Table of Contents

Description
Clinical Pharmacology
Clinical Studies
Indications and Usage
Contraindications
Warnings
Precautions
Adverse Reactions
Overdosage
Dosage and Administration
How Supplied
References

Rx only
Tear at Perforation to Dispense Patient Information

WARNING RISK OF INFECTIONS Cases of tuberculosis (frequently disseminated or extrapulmonary at clinical presentation) have been observed in patients receiving HUMIRA. 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 HUMIRA.

DESCRIPTION

HUMIRA (adalimumab) is a recombinant human IgG1 monoclonal antibody specific for human tumor necrosis factor (TNF). HUMIRA was created using phage display technology resulting in an antibody with human derived heavy and light chain variable regions and human IgG1:k constant regions. HUMIRA 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, and also 2 mL glass vials as a sterile, preservative-free solution for subcutaneous 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 vial contains approximately 0.9 mL of solution to deliver 0.8 mL (40 mg) of drug product. Each 0.8 mL 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, USP. Sodium hydroxide added as necessary to adjust pH.

Return to Table of Contents

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 X 10^-10M).

Pharmacodynamics

After treatment with HUMIRA, 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 HUMIRA administration.

Pharmacokinetics

The maximum serum concentration (C_max) and the time to reach the maximum concentration (T_max) were 4.7 ± 1.6 µg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of HUMIRA to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three studies following a single 40 mg subcutaneous dose was 64%. The pharmacokinetics of adalimumab were linear over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose.

The single dose pharmacokinetics of adalimumab were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The distribution volume (V_ss) ranged from 4.7 to 6.0 L. The systemic clearance of adalimumab is approximately 12 mL/hr. The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. Adalimumab concentrations in the synovial fluid from five rheumatoid arthritis patients ranged from 31- 96% of those in serum.

Adalimumab mean steady-state trough concentrations of approximately 5 µg/mL and 8 to 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 subcutaneous dosing. In long-term studies with dosing more than two 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.

HUMIRA has not been studied in children.

Drug Interactions

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

Return to Table of Contents

CLINICAL STUDIES

The efficacy and safety of HUMIRA 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. HUMIRA 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 one but no more than four DMARDs and had inadequate response to MTX. Doses of 20, 40 or 80 mg of HUMIRA or placebo were given every other week for 24 weeks.

Study II evaluated 544 patients who had failed therapy with at least one DMARD. Doses of placebo, 20 or 40 mg of HUMIRA 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 HUMIRA every other week with placebo injections on alternate weeks, or 20 mg of HUMIRA 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).

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 HUMIRA or placebo every other week for 24 weeks.

The percent of HUMIRA treated patients achieving ACR 20, 50 and 70 responses in Studies II and III are shown in Table 1.

Table 1 : ACR Responses in Placebo-Controlled Trials (Percent of Patients)

	Study II Monotherapy (26 weeks)			Study III Methotrexate Combination (24 and 52 weeks)
Response	Placebo     N=110	HUMIRA 40 mg every other week N=113	HUMIRA 40 mg weekly   N=103	Placebo/MTX     N=200	HUMIRA/MTX 40 mg every other week N=207
ACR20
Month 6	19%	46%*	53%*	30%	63%*
Month 12	NA	NA	NA	24%	59%*
ACR50
Month 6	8%	22%*	35%*	10%	39%*
Month 12	NA	NA	NA	10%	42%*
ACR70
Month 6	2%	12%*	18%*	3%	21%*
Month 12	NA	NA	NA	5%	23%*

* p<0.01, HUMIRA vs. placebo

The results of Study I were similar to Study III; patients receiving HUMIRA 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 2. Improvement was seen in all components and was maintained to week 52.

Table 2: Components of ACR Response in Studies II and III

Parameter (median)	Study II				Study III
	Placebo N=110		HUMIRAa N=113		Placebo/MTX N=200		HUMIRAa/MTX N=207
	Baseline	Wk 26	Baseline	Wk 26	Baseline	Wk 24	Baseline	Wk 24
Number of tender joints (0-68)	35	26	31	16*	26	15	24	8*
Number of swollen joints (0-66)	19	16	18	10*	17	11	18	5*
Physician global assessmentb	7.0	6.1	6.6	3.7*	6.3	3.5	6.5	2.0*
Patient global assessmentb	7.5	6.3	7.5	4.5*	5.4	3.9	5.2	2.0*
Painb	7.3	6.1	7.3	4.1*	6.0	3.8	5.8	2.1*
Disability index (HAQ)c	2.0	1.9	1.9	1.5*	1.5	1.3	1.5	0.8*
CRP (mg/dL)	3.9	4.3	4.6	1.8*	1.0	0.9	1.0	0.4*

^a 40 mg HUMIRA administered every other week
^b Visual analogue scale; 0 = best, 10 = worst
^c Disability Index of the Health Assessment Questionnaire²; 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, HUMIRA vs. placebo, based on mean change from baseline

The time course of ACR 20 response for Study III is shown in Figure 1.
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.

Figure 1: Study III ACR 20 Responses over 52 Weeks

In Study IV, 53% of patients treated with HUMIRA 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 HUMIRA and other DMARDs were observed.

In all four studies, HUMIRA 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).

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. HUMIRA/MTX treated patients demonstrated less radiographic progression than patients receiving MTX alone.

Table 3: Radiographic Mean Changes Over 12 Months in Study III

	Placebo/MTX	HUMIRA/MTX 40 mg every other week	Placebo/MTX- HUMIRA/MTX (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 HUMIRA.
Based on rank analysis

Return to Table of Contents

INDICATIONS AND USAGE

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

CONTRAINDICATIONS

HUMIRA should not be administered to patients with known hypersensitivity to HUMIRA or any of its components.

Return to Table of Contents

WARNINGS

SERIOUS INFECTIONS AND SEPSIS, INCLUDING FATALITIES, HAVE BEEN REPORTED WITH THE USE OF TNF BLOCKING AGENTS INCLUDING HUMIRA. 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 HUMIRA.

TREATMENT WITH HUMIRA SHOULD NOT BE INITIATED IN PATIENTS WITH ACTIVE INFECTIONS INCLUDING CHRONIC OR LOCALIZED INFECTIONS. PATIENTS WHO DEVELOP A NEW INFECTION WHILE UNDERGOING TREATMENT WITH HUMIRA SHOULD BE MONITORED CLOSELY. ADMINISTRATION OF HUMIRA SHOULD BE DISCONTINUED IF A PATIENT DEVELOPS A SERIOUS INFECTION. PHYSICIANS SHOULD EXERCISE CAUTION WHEN CONSIDERING THE USE OF HUMIRA 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 HUMIRA TREATMENT SHOULD BE CAREFULLY CONSIDERED BEFORE INITIATION OF HUMIRA THERAPY.

Neurologic Events

Use of TNF blocking agents, including HUMIRA, 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 HUMIRA in patients with preexisting or recent-onset central nervous system demyelinating disorders.

Malignancies

Lymphomas have been observed in patients treated with TNF blocking agents including HUMIRA. In clinical trials, patients treated with HUMIRA had a higher incidence of lymphoma than the expected rate in the general population (see ADVERSE REACTIONS-Malignancies). While patients with rheumatoid arthritis, particularly those with highly active disease, may be at a higher risk (up to several fold) for the development of lymphoma, the role of TNF blockers in the development of malignancy is not known^4,5.

Return to Table of Contents

PRECAUTIONS

General

Allergic reactions have been observed in approximately 1% of patients receiving HUMIRA. If an anaphylactic reaction or other serious allergic reaction occurs, administration of HUMIRA should be discontinued immediately and appropriate therapy initiated.

Information to Patients

The first injection should be performed under the supervision of a qualified health care professional. If a patient or caregiver is to administer HUMIRA, he/she should be instructed in injection techniques and their ability to inject subcutaneously should be assessed to ensure the proper administration of HUMIRA (see HUMIRA, PATIENT INFORMATION LEAFLET). 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 HUMIRA 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 HUMIRA 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 HUMIRA, 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 guidelines⁶ 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.

Immunosuppression

The possibility exists for TNF blocking agents, including HUMIRA, 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 HUMIRA, there was no evidence of depression of delayed-type hypersensitivity, depression of immunoglobulin levels, or change in enumeration of effector T- and B-cells and NK-cells, monocyte/macrophages, and neutrophils. The impact of treatment with HUMIRA on the development and course of malignancies, as well as active and/or chronic infections is not fully understood (see WARNINGS, ADVERSE REACTIONS, Infections and Malignancies). The safety and efficacy of HUMIRA in patients with immunosuppression have not been evaluated.

Immunizations

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

Autoimmunity

Treatment with HUMIRA 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 HUMIRA, treatment should be discontinued (see ADVERSE REACTIONS, Autoantibodies).

Drug Interactions

HUMIRA has been studied in rheumatoid arthritis patients taking concomitant MTX (see CLINICAL PHARMACOLOGY: Drug Interactions). The data do not suggest the need for dose adjustment of either HUMIRA or MTX.

Carcinogenesis, Mutagenesis, and Impairment of Fertility

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

Pregnancy

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 subcutaneous with MTX every week or 373 times human AUC when given 40 mg subcutaneous 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, HUMIRA should be used during pregnancy only if clearly needed.

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 HUMIRA, 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 HUMIRA 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 HUMIRA in clinical studies. No overall difference in effectiveness was observed between these subjects and younger subjects. The frequency of serious infection and malignancy among HUMIRA 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.

Return to Table of Contents

ADVERSE REACTIONS

General

The most serious adverse reactions were (see WARNINGS):

• Serious Infections
• Neurologic Events
• Malignancies

The most common adverse reaction with HUMIRA was injection site reactions. In placebo-controlled trials, 20% of patients treated with HUMIRA 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 HUMIRA and 4% for placebo-treated patients. The most common adverse events leading to discontinuation of HUMIRA 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 per patient year in the HUMIRA treated patients and 0.9 per 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 HUMIRA after the infection resolved. The incidence of serious infections was 0.04 per patient year in HUMIRA treated patients and 0.02 per 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 cases of tuberculosis, including miliary, lymphatic, peritoneal, and pulmonary were reported in clinical trials. Most of the cases of tuberculosis occurred within the first eight months after initiation of therapy and may reflect recrudescence of latent disease. Six 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 treated in clinical trials with HUMIRA for a median of 24 months, 48 malignancies of various types were observed, including 10 patients with lymphoma. The Standardized Incidence Ratio (SIR) (ratio of observed rate to age-adjusted expected frequency in the general population) for malignancies was 1.0 (95% CI, 0.7, 1.3) and for lymphomas was 5.4 (95% CI, 2.6, 10.0). An increase of up to several fold in the rate of lymphomas has been reported in the rheumatoid arthritis patient population⁴, and may be further increased in patients with more severe disease activity⁵ (see WARNINGS-Malignancies). The other malignancies observed during use of HUMIRA were breast, colon-rectum, uterine-cervical, prostate, melanoma, gallbladder-bile ducts, and other carcinomas.

Autoantibodies

In the controlled trials, 12% of patients treated with HUMIRA and 7% of placebo-treated patients that had negative baseline ANA titers developed positive titers at week 24. One patient out of 2334 treated with HUMIRA 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 HUMIRA 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 to 12 month period. Approximately 5% (58 of 1,062) of adult rheumatoid arthritis patients receiving HUMIRA 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 HUMIRA monotherapy (1% versus 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 HUMIRA 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 HUMIRA in 2334 patients, including 2073 exposed for 6 months, 1497 exposed for greater than one year and 1380 in adequate and well-controlled studies (Studies I, II, III, and IV). HUMIRA 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 HUMIRA every other week.

Table 4 summarizes events reported at a rate of at least 5% in patients treated with HUMIRA 40 mg every other week compared to placebo and with an incidence higher than placebo. Adverse event rates in patients treated with HUMIRA 40 mg weekly were similar to rates in patients treated with HUMIRA 40 mg every other week.

Table 4: Adverse Events Reported by > 5% of Patients Treated with HUMIRA During Placebo-Controlled Period of Rheumatoid Arthritis Studies

	HUMIRA 40 mg subcutaneous Every Other Week (N=705)	Placebo     (N=690)
Adverse Event (Preferred Term)	Percentage	Percentage
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 HUMIRA 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

Metabolic And Nutritional Disorders: Dehydration, healing abnormal, ketosis, paraproteinemia, peripheral edema

Musculo-Skeletal 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

Return to Table of Contents

OVERDOSAGE

The maximum tolerated dose of HUMIRA 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.

Return to Table of Contents

DOSAGE AND ADMINISTRATION

The recommended dose of HUMIRA for adult patients with rheumatoid arthritis is 40 mg administered every other week as a subcutaneous injection. MTX, glucocorticoids, salicylates, nonsteroidal anti-inflammatory drugs (NSAIDs), analgesics or other DMARDs may be continued during treatment with HUMIRA. Some patients not taking concomitant MTX may derive additional benefit from increasing the dosing frequency of HUMIRA to 40 mg every week.

HUMIRA is intended for use under the guidance and supervision of a physician. Patients may self-inject HUMIRA 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 and in the vial should be carefully inspected visually for particulate matter and discoloration prior to subcutaneous administration. If particulates and discolorations are noted, the product should not be used. HUMIRA does not contain preservatives; therefore, unused portions of drug remaining from the syringe or vial 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 HUMIRA. For patients and institutions using vials, 0.8 mL of solution providing 40 mg of HUMIRA should be withdrawn from the vial and administered 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 PATIENT INFORMATION LEAFLET).

Instructions For Activating the Needle Stick Device: Cartons for institutional use contain a syringe and needle with a needle protection device (see HOW SUPPLIED). To activate the needle stick protection device after injection, hold the syringe in one hand and, with the other hand, slide the outer protective shield over the exposed needle until it locks into place.

Storage and Stability

Do not use beyond the expiration date on the container. HUMIRA 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.

Return to Table of Contents

HOW SUPPLIED

HUMIRAä (adalimumab) is supplied in glass vials and syringes as a preservative-free, sterile solution for subcutaneous administration. The following packaging configurations are available:

Patient Use Syringe Carton
HUMIRA is dispensed in a carton containing two alcohol preps and two dose trays. Each dose tray consists of a single-use, 1 mL pre-filled glass syringe with a fixed 27 gauge ˝ inch needle, providing 40 mg (0.8 mL) of HUMIRA. The NDC number is 0074-3799-02.

Patient Use Vial Carton
HUMIRA is dispensed in a carton containing four alcohol preps and two trays. Each dose tray consists of a single-use, 2 mL glass vial providing 40 mg (0.8 mL) of HUMIRA and one sterile 1 mL syringe with a fixed 25 gauge 5/8 inch needle. The NDC number is 0074-3797-02.

Institutional Use Syringe Carton
Each carton contains two alcohol preps and one tray. Each dose tray consists of a single use, 1 mL pre-filled glass syringe with a fixed 27 gauge ˝ inch needle (with a needle stick protection device) providing 40 mg (0.8 mL) HUMIRA. The NDC number is 0074-3799-01.

Institutional Use Vial Carton
Each carton contains two alcohol preps and one tray. Each dose tray consists of a 2 mL glass vial providing 40 mg (0.8 mL) of HUMIRA, and one sterile syringe with a fixed 27 gauge ˝ inch needle (with needle stick protection device). The NDC number is 0074-3797-01.

Return to Table of Contents

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.” 2^nd ed. 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. Rheumatiod 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.

Return to Table of Contents

Last Updated: 1/27/2003

Date created: September 26, 2003

CDER Home Page | CDER Site Info | Contact CDER | What's New @ CDER
FDA Home Page | Search FDA Site | FDA A-Z Index | Contact FDA | HHS Home Page

FDA/Center for Drug Evaluation and Research