepsis, candidiasis and influenza),</span></p><p class='p_style37'><span class='style1'>intestinal infections (including gastroenteritis viral),</span></p><p class='p_style37'><span class='style1'>skin and soft tissue infections (including paronychia, cellulitis, impetigo, necrotising fasciitis and herpes zoster),</span></p><p class='p_style37'><span class='style1'>ear infections, </span><br><span class='style1'>oral infections (including herpes simplex, oral herpes and tooth infections),</span></p><p class='p_style37'><span class='style1'>reproductive tract infections (including vulvovaginal mycotic infection), urinary tract infections (including pyelonephritis),</span></p><p class='p_style37'><span class='style1'>fungal infections, </span><br><span class='style1'>joint infections</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Uncommon</span></p></td><td><p class='p_style37'><span class='style1'>Neurological infections (including viral meningitis),</span></p><p class='p_style37'><span class='style1'>opportunistic infections and tuberculosis (including coccidioidomycosis, histoplasmosis and mycobacterium avium complex infection), bacterial infections, </span><br><span class='style1'>eye infections, </span><br><span class='style1'>diverticulitis</span><span class='style6'>1)</span></p></td></tr> <tr><td rowspan='2'><p class='p_style37'><span class='style1'>Neoplasms benign, malignant and unspecified (including cysts and polyps)*</span></p></td><td><p class='p_style37'><span class='style1'>Common</span></p></td><td><p class='p_style37'><span class='style1'>Skin cancer excluding melanoma (including basal cell carcinoma and squamous cell carcinoma),</span></p><p class='p_style37'><span class='style1'>benign neoplasm</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Uncommon</span></p></td><td><p class='p_style37'><span class='style1'>Lymphoma**, </span><br><span class='style1'>solid organ neoplasm (including breast cancer, lung neoplasm and thyroid neoplasm), melanoma**</span></p></td></tr> <tr> <td><p class='p_style37'><span class='style1'>Rare</span></p></td><td><p class='p_style37'><span class='style1'>Leukaemia</span><span class='style6'>1)</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Not known</span></p></td><td><p class='p_style37'><span class='style1'>Hepatosplenic T-cell lymphoma</span><span class='style7'>1)</span><span class='style1'>,</span></p></td></tr> <tr><td><p class='p_style34'><span class='style0'>System Organ Class</span></p></td><td><p class='p_style35'><span class='style0'>Frequency</span></p></td><td><p class='p_style36'><span class='style0'>Adverse Reaction</span></p></td></tr> <tr> <td><p class='p_style37'><span class='style1'>Merkel cell carcinoma (neuroendocrine carcinoma of the skin)</span><span class='style7'>1)</span><span class='style1'>,</span></p><p class='p_style37'><span class='style1'>Kaposi’s sarcoma</span></p></td></tr> <tr><td rowspan='4'><p class='p_style37'><span class='style1'>Blood and the lymphatic system disorders*</span></p></td><td><p class='p_style37'><span class='style1'>Very common</span></p></td><td><p class='p_style37'><span class='style1'>Leukopenia (including neutropenia and agranulocytosis),</span></p><p class='p_style37'><span class='style1'>anaemia</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Common</span></p></td><td><p class='p_style37'><span class='style1'>Leucocytosis, </span><br><span class='style1'>thrombocytopenia</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Uncommon</span></p></td><td><p class='p_style37'><span class='style1'>Idiopathic thrombocytopenic purpura</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Rare</span></p></td><td><p class='p_style37'><span class='style1'>Pancytopenia</span></p></td></tr> <tr><td rowspan='3'><p class='p_style37'><span class='style1'>Immune system disorders*</span></p></td><td><p class='p_style37'><span class='style1'>Common</span></p></td><td><p class='p_style37'><span class='style1'>Hypersensitivity, </span><br><span class='style1'>allergies (including seasonal allergy)</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Uncommon</span></p></td><td><p class='p_style37'><span class='style1'>Sarcoidosis</span><span class='style6'>1)</span><span class='style1'>, </span><br><span class='style1'>vasculitis</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Rare</span></p></td><td><p class='p_style37'><span class='style1'>Anaphylaxis</span><span class='style6'>1)</span></p></td></tr> <tr><td rowspan='2'><p class='p_style37'><span class='style1'>Metabolism and nutrition disorders</span></p></td><td><p class='p_style37'><span class='style1'>Very common</span></p></td><td><p class='p_style37'><span class='style1'>Lipids increased</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Common</span></p></td><td><p class='p_style37'><span class='style1'>Hypokalaemia, </span><br><span class='style1'>uric acid increased, </span><br><span class='style1'>blood sodium abnormal, </span><br><span class='style1'>hypocalcaemia, </span><br><span class='style1'>hyperglycaemia, </span><br><span class='style1'>hypophosphatemia, </span><br><span class='style1'>dehydration</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Psychiatric disorders</span></p></td><td><p class='p_style37'><span class='style1'>Common</span></p></td><td><p class='p_style37'><span class='style1'>Mood alterations (including depression), anxiety, </span><br><span class='style1'>insomnia</span></p></td></tr> <tr><td rowspan='2'><p class='p_style37'><span class='style1'>Nervous system disorders*</span></p></td><td><p class='p_style37'><span class='style1'>Very common</span></p></td><td><p class='p_style37'><span class='style1'>Headache</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Common</span></p></td><td><p class='p_style37'><span class='style1'>Paraesthesias (including hypoesthesia), migraine, </span><br><span class='style1'>nerve root compression</span></p></td></tr> <tr><td><p class='p_style34'><span class='style0'>System Organ Class</span></p></td><td><p class='p_style35'><span class='style0'>Frequency</span></p></td><td><p class='p_style36'><span class='style0'>Adverse Reaction</span></p></td></tr> <tr> <td><p class='p_style37'><span class='style1'>Uncommon</span></p></td><td><p class='p_style37'><span class='style1'>Cerebrovascular accident</span><span class='style7'>1)</span><span class='style1'>, tremor, </span><br><span class='style1'>neuropathy</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Rare</span></p></td><td><p class='p_style37'><span class='style1'>Multiple sclerosis, </span><br><span class='style1'>demyelinating disorders (e.g. optic neuritis, Guillain-Barr syndrome)</span> <span class='style7'> 1)</span></p></td></tr> <tr><td rowspan='2'><p class='p_style37'><span class='style1'>Eye disorders</span></p></td><td><p class='p_style37'><span class='style1'>Common</span></p></td><td><p class='p_style37'><span class='style1'>Visual impairment, </span><br><span class='style1'>conjunctivitis, </span><br><span class='style1'>blepharitis, </span><br><span class='style1'>eye swelling</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Uncommon</span></p></td><td><p class='p_style37'><span class='style1'>Diplopia</span></p></td></tr> <tr><td rowspan='2'><p class='p_style37'><span class='style1'>Ear and labyrinth disorders</span></p></td><td><p class='p_style37'><span class='style1'>Common</span></p></td><td><p class='p_style37'><span class='style1'>Vertigo</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Uncommon</span></p></td><td><p class='p_style37'><span class='style1'>Deafness, </span><br><span class='style1'>tinnitus</span></p></td></tr> <tr><td rowspan='3'><p class='p_style37'><span class='style1'>Cardiac disorders*</span></p></td><td><p class='p_style37'><span class='style1'>Common</span></p></td><td><p class='p_style37'><span class='style1'>Tachycardia</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Uncommon</span></p></td><td><p class='p_style37'><span class='style1'>Myocardial infarction</span><span class='style6'>1)</span><span class='style1'>, </span><br><span class='style1'>arrhythmia, </span><br><span class='style1'>congestive heart failure</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Rare</span></p></td><td><p class='p_style37'><span class='style1'>Cardiac arrest</span></p></td></tr> <tr><td rowspan='2'><p class='p_style37'><span class='style1'>Vascular disorders</span></p></td><td><p class='p_style37'><span class='style1'>Common</span></p></td><td><p class='p_style37'><span class='style1'>Hypertension, </span><br><span class='style1'>flushing, </span><br><span class='style1'>haematoma</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Uncommon</span></p></td><td><p class='p_style37'><span class='style1'>Aortic aneurysm, </span><br><span class='style1'>vascular arterial occlusion, thrombophlebitis</span></p></td></tr> <tr><td rowspan='2'><p class='p_style37'><span class='style1'>Respiratory, thoracic and mediastinal disorders*</span></p></td><td><p class='p_style37'><span class='style1'>Common</span></p></td><td><p class='p_style37'><span class='style1'>Asthma, </span><br><span class='style1'>dyspnoea, </span><br><span class='style1'>cough</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Uncommon</span></p></td><td><p class='p_style37'><span class='style1'>Pulmonary embolism</span><span class='style6'>1)</span><span class='style1'>, </span><br><span class='style1'>interstitial lung disease, </span><br><span class='style1'>chronic obstructive pulmonary disease, pneumonitis,</span></p></td></tr> <tr><td><p class='p_style34'><span class='style0'>System Organ Class</span></p></td><td><p class='p_style35'><span class='style0'>Frequency</span></p></td><td><p class='p_style36'><span class='style0'>Adverse Reaction</span></p></td></tr> <tr> <td><p class='p_style37'><span class='style1'>pleural effusion</span><span class='style6'>1)</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Rare</span></p></td><td><p class='p_style37'><span class='style1'>Pulmonary fibrosis</span><span class='style6'>1)</span></p></td></tr> <tr><td rowspan='4'><p class='p_style37'><span class='style1'>Gastrointestinal disorders</span></p></td><td><p class='p_style37'><span class='style1'>Very common</span></p></td><td><p class='p_style37'><span class='style1'>Abdominal pain, </span><br><span class='style1'>nausea and vomiting</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Common</span></p></td><td><p class='p_style37'><span class='style1'>GI haemorrhage, </span><br><span class='style1'>dyspepsia, </span><br><span class='style1'>gastroesophageal reflux disease, sicca syndrome</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Uncommon</span></p></td><td><p class='p_style37'><span class='style1'>Pancreatitis, </span><br><span class='style1'>dysphagia, </span><br><span class='style1'>face oedema</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Rare</span></p></td><td><p class='p_style37'><span class='style1'>Intestinal perforation</span><span class='style6'>1)</span></p></td></tr> <tr><td rowspan='4'><p class='p_style37'><span class='style1'>Hepato-biliary disorders*</span></p></td><td><p class='p_style37'><span class='style1'>Very Common</span></p></td><td><p class='p_style37'><span class='style1'>Elevated liver enzymes</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Uncommon</span></p></td><td><p class='p_style37'><span class='style1'>Cholecystitis and cholelithiasis, hepatic steatosis, </span><br><span class='style1'>bilirubin increased</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Rare</span></p></td><td><p class='p_style37'><span class='style1'>Hepatitis </span><br><span class='style1'>reactivation of hepatitis B</span><span class='style7'>1)</span> <span class='style1'> autoimmune hepatitis</span><span class='style6'>1)</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Not known</span></p></td><td><p class='p_style37'><span class='style1'>Liver failure</span><span class='style6'>1)</span></p></td></tr> <tr><td rowspan='3'><p class='p_style37'><span class='style1'>Skin and subcutaneous tissue disorders</span></p></td><td><p class='p_style37'><span class='style1'>Very Common</span></p></td><td><p class='p_style37'><span class='style1'>Rash (including exfoliative rash)</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Common</span></p></td><td><p class='p_style37'><span class='style1'>Worsening or new onset of psoriasis(including palmoplantar pustular psoriasis)</span><span class='style7'>1)</span><span class='style1'>,</span></p><p class='p_style37'><span class='style1'>urticaria, </span><br><span class='style1'>bruising (including purpura), dermatitis (including eczema), onychoclasis, </span><br><span class='style1'>hyperhidrosis, </span><br><span class='style1'>alopecia</span><span class='style6'>1)</span><span class='style1'>, </span><br><span class='style1'>pruritus</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Uncommon</span></p></td><td><p class='p_style37'><span class='style1'>Night sweats, </span><br><span class='style1'>scar</span></p></td></tr> <tr><td><p class='p_style34'><span class='style0'>System Organ Class</span></p></td><td><p class='p_style35'><span class='style0'>Frequency</span></p></td><td><p class='p_style36'><span class='style0'>Adverse Reaction</span></p></td></tr> <tr> <td><p class='p_style37'><span class='style1'>Rare</span></p></td><td><p class='p_style37'><span class='style1'>Erythema multiforme</span><span class='style6'>1)</span><span class='style1'>, </span><br><span class='style1'>Stevens-Johnson syndrome</span><span class='style7'>1)</span><span class='style1'>, angioedema</span><span class='style6'>1)</span><span class='style1'>,</span></p><p class='p_style37'><span class='style1'>cutaneous vasculitis</span><span class='style6'>1) </span><br> <span class='style1'>lichenoid skin reaction</span><span class='style7'>1)</span></p></td></tr> <tr><td><p class='p_style37'><span class='style1'>Not known</span></p></td><td><p class='p_style37'><span class='style1'>Worsening of symptoms of dermatomyositis</span><span class='style7'>1)</span></p></td></tr> <tr><td rowspan='4'><p class='p_style37'><span class='style1'>Musculoskeletal and connective tissue disorders</span></p></td><td><p class='p_style37'><span class='style1'>Very common</span></p></td><td><p class='p_style37'><span class='style1'>Musculoskeletal pain</span></p></td></tr> <tr><td><p class='p_style37'></html>";
Document doc = new Document();
DocumentBuilder builder = new DocumentBuilder(doc);
builder.PageSetup.BottomMargin = 10;
builder.PageSetup.TopMargin = 10;
builder.PageSetup.LeftMargin = 20;
builder.PageSetup.RightMargin = 10;
builder.InsertHtml(sHtml);
// Adjust page height to fit while HTML document content on one page.
PageSetup pageSetup = doc.FirstSection.PageSetup;
double pageContentHeight = pageSetup.PageHeight - pageSetup.TopMargin - pageSetup.BottomMargin;
// Check whether document fits one page. If not increase page height.
while (doc.PageCount > 1)
{
double addition = doc.PageCount > 2 ? (doc.PageCount - 2) * pageContentHeight : 10;
pageSetup.PageHeight = pageSetup.PageHeight + addition;
doc.UpdatePageLayout();
}
// Create LayoutCollector and LayoutEnumerator to calculate actual max table width in the document
LayoutCollector collector = new LayoutCollector(doc);
LayoutEnumerator enumerator = new LayoutEnumerator(doc);
foreach (Section s in doc.Sections)
{
double maxTableWidth = 0;
foreach (Table t in s.Body.Tables)
foreach (Row r in t.Rows)
{
enumerator.Current = collector.GetEntity(r.FirstCell.FirstParagraph);
// Move enumerator to the row.
while (enumerator.Type != LayoutEntityType.Row)
enumerator.MoveParent();
maxTableWidth = System.Math.Max(maxTableWidth, enumerator.Rectangle.Width);
}
PageSetup ps = s.PageSetup;
double visiblePageWidht = ps.PageWidth - ps.LeftMargin - ps.RightMargin;
if (visiblePageWidht < maxTableWidth)
ps.PageWidth = maxTableWidth + ps.LeftMargin + ps.RightMargin;
}
doc.UpdatePageLayout();
doc.Save(@"C:\Temp\out.pdf");