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Adalimumab  (3582)
[ a-dal-aye'-mu-mab ]
Ingredients: Adalimumab
Indications: Arthritis, rheumatoid
Pregnancy Category: B
FDA Approved: 2002- 12- 01
Classes: Disease modifying antirheumatic drugs; Immunomodulators; Monoclonal antibodies; Tumor necrosis factor modulators; WHO Formulary
Brand Names: Humira - US; Argentina, Australia, Chile, Colombia, England, Hong-kong, Mexico, Paraguay, Peru, Singapore ;
DEA schedules: (none)
Cost of therapy: $1,437.80 ( Rheumatoid Arthritis ; Humira ; 40 mg/0.8ml ; 40 mg every other week ; 28 day supply )

BOXED WARNING
 
RISK OF INFECTIONS
Cases of tuberculosis (frequently disseminated or extrapulmonary at clinical presentation) have been observed in patients receiving adalimumab.
Patients should be evaluated for latent tuberculosis infection with a tuberculin skin test. Treatment of latent tuberculosis infection should be initiated prior to therapy with adalimumab.

DESCRIPTION
  Adalimumab is a recombinant human IgG1 monoclonal antibody specific for human tumor necrosis factor (TNF). Adalimumab was created using phage display technology resulting in an antibody with human derived heavy and light chain variable regions and human IgG1:κ constant regions. Adalimumab is produced by recombinant DNA technology in a mammalian cell expression system and is purified by a process that includes specific viral inactivation and removal steps. It consists of 1330 amino acids and has a molecular weight of approximately 148 kilodaltons.
Humira is supplied in single- use, 1 ml pre- filled glass syringes, as a sterile, preservative- free solution for SC administration. The solution of Humira is clear and colorless, with a pH of about 5.2. Each syringe delivers 0.8 ml (40 mg) of drug product. Each 0.8 ml of Humira contains 40 mg adalimumab, 4.93 mg sodium chloride, 0.69 mg monobasic sodium phosphate dihydrate, 1.22 mg dibasic sodium phosphate dihydrate, 0.24 mg sodium citrate, 1.04 mg citric acid monohydrate, 9.6 mg mannitol, 0.8 mg polysorbate 80 and water for injection. Sodium hydroxide added as necessary to adjust pH.

CLINICAL PHARMACOLOGY
 

General
  Adalimumab binds specifically to TNF- alpha and blocks its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface TNF expressing cells in vitro in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (TNF- beta). TNF is a naturally occurring cytokine that is involved in normal inflammatory and immune responses. Elevated levels of TNF are found in the synovial fluid of rheumatoid arthritis patients and play an important role in both the pathologic inflammation and the joint destruction that are hallmarks of rheumatoid arthritis.
Adalimumab also modulates biological responses that are induced or regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration (ELAM- 1, VCAM- 1, and ICAM- 1 with an IC50 of 1- 2 × 10- 10M).

Pharmacodynamics
  After treatment with adalimumab, a rapid decrease in levels of acute phase reactants of inflammation (C- reactive protein (CRP) and erythrocyte sedimentation rate (ESR)) and serum cytokines (IL- 6) was observed compared to baseline in patients with rheumatoid arthritis. Serum levels of matrix metalloproteinases (MMP- 1 and MMP- 3) that produce tissue remodeling responsible for cartilage destruction were also decreased after adalimumab administration.

Pharmacokinetics
  The maximum serum concentration (Cmax ) and the time to reach the maximum concentration (Tmax ) were 4.7 ± 1.6 μg/ ml and 131 ± 56 hours respectively, following a single 40 mg SC administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three studies following a single 40 mg SC dose was 64%. The pharmacokinetics of adalimumab were linear over the dose range of 0.5- 10.0 mg/ kg following a single IV dose.
The single dose pharmacokinetics of adalimumab were determined in several studies with IV doses ranging from 0.25 to 10 mg/ kg. The distribution volume (Vss ) ranged from 4.7- 6.0 L. The systemic clearance of adalimumab is approximately 12 ml/ h. The mean terminal half- life was approximately 2 weeks, ranging from 10- 20 days across studies. Adalimumab concentrations in the synovial fluid from 5 rheumatoid arthritis patients ranged from 31- 96% of those in serum.
Adalimumab mean steady- state trough concentrations of approximately 5 μg/ ml and 8- 9 μg/ ml, were observed without and with methotrexate (MTX) respectively. The serum adalimumab trough levels at steady- state increased approximately proportionally with dose following 20, 40 and 80 mg every other week and every week SC dosing. In long- term studies with dosing more than 2 years, there was no evidence of changes in clearance over time.
Population pharmacokinetic analyses revealed that there was a trend toward higher apparent clearance of adalimumab in the presence of anti- adalimumab antibodies, and lower clearance with increasing age in patients aged 40 to >75 years.
Minor increases in apparent clearance were also predicted in patients receiving doses lower than the recommended dose and in patients with high rheumatoid factor or CRP concentrations. These increases are not likely to be clinically important.
No gender- related pharmacokinetic differences were observed after correction for a patient's body weight. Healthy volunteers and patients with rheumatoid arthritis displayed similar adalimumab pharmacokinetics.
No pharmacokinetic data are available in patients with hepatic or renal impairment.
Adalimumab has not been studied in children.

Drug Interactions
  MTX reduced adalimumab apparent clearance after single and multiple dosing by 29% and 44% respectively.

CLINICAL STUDIES
  The efficacy and safety of adalimumab were assessed in four randomized, double- blind studies in patients ≥ age 18 with active rheumatoid arthritis diagnosed according to American College of Rheumatology (ACR) criteria. Patients had at least 6 swollen and 9 tender joints. Adalimumab was administered subcutaneously in combination with MTX (12.5 to 25 mg, Studies I and III) or as monotherapy (Study II) or with other disease- modifying anti- rheumatic drugs (DMARDs) (Study IV).
Study I evaluated 271 patients who had failed therapy with at least 1 but no more than 4 DMARDs and had inadequate response to MTX. Doses of 20, 40 or 80 mg of adalimumab or placebo were given every other week for 24 weeks.
Study II evaluated 544 patients who had failed therapy with at least 1 DMARD. Doses of placebo, 20 or 40 mg of adalimumab were given as monotherapy every other week or weekly for 26 weeks.
Study III evaluated 619 patients who had an inadequate response to MTX. Patients received placebo, 40 mg of adalimumab every other week with placebo injections on alternate weeks, or 20 mg of adalimumab weekly for up to 52 weeks. Study III had an additional primary endpoint at 52 weeks of inhibition of disease progression (as detected by X- ray results). Upon completion of the first 52 weeks, 457 patients enrolled in an open- label extension phase in which 40 mg of adalimumab was administered every other week for up to 104 weeks.
Study IV assessed safety in 636 patients who were either DMARD- naive or were permitted to remain on their pre- existing rheumatologic therapy provided that therapy was stable for a minimum of 28 days. Patients were randomized to 40 mg of adalimumab or placebo every other week for 24 weeks.
The percent of adalimumab treated patients achieving ACR 20, 50 and 70 responses in Studies II and III are shown in TABLE 1A and TABLE 1B .
TABLE 1A    ACR Responses in Placebo- Controlled Trials: Study II Monotherapy (26 Weeks)
      Adalimumab 40 mg
    Placebo Every Other Week Weekly
Response n=110 n=113 n=103
ACR20
  Month 6 19% 46%* 53%*
  Month 12 NA NA NA
ACR50
  Month 6 8% 22%* 35%*
  Month 12 NA NA NA
ACR70
  Month 6 2% 12%* 18%*
  Month 12 NA NA NA
* p <0.01, adalimumab versus placebo.

TABLE 1B    ACR Responses in Placebo- Controlled Trials: Study III Methotrexate Combination (24 and 52 Weeks)
    Placebo/ MTX Adalimumab/ MTX 40 mg Every Other Week
Response n=200 n=207
ACR20
  Month 6 30% 63%*
  Month 12 24% 59%*
ACR50
  Month 6 10% 39%*
  Month 12 10% 42%*
ACR70
  Month 6 3% 21%*
  Month 12 5% 23%*
* p <0.01, adalimumab versus placebo.

The results of Study I were similar to Study III; patients receiving adalimumab 40 mg every other week in Study I also achieved ACR 20, 50 and 70 response rates of 65%, 52% and 24%, respectively, compared to placebo responses of 13%, 7% and 3% respectively, at 6 months (p <0.01).
The results of the components of the ACR response criteria for Studies II and III are shown in TABLE 2A and TABLE 2B . ACR response rates and improvement in all components of ACR response were maintained to Week 104. Over the 2 years in Study III, 20% of adalimumab patients receiving 40mg every other week (eow) achieved a major clinical response, defined as maintenance of an ACR 70 response over a 6- month period.
TABLE 2A    Components of ACR Response in Study II
  Placebo Adalimumab*
  n=110 n=113
Parameter (median) Baseline Wk 26 Baseline Wk 26
Number of tender joints (0- 68) 35 26 31 16§
Number of swollen joints (0- 66) 19 16 18 10§
Physician global assessment† 7.0 6.1 6.6 3.7§
Patient global assessment† 7.5 6.3 7.5 4.5§
Pain† 7.3 6.1 7.3 4.1§
Disability index (HAQ)‡ 2.0 1.9 1.9 1.5§
CRP (mg/ dl) 3.9 4.3 4.6 1.8§
* 40 mg adalimumab administered every other week.
† Visual analogue scale; 0=best, 10=worst.
‡ Disability Index of the Health Assessment Questionnaire 2 ; 0 = best, 3 = worst, measures the patient's ability to perform the following: dress/ groom, arise, eat, walk, reach, grip, maintain hygiene, and maintain daily activity.
§ p <0.001, adalimumab versus placebo, based on mean change from baseline.

TABLE 2B    Components of ACR Response in Study III
  Placebo/ MTX Adalimumab*/ MTX
  n=200 n=207
Parameter (median) Baseline Wk 24 Baseline Wk 24
Number of tender joints (0- 68) 26 15 24 8§
Number of swollen joints (0- 66) 17 11 18 5§
Physician global assessment† 6.3 3.5 6.5 2.0§
Patient global assessment† 5.4 3.9 5.2 2.0§
Pain† 6.0 3.8 5.8 2.1§
Disability index (HAQ)‡ 1.5 1.3 1.5 0.8§
CRP (mg/ dl) 1.0 0.9 1.0 0.4§
* 40 mg adalimumab administered every other week.
† Visual analogue scale; 0 = best, 10 = worst.
‡ Disability Index of the Health Assessment Questionnaire 2 ; 0 = best, 3 = worst, measures the patient's ability to perform the following: dress/ groom, arise, eat, walk, reach, grip, maintain hygiene, and maintain daily activity.
§ p <0.001, adalimumab versus placebo, based on mean change from baseline.

In Study III, 85% of patients with ACR 20 responses at Week 24 maintained the response at 52 weeks. The time course of ACR 20 response for Study I and Study II were similar.
In Study IV, 53% of patients treated with adalimumab 40 mg every other week plus standard of care had an ACR 20 response at Week 24 compared to 35% on placebo plus standard of care (p <0.001). No unique adverse reactions related to the combination of adalimumab and other DMARDs were observed.

Radiographic Response
  In Study III, structural joint damage was assessed radiographically and expressed as change in Total Sharp Score (TSS) and its components, the erosion score and Joint Space Narrowing (JSN) score, at Month 12 compared to baseline. At baseline, the median TSS was approximately 55 in the placebo and 40 mg every other week groups. The results are shown in TABLE 3 . Adalimumab/ MTX treated patients demonstrated less radiographic progression than patients receiving MTX alone at 52 weeks.
TABLE 3    Radiographic Mean Changes Over 12 Months in Study III
    Adalimumab/ MTX Placebo/ MTX- Adalimumab/ MTX  
  Placebo/ MTX 40 mg Every Other Week (95% Confidence Interval)* P- value†
Total Sharp score 2.7 0.1 2.6 (1.4, 3.8) <0.001
Erosion score 1.6 0.0 1.6 (0.9, 2.2) <0.001
JSN score 1.0 0.1 0.9 (0.3, 1.4) 0.002
* 95% confidence intervals for the differences in change scores between MTX and adalimumab.
† Based on rank analysis.

Physical Function Response
  In all four studies, adalimumab showed significantly greater improvement than placebo in the disability index of Health Assessment Questionnaire (HAQ) from baseline to the end of study, and significantly greater improvement than placebo in the health- outcomes as assessed by The Short Form Health Survey (SF 36). Improvement was seen in both the Physical Component Summary (PCS) and the Mental Component Summary (MCS).
In Study III, the mean (95% CI) improvement in HAQ- DI from baseline at Week 52 was 0.60 (0.55, 0.65) for the adalimumab patients and 0.25 (0.17, 0.33) for placebo/ MTX (p <0.001) patients. Eighty- two percent (82%) of adalimumab- treated patients who achieved a 0.5 or greater improvement in HAQ- DI at Week 52 in the double- blind portion of the study maintained that improvement through Week 104 of open- label treatment. Improvement in SF- 36 was also maintained through Week 104.

INDICATIONS AND USAGE
  Adalimumab is indicated for reducing signs and symptoms- inhibiting the progression of structural damage and improving physical function in adult patients with moderately to severely active rheumatoid arthritis who have had an inadequate response to one or more DMARDs. Adalimumab can be used alone or in combination with MTX or other DMARDs.

CONTRAINDICATIONS
  Adalimumab should not be administered to patients with known hypersensitivity to adalimumab or any of its components.

WARNINGS
 

SERIOUS INFECTIONS
  SERIOUS INFECTIONS AND SEPSIS, INCLUDING FATALITIES, HAVE BEEN REPORTED WITH THE USE OF TNF BLOCKING AGENTS INCLUDING ADALIMUMAB. MANY OF THE SERIOUS INFECTIONS HAVE OCCURRED IN PATIENTS ON CONCOMITANT IMMUNOSUPPRESSIVE THERAPY THAT, IN ADDITION TO THEIR RHEUMATOID ARTHRITIS, COULD PREDISPOSE THEM TO INFECTIONS. TUBERCULOSIS AND INVASIVE OPPORTUNISTIC FUNGAL INFECTIONS HAVE BEEN OBSERVED IN PATIENTS TREATED WITH TNF BLOCKING AGENTS INCLUDING ADALIMUMAB.
TREATMENT WITH ADALIMUMAB SHOULD NOT BE INITIATED IN PATIENTS WITH ACTIVE INFECTIONS INCLUDING CHRONIC OR LOCALIZED INFECTIONS. PATIENTS WHO DEVELOP A NEW INFECTION WHILE UNDERGOING TREATMENT WITH ADALIMUMAB SHOULD BE MONITORED CLOSELY. ADMINISTRATION OF ADALIMUMAB SHOULD BE DISCONTINUED IF A PATIENT DEVELOPS A SERIOUS INFECTION. PHYSICIANS SHOULD EXERCISE CAUTION WHEN CONSIDERING THE USE OF ADALIMUMAB IN PATIENTS WITH A HISTORY OF RECURRENT INFECTION OR UNDERLYING CONDITIONS WHICH MAY PREDISPOSE THEM TO INFECTIONS, OR PATIENTS WHO HAVE RESIDED IN REGIONS WHERE TUBERCULOSIS AND HISTOPLASMOSIS ARE ENDEMIC (see PRECAUTIONS, Tuberculosis and ADVERSE REACTIONS, Infections ). THE BENEFITS AND RISKS OF ADALIMUMAB TREATMENT SHOULD BE CAREFULLY CONSIDERED BEFORE INITIATION OF ADALIMUMAB THERAPY.

Use with Anakinra
  Serious infections were seen in clinical studies with concurrent use of anakinra (an interleukin- 1 antagonist) and another TNF- blocking agent, with no added benefit. Because of the nature of the adverse events seen with this combination therapy, similar toxicities may also result from combination of anakinra and other TNF blocking agents. Therefore, the combination of adalimumab and anakinra is not recommended (see DRUG INTERACTIONS ).

Neurologic Events
  Use of TNF blocking agents, including adalimumab, has been associated with rare cases of exacerbation of clinical symptoms and/ or radiographic evidence of demyelinating disease. Prescribers should exercise caution in considering the use of adalimumab in patients with preexisting or recent- onset central nervous system demyelinating disorders.

Malignancies
  In the controlled portions of clinical trials of all the TNF- blocking agents, more cases of lymphoma have been observed among patients receiving TNF blockers compared to control patients. During the controlled portions of adalimumab trials in patients with moderately to severely active rheumatoid arthritis, 2 lymphomas were observed among 1380 adalimumab- treated patients versus 0 among 690 control patients (mean duration of controlled treatment approximately 7 months). In the controlled and open- label portions of these clinical trials of adalimumab in rheumatoid arthritis patients, 10 lymphomas were observed in 2468 patients over 4870 patient- years of therapy. This is approximately 5- fold higher than expected in the general population. Rates in clinical trials for adalimumab cannot be compared to rates of clinical trials of other TNF blockers and may not predict the rates observed in a broader patient population. Patients with rheumatoid arthritis, particularly those with highly active disease, are at a higher risk for the development of lymphoma. The potential role of TNF- blocking therapy in the development of malignancies is not known (see ADVERSE REACTIONS, Malignancies ). 4, 5

Hypersensitivity Reactions
  In postmarketing experience, anaphylaxis has been reported rarely following adalimumab administration. If an anaphylactic or other serious allergic reaction occurs, administration of adalimumab should be discontinued immediately and appropriate therapy instituted. In clinical trials of adalimumab, allergic reactions overall ( e.g., allergic rash, anaphylactoid reaction, fixed drug reaction, non- specified drug reaction, urticaria) have been observed in approximately 1% of patients.

Hematologic Events
  Rare reports of pancytopenia including aplastic anemia have been reported with TNFα- blocking agents. Adverse events of the hematologic system, including medically significant cytopenia ( e.g., thrombocytopenia, leukopenia) have been infrequently reported with adalimumab (see ADVERSE REACTIONS, Other Adverse Reactions ). The causal relationship of these reports to adalimumab remains unclear. All patients should be advised to seek immediate medical attention if they develop signs and symptoms suggestive of blood dyscrasias or infection ( e.g., persistent fever, bruising, bleeding, pallor) while on adalimumab. Discontinuation of adalimumab therapy should be considered in patients with confirmed significant hematologic abnormalities.

PRECAUTIONS
 

Information for the Patient
  The first injection should be performed under the supervision of a qualified health care professional. If a patient or caregiver is to administer adalimumab, he/ she should be instructed in injection techniques and their ability to inject subcutaneously should be assessed to ensure the proper administration of adalimumab (see the patient information leaflet that is included with the prescription). A puncture- resistant container for disposal of needles and syringes should be used. Patients or caregivers should be instructed in the technique as well as proper syringe and needle disposal, and be cautioned against reuse of these items.

Tuberculosis
  As observed with other TNF blocking agents, tuberculosis associated with the administration of adalimumab in clinical trials has been reported (see WARNINGS ). While cases were observed at all doses, the incidence of tuberculosis reactivations was particularly increased at doses of adalimumab that were higher than the recommended dose. All patients recovered after standard antimicrobial therapy. No deaths due to tuberculosis occurred during the clinical trials.
Before initiation of therapy with adalimumab, patients should be evaluated for active or latent tuberculosis infection with a tuberculin skin test. If latent infection is diagnosed, appropriate prophylaxis in accordance with the Centers for Disease Control and Prevention guidelines 6 should be instituted. Patients should be instructed to seek medical advice if signs/ symptoms ( e.g., persistent cough, wasting/ weight loss, low grade fever) suggestive of a tuberculosis infection occur.

Patients With Heart Failure
  Cases of worsening congestive heart failure (CHF) and new onset CHF have been reported with TNF blockers. Cases of worsening CHF have also been observed with adalimumab. Adalimumab has not been formally studied in patients with CHF; however, in clinical trials of another TNF blocker, a higher rate of serious CHF- related adverse events was observed. Physicians should exercise caution when using adalimumab in patients who have heart failure and monitor them carefully.

Immunosuppression
  The possibility exists for TNF blocking agents, including adalimumab, to affect host defenses against infections and malignancies since TNF mediates inflammation and modulates cellular immune responses. In a study of 64 patients with rheumatoid arthritis treated with adalimumab, there was no evidence of depression of delayed- type hypersensitivity, depression of immunoglobulin levels, or change in enumeration of effector T- and B- cells and NK- cells, monocyte/ macrophages, and neutrophils. The impact of treatment with adalimumab on the development and course of malignancies, as well as active and/ or chronic infections is not fully understood (see WARNINGS and ADVERSE REACTIONS: Infections and Malignancies ). The safety and efficacy of adalimumab in patients with immunosuppression have not been evaluated.

Immunizations
  No data are available on the effects of vaccination in patients receiving adalimumab. Live vaccines should not be given concurrently with adalimumab. No data are available on the secondary transmission of infection by live vaccines in patients receiving adalimumab.

Autoimmunity
  Treatment with adalimumab may result in the formation of autoantibodies and, rarely, in the development of a lupus- like syndrome. If a patient develops symptoms suggestive of a lupus- like syndrome following treatment with adalimumab, treatment should be discontinued (see ADVERSE REACTIONS, Autoantibodies ).

Carcinogenesis, Mutagenesis, and Impairment of Fertility
  Long- term animal studies of adalimumab have not been conducted to evaluate the carcinogenic potential or its effect on fertility. No clastogenic or mutagenic effects of adalimumab were observed in the in vivo mouse micronucleus test or the Salmonella- Escherichia coli (Ames) assay, respectively.

Pregnancy Category B
  An embryo- fetal perinatal developmental toxicity study has been performed in cynomolgus monkeys at dosages up to 100 mg/ kg (266 times human AUC when given 40 mg SC with MTX every week or 373 times human AUC when given 40 mg SC without MTX) and has revealed no evidence of harm to the fetuses due to adalimumab. There are, however, no adequate and well- controlled studies in pregnant women. Because animal reproduction and developmental studies are not always predictive of human response, adalimumab should be used during pregnancy only if clearly needed.

Pregnancy Registry: To monitor outcomes of pregnant women exposed to Humira, a pregnancy registry has been established. Physicians are encouraged to register patients by calling 1- 877- 311- 8972.

Nursing Mothers
  It is not known whether adalimumab is excreted in human milk or absorbed systemically after ingestion. Because many drugs and immunoglobulins are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from adalimumab, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use
  Safety and effectiveness of adalimumab in pediatric patients have not been established.

Geriatric Use
  A total of 519 patients 65 years of age and older, including 107 patients 75 years and older, received adalimumab in clinical studies. No overall difference in effectiveness was observed between these subjects and younger subjects. The frequency of serious infection and malignancy among adalimumab treated subjects over age 65 was higher than for those under age 65. Because there is a higher incidence of infections and malignancies in the elderly population in general, caution should be used when treating the elderly.

DRUG INTERACTIONS
 

Methotrexate
  Adalimumab has been studied in rheumatoid arthritis patients taking concomitant MTX (see CLINICAL PHARMACOLOGY, Drug Interations ). The data do not suggest the need for dose adjustment of either adalimumab or MTX.

Anakinra
  Concurrent administration of anakinra (an interleukin- l antagonist) and another TNF- blocking agent has been associated with an increased risk of serious infections, an increased risk of neutropenia and no additional benefit compared to these medicinal products alone. Therefore, the combination of anakinra with other TNF- blocking agents, including adalimumab, may also result in similar toxicities (see WARNINGS, Serious Infections ).

ADVERSE REACTIONS
 

General
  The most serious adverse reactions were (see WARNINGS ):
• Serious infections.
• Neurologic events.
• Malignancies.

The most common adverse reaction with adalimumab was injection site reactions. In placebo- controlled trials, 20% of patients treated with adalimumab developed injection site reactions (erythema and/ or itching, hemorrhage, pain or swelling), compared to 14% of patients receiving placebo. Most injection site reactions were described as mild and generally did not necessitate drug discontinuation.
The proportion of patients who discontinued treatment due to adverse events during the double- blind, placebo- controlled portion of Studies I, II, III and IV was 7% for patients taking adalimumab and 4% for placebo- treated patients. The most common adverse events leading to discontinuation of adalimumab were clinical flare reaction (0.7%), rash (0.3%) and pneumonia (0.3%).
Because clinical trials are conducted under widely varying and controlled conditions, adverse reaction rates observed in clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not predict the rates observed in a broader patient population in clinical practice.

Infections
  In placebo- controlled trials, the rate of infection was 1/ patient year in the adalimumab treated patients and 0.9/ patient year in the placebo- treated patients. The infections consisted primarily of upper respiratory tract infections, bronchitis and urinary tract infections. Most patients continued on adalimumab after the infection resolved. The incidence of serious infections was 0.04/ patient year in adalimumab treated patients and 0.02/ patient year in placebo- treated patients. Serious infections observed included pneumonia, septic arthritis, prosthetic and post- surgical infections, erysipelas, cellulitis, diverticulitis, and pyelonephritis (see WARNINGS ).
Thirteen (13) cases of tuberculosis, including miliary, lymphatic, peritoneal, and pulmonary were reported in clinical trials. Most of the cases of tuberculosis occurred within the first 8 months after initiation of therapy and may reflect recrudescence of latent disease. Six (6) cases of invasive opportunistic infections caused by histoplasma, aspergillus, and nocardia were also reported in clinical trials (see WARNINGS ).

Malignancies
  Among 2468 rheumatoid arthritis patients with moderately to severely active disease treated with adalimumab in clinical trials for a mean of 24 months (4870 patient- years of therapy), 10 lymphomas were observed for a rate of 0.21 cases per 100 patient- years. This is approximately 5- fold higher than expected in an age- and sex- matched general population based on theSurveillance, Epidemiology, and End Results Database. 7 Rates in clinical trials for adalimumab can not be compared to rates of clinical trials of other TNF blockers and may not predict the rates observed in a broader patient population. (see WARNNGS, Malignancies .) An increased rate of lymphoma has been reported in the rheumatoid arthritis patient population. 5, 6 Patients with rheumatoid arthritis, particularly those with highly active disease, are at a higher risk for the development of lymphoma. The potential role of TNF- blocking therapy in the development of malignancies is not known. Thirty- eight (38) malignancies, other than lymphoma, were observed. Of these, the most common malignancies were breast, colon, prostate, and uterine, which were similar in type and number to what would be expected in the general population. 7

Autoantibodies
  In the controlled trials, 12% of patients treated with adalimumab and 7% of placebo- treated patients that had negative baseline ANA titers developed positive titers at Week 24. One (1) patient out of 2334 treated with adalimumab developed clinical signs suggestive of new- onset lupus- like syndrome. The patient improved following discontinuation of therapy. No patients developed lupus nephritis or central nervous system symptoms. The impact of long- term treatment with adalimumab on the development of autoimmune diseases is unknown.

Immunogenicity
  Patients in Studies I, II, and III were tested at multiple time points for antibodies to adalimumab during the 6- 12 month period. Approximately 5% (58 of 1062) of adult rheumatoid arthritis patients receiving adalimumab developed low- titer antibodies to adalimumab at least once during treatment, which were neutralizing in vitro. Patients treated with concomitant MTX had a lower rate of antibody development than patients on adalimumab monotherapy (1% vs 12%). No apparent correlation of antibody development to adverse events was observed. With monotherapy, patients receiving every other week dosing may develop antibodies more frequently than those receiving weekly dosing. In patients receiving the recommended dosage of 40 mg every other week as monotherapy, the ACR 20 response was lower among antibody- positive patients than among antibody- negative patients. The long- term immunogenicity of adalimumab is unknown.
The data reflect the percentage of patients whose test results were considered positive for antibodies to adalimumab in an ELISA assay, and are highly dependent on the sensitivity and specificity of the assay. Additionally the observed incidence of antibody positivity in an assay may be influenced by several factors including sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to adalimumab with the incidence of antibodies to other products may be misleading.

Other Adverse Reactions
  The data described below reflect exposure to adalimumab in 2468 patients, including 2073 exposed for 6 months, 1497 exposed for greater than 1 year and 1380 in adequate and well- controlled studies (Studies I, II, III, and IV). Adalimumab was studied primarily in placebo- controlled trials and in long- term follow up studies for up to 36 months duration. The population had a mean age of 54 years, 77% were female, 91% were Caucasian and had moderately to severely active rheumatoid arthritis. Most patients received 40 mg adalimumab every other week.
TABLE 4 summarizes events reported at a rate of at least 5% in patients treated with adalimumab 40 mg every other week compared to placebo and with an incidence higher than placebo. Adverse event rates in patients treated with adalimumab 40 mg weekly were similar to rates in patients treated with adalimumab 40 mg every other week. In Study III, the types and frequencies of adverse events in the second year open- label extension were similar to those observed in the 1- year double- blind portion.
TABLE 4    Adverse Events Reported by ≥5% of Patients Treated With Adalimumab During Placebo- Controlled Period of Rheumatoid Arthritis Studies
    Adalimumab 40 mg Subcutaneous  
    Every Other Week Placebo
Adverse Event (Preferred Term) (n=705) (n=690)
Respiratory
  Upper respiratory infection 17% 13%
  Sinusitis 11% 9%
  Flu syndrome 7% 6%
Gastrointestinal
  Nausea 9% 8%
  Abdominal pain 7% 4%
Laboratory Tests *
  Laboratory test abnormal 8% 7%
  Hypercholesterolemia 6% 4%
  Hyperlipidemia 7% 5%
  Hematuria 5% 4%
  Alkaline phosphatase increased 5% 3%
Other
  Injection site pain 12% 12%
  Headache 12% 8%
  Rash 12% 6%
  Accidental injury 10% 8%
  Injection site reaction† 8% 1%
  Back pain 6% 4%
  Urinary tract infection 8% 5%
  Hypertension 5% 3%
* Laboratory test abnormalities were reported as adverse events in European trials.
† Does not include erythema and/ or itching, hemorrhage, pain or swelling.

Other Adverse Events
  Other infrequent serious adverse events occurring at an incidence of less than 5% in patients treated with adalimumab were:
Body As A Whole: Fever, infection, pain in extremity, pelvic pain, sepsis, surgery, thorax pain, tuberculosis reactivated.
Cardiovascular System: Arrhythmia, atrial fibrillation, cardiovascular disorder, chest pain, congestive heart failure, coronary artery disorder, heart arrest, hypertensive encephalopathy, myocardial infarct, palpitation, pericardial effusion, pericarditis, syncope, tachycardia, vascular disorder.
Collagen Disorder: Lupus erythematosus syndrome.
Digestive System: Cholecystitis, cholelithiasis, esophagitis, gastroenteritis, gastrointestinal disorder, gastrointestinal hemorrhage, hepatic necrosis, vomiting.
Endocrine System: Parathyroid disorder.
Hemic and Lymphatic System: Agranulocytosis, granulocytopenia, leukopenia, lymphoma like reaction, pancytopenia, polycythemia (see WARNINGS, Hematologic Events ).
Metabolic and Nutritional Disorders: Dehydration, healing abnormal, ketosis, paraproteinemia, peripheral edema.
Musculoskeletal System: Arthritis, bone disorder, bone fracture (not spontaneous), bone necrosis, joint disorder, muscle cramps, myasthenia, pyogenic arthritis, synovitis, tendon disorder.
Neoplasia: Adenoma, carcinomas such as breast, gastrointestinal, skin, urogenital, and others; lymphoma and melanoma.
Nervous System: Confusion, multiple sclerosis, paresthesia, subdural hematoma, tremor.
Respiratory System: Asthma, bronchospasm, dyspnea, lung disorder, lung function decreased, pleural effusion, pneumonia.
Skin and Appendages: Cellulitis, erysipelas, herpes zoster.
Special Senses: Cataract.
Thrombosis: Thrombosis leg.
Urogenital System: Cystitis, kidney calculus, menstrual disorder, pyelonephritis.

Adverse Reaction Information From Spontaneous Reports
  Adverse events have been reported during post- approval use of adalimumab. Because these events are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to adalimumab exposure.
Hematologic Events: Thrombocytopenia (see WARNINGS, Hematologic Events ).
Hypersensitivity Reactions: Anaphylaxis (see WARNINGS, Hypersensitivity Reactions ).
Skin Reactions: Cutaneous vasculitis.

OVERDOSAGE
  The maximum tolerated dose of adalimumab has not been established in humans. Multiple doses up to 10 mg/ kg have been administered to patients in clinical trials without evidence of dose- limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately.

DOSAGE AND ADMINISTRATION
  The recommended dose of adalimumab for adult patients with rheumatoid arthritis is 40 mg administered every other week as a SC injection. MTX, glucocorticoids, salicylates, nonsteroidal anti- inflammatory drugs (NSAIDs), analgesics or other DMARDs may be continued during treatment with adalimumab. Some patients not taking concomitant MTX may derive additional benefit from increasing the dosing frequency of adalimumab to 40 mg every week.
Adalimumab is intended for use under the guidance and supervision of a physician. Patients may self- inject adalimumab if their physician determines that it is appropriate and with medical follow- up, as necessary, after proper training in injection technique.
The solution in the syringe should be carefully inspected visually for particulate matter and discoloration prior to SC administration. If particulates and discolorations are noted, the product should not be used. Adalimumab does not contain preservatives; therefore, unused portions of drug remaining from the syringe should be discarded. NOTE: The needle cover of the syringe contains dry rubber (latex), which should not be handled by persons sensitive to this substance.
Patients using the pre- filled syringes should be instructed to inject the full amount in the syringe (0.8 ml), which provides 40 mg of adalimumab according to the directions provided in the Patient Information Leaflet.
Injection sites should be rotated and injections should never be given into areas where the skin is tender, bruised, red or hard (see the patient information leaflet that is included with the prescription).

References
 

1. Arnett FC, Edworthy SM, Bloch DA, et al. The American Rheumatology Association 1987 Revised Criteria for the Classification of Rheumatoid Arthritis. Arthritis Rheum 1988; 31:315- 24.

2. Ramey DR, Fries JF, Singh G. The Health Assessment Questionnaire 1995 — Status and Review. In: Spilker B, ed. "Quality of Life and Pharmacoeconomics in Clinical Trials." 2nded. Philadelphia, PA. Lippincott- Raven 1996.

3. Ware JE, Gandek B. Overview of the SF- 36 Health Survey and the International Quality of Life Assessment (IQOLA) Project. J Clin Epidemiol 1998; 51(11):903- 12.

4. Mellemkjaer L, Linet MS, Gridley G, et al. Rheumatoid Arthritis and Cancer Risk. European Journal of Cancer 1996; 32A (10): 1753- 1757.

5. Baecklund E, Ekbom A, Sparen P, et al. Disease Activity and Risk of Lymphoma in Patients With Rheumatoid Arthritis: Nested Case- Control Study. BMJ 1998; 317: 180- 181.

6. Centers for Disease Control and Prevention. Targeted Tuberculin Testing and Treatment of Latent Tuberculosis Infection. MMWR 2000; 49(No. RR- 6):26- 38.

7. National Cancer Institute. Surveillance, Epidemiology, and End Results Database (SEER)Program. SEER Incidence Crude Rates, 11 Registries, 1992- 1999.

HOW SUPPLIED
  Humira is supplied in pre- filled syringes as a preservative- free, sterile solution for SC administration. The following packaging configurations are available:
Patient Use Syringe Carton: Humira is dispensed in a carton containing 2 alcohol preps and 2 dose trays. Each dose tray consists of a single- use, 1- ml pre- filled glass syringe with a fixed 27 gauge ½ inch needle, providing 40 mg (0.8 ml) of Humira.
Institutional Use Syringe Carton: Each carton contains 2 alcohol preps and 1 dose tray. Each dose tray consists of a single use, 1- ml pre- filled glass syringe with a fixed 27 gauge ½ inch needle (with a needle stick protection device) providing 40 mg (0.8 ml) Humira.

Storage and Stability
  Do not use beyond the expiration date on the container. Adalimumab must be refrigerated at 2- 8°C (36- 46°F). DO NOT FREEZE. Protect the vial or/ and pre- filled syringe from exposure to light. Store in original carton until time of administration.

PRODUCT IDENTIFICATION
  None Available

PATIENT DRUG CONSULT HANDOUT
  Adalimumab (injection)

PRODUCT LISTING - EQUIVALENTS NOT AVAILABLE
 
solution - subcutaneous - 40 mg -
0.8 ml $657.90 Humira
Abbott Pharmaceutical 		00074379901
0.8 ml x 2.0 $1315.81 Humira
Abbott Pharmaceutical 		00074379902

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