Unless otherwise instructed by a healthcare professional (e.g., doctor, nurse or pharmacist), used alcohol pads may be placed in the trash. Dose trays and covers may be recyclable.
Dosage and Administration
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 subcutaneous injection technique.
Methotrexate (MTX), glucocorticoids, salicylates, nonsteroidal anti-inflammatory drugs (NSAIDs), analgesics or other DMARDs may be continued during treatment with adalimumab. When treated with HUMIRA as monotherapy, some rheumatoid arthritis patients who experience a decrease in their response to HUMIRA 40 mg every other week, may benefit from an increase in dose intensity to 40 mg HUMIRA every week.
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.
Healthy volunteers and patients with rheumatoid arthritis displayed similar adalimumab pharmacokinetics.
The recommended dose of HUMIRA (adalimumab) for adult patients with psoriatic arthritis (PsA) is 40 mg administered every other week as a subcutaneous (s.c.) injection.
For the RA and PsA indications, available data suggest that the clinical response is usually achieved within 12 weeks of treatment. Continued therapy should be carefully reconsidered in a patient not responding within this time period.
Evidence from clinical studies and experience suggests that use of HUMIRA (adalimumab) in the geriatric population is not associated with differences in safety or effectiveness. A brief discussion can be found under Warnings and Precautions, Special Populations, Geriatrics (>65 years of age).
The recommended dose of HUMIRA (adalimumab) for patients with ankylosing spondylitis (AS) is 40 mg adalimumab administered every other week as a single dose via subcutaneous (s.c.) injection. Glucocorticoids, salicylates, nonsteroidal anti-inflammatory drugs, analgesics or disease modifying anti-rheumatic drugs can be continued during treatment with HUMIRA.
The recommended HUMIRA (adalimumab) induction dose regimen for adult patients with Crohn’s disease is 160 mg at Week 0 (dose can be administered as four subcutaneous (s.c.) injections in one day or as two subcutaneous (s.c.) injections per day for two consecutive days), followed by 80 mg at Week 2.
The recommended HUMIRA maintenance dose regimen for adult patients with Crohn’s disease is 40 mg every other week beginning at Week 4.
During treatment with HUMIRA, other concomitant therapies (e.g., corticosteroids and/or immunomodulatory agents) should be optimized.
For patients who experience a disease flare, dose escalation may be considered.
Some patients who have not responded by Week 4 (induction period) may benefit from continued maintenance therapy through Week 12. Available data suggest that the clinical response is usually achieved at Week 4 of treatment. Continued therapy should be carefully reconsidered in a patient not responding within this time period.
The use of HUMIRA in Crohn’s disease beyond one year has not been evaluated in controlled clinical studies.
No differences in immunoglobulin clearance would be expected among races. From limited data in non-Caucasians, no important kinetic differences were observed for adalimumab. Dosage adjustment is not required.
The solution in the syringe or Pen should be carefully inspected visually for particulate matter and discolouration prior to subcutaneous administration. If particulates and discolourations are noted, the product should not be used. HUMIRA does not contain preservatives; therefore, unused portions of drug remaining in the syringe should be discarded.
Note: The needle cover of the syringe contains a dry natural 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, according to the directions provided in the Information for the Patient.
Injection sites should be rotated and injections should never be given into areas where the skin is tender, bruised, red or hard (see Information for the Patient).
No pharmacokinetic data are available in patients with hepatic or renal impairment. No dose recommendation can be made.
The recommended dose of HUMIRA (adalimumab) for adult patients with psoriasis (Ps) is an initial dose of 80 mg administered subcutaneously, followed by 40 mg subcutaneously given every other week starting one week after the initial dose.
Continued therapy beyond 16 weeks should be carefully reconsidered in a patient not responding within this time period.
Patients who miss a dose of HUMIRA should be advised to inject this missed dose as soon as they become aware of it, and then follow with their next scheduled dose.
Safety and effectiveness in pediatric patients have not been established.
The recommended dose of HUMIRA (adalimumab) for adult patients with rheumatoid arthritis (RA) is 40 mg administered every other week as a subcutaneous (s.c.) injection.
Adverse Reactions
postoperative wound complication.
Because clinical trials are conducted under very specific conditions, the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.
pleural effusion, pneumonitis, bronchospasm, lung infiltration, pleurisy, respiratory failure.
psoriasis, pustular psoriasis, rash.
Number and Percentage of Subjects ≥1% Reporting Treatment-emergent Adverse Events Possibly or Probably Related to Study Drug in Controlled Psoriasis Studies (Studies I, II and III)
| System Organ Class (SOC) | Adalimumab
80 mg×1, then
40 mg s.c. eow
N=966
N (%) | Placebo + MTX
N=613
N (%) |
| Gastrointestinal Disorders |
| Nausea | 10 (1.0) | 11 (1.8) |
| General Disorders and Administration Site Conditions |
| Injection site reaction | 29 (3.0) | 9 (1.5) |
| Injection site irritation | 16 (1.7) | 6 (1.0) |
| Injection site pain | 14 (1.5) | 9 (1.5) |
| Fatigue | 10 (1.0) | 5 (0.8) |
| Infections and Infestations |
| Upper respiratory infection | 12 (1.2) | 3 (0.5) |
| Musculoskeletal and Connective Tissue Disorders |
| Arthralgia | 10 (1.0) | 3 (0.5) |
| Nervous System Disorders |
| Headache | 19 (2.0) | 14 (2.3) |
Formation of anti-adalimumab antibodies is associated with increased clearance and reduced efficacy of adalimumab. There is no apparent correlation between the presence of anti-adalimumab antibodies and adverse events.
Rheumatoid arthritis patients in Studies RA I, RA II, and RA III were tested at multiple time points for antibodies to adalimumab during the 6- to 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 methotrexate (MTX) had a lower rate of antibody development than patients on adalimumab monotherapy (1% versus 12 %). 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 immunogenicity of adalimumab long-term is unknown.
In patients with psoriatic arthritis, adalimumab antibodies were identified in 38/376 subjects (10%) treated with adalimumab. In patients not given concomitant methotrexate, the incidence was 13.5 % (24/178 subjects), compared to 7 % (14 of 198 subjects) when adalimumab was used as add-on to methotrexate.
In patients with ankylosing spondylitis antibodies were identified in 17/204 subjects (8.3%) treated with adalimumab. In patients not given concomitant methotrexate, the incidence was 16/185 (8.6%), compared to 1/19 (5.3%) when adalimumab was used as add-on to methotrexate.
In patients with Crohn’s disease, adalimumab antibodies were identified in 2.6% (7 of 269) of patients receiving adalimumab.
In patients with psoriasis, anti-adalimumab antibodies were identified in 77/920 subjects (8.4%) treated with adalimumab monotherapy.
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.
rheumatoid arthritis, arthritis, arthropathy, back pain, muscular weakness, musculoskeletal chest pain, osteitis, systemic lupus erythematosus.
pneumonia, arthritis bacterial, cellulitis, escherichia sepsis, perianal abscess, urinary tract infection, wound infection, sinusitis, bronchitis, cystitis, device related infection, diverticulitis, erysipelas, gastroenteritis, herpes virus infection, herpes zoster, histoplasmosis, infected skin ulcer, infection, lobar pneumonia, lower respiratory tract infection, meningitis viral, mycobacterium avium complex infection, necrotizing fasciitis, pneumonia pneumococcal, pyelonephritis, respiratory tract infection, sepsis, septic shock, tuberculosis, urosepsis, abscess, abscess limb.
cervical dysplasia, endometrial hyperplasia.
The data described below reflect exposure to HUMIRA (adalimumab) in 3046 patients, including more than 2000 patients exposed for 6 months, and more than 1500 exposed for more than one year (Studies RA I, RA II, RA III, RA IV, and RA V). Adalimumab was studied in placebo-controlled trials and in long-term follow-up studies for up to 60 months duration in patients with moderately to severely active rheumatoid arthritis who had failed previous DMARD therapy; the mean age was 54 years, 77% were female and 91% Caucasian (Studies RA I, RA II, RA III, RA IV). A further study (Study RA V) was in patients with recently diagnosed rheumatoid arthritis who had not previously been treated with methotrexate. Most patients received 40 mg adalimumab every other week.
reactivation of hepatitis B virus (HBV).
cutaneous vasculitis, Stevens-Johnson Syndrome, erythema multiforme, new onset or worsening of psoriasis (including palmoplantar pustular psoriasis).
circulatory collapse, rheumatoid vasculitis.
More cases of malignancy have been observed in HUMIRA-treated patients compared to control-treated patients in clinical trials (see Warnings and Precautions, Malignancies).
double stranded DNA antibody, hepatic enzyme increased.
lymphadenopathy, pancytopenia, agranulocytosis, eosinophilia, leukopenia, lymphocytosis, neutropenia, anaemia.
In the 15 controlled trials, 14% of patients treated with HUMIRA developed injection site reactions (erythema and/or itching, hemorrhage, pain or swelling), compared to 8% of patients receiving placebo or active control. Injection site reactions generally did not necessitate discontinuation of the medicinal product.
hepatosplenic T-cell lymphoma.
B-cell lymphoma, breast cancer, malignant melanoma in situ, metastases to liver, ovarian cancer, basal cell carcinoma, squamous cell carcinoma, testicular seminoma (pure).
Infrequent serious adverse drug reactions occurring at an incidence of less than 1% in patients treated with HUMIRA in Studies RA I to RA V, Studies PsA I and PsA II, Studies AS I and AS II, CD Maintenance Studies, and Ps Studies I to III:
The following post-market adverse drug reactions have been rarely reported:
There are no known laboratory tests that may be helpful in following the patient's response or in identifying possible adverse reactions.
Rheumatoid Arthritis Clinical Trials: In controlled rheumatoid arthritis clinical trials (RA Studies I-IV), elevations of ALT were similar in patients receiving adalimumab or placebo. In patients with early rheumatoid arthritis (disease duration of less than 3 years) (RA Study V), elevations of ALT were more common in the combination arm (HUMIRA/methotrexate) compared to the methotrexate monotherapy arm or the HUMIRA monotherapy arm.
Psoriatic Arthritis Clinical Trials: Elevations in ALT were more common in psoriatic arthritis patients compared with patients in rheumatoid arthritis clinical studies.
Crohn’s Disease Clinical Trials: In controlled clinical trials, elevations of ALT were similar in patients receiving adalimumab or placebo.
In all indications, patients with raised ALT were asymptomatic and in most cases, elevations were transient and resolved on continued treatment.
arrhythmia superventricular, cardiac arrest, palpitations.
chest pain, death, non-cardiac chest pain, pyrexia.
Patients had serum samples tested for autoantibodies at multiple time points in studies RA I to RA V. In those rheumatoid arthritis controlled trials, 11.9% of patients treated with adalimumab and 8.1% of placebo- or active control-treated patients who had negative baseline antinuclear antibody (ANA) titers, developed positive titers at Week 24. Two patients out of 3441 treated with adalimumab 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. The impact of long-term treatment with adalimumab on the development of autoimmune diseases is unknown.
interstitial lung disease, including pulmonary fibrosis.
anaphylaxis and angioneurotic edema (see Warnings and Precautions, Hypersensitivity Reactions).
thrombocytopenia (see Warnings and Precautions, Hematologic Events).
The most serious adverse reactions were (see Warnings and Precautions): serious infections, neurologic events, malignancies.
The most common adverse reaction in rheumatoid arthritis patients treated with HUMIRA (adalimumab) was injection site reactions. In the fifteen controlled trials for rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn’s disease, and psoriasis, 14% of patients treated with adalimumab developed injection site reactions (erythema and/or itching, hemorrhage, pain or swelling), compared to 8% of patients receiving control treatment. Most injection site reactions were described as mild and generally did not necessitate drug discontinuation.
The proportion of rheumatoid arthritis patients who discontinued treatment due to adverse events during the double-blind, placebo-controlled portion of rheumatoid arthritis Studies RA I, RA II, RA III, and RA IV was 7.0% for patients taking adalimumab, and 4.0% 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%).
Among patients with rheumatoid arthritis in placebo-controlled studies, deaths occurred in 8 of 1380 (0.58%) HUMIRA-treated patients compared to 1 of 690 (0.14%) placebo-treated patients. The rate of deaths in both treatment arms is less than expected in the normal population with a Standardized Mortality Ratio (SMR) of 0.87 (0.38, 1.72; 95% CI) in the adalimumab group and 0.25 (0.00, 1.37; 95% CI) in the placebo group.
HUMIRA has also been studied in 542 patients with early rheumatoid arthritis (disease duration less than 3 years) who were methotrexate (MTX) naïve (Study RA V). No new safety signals were seen in this patient population compared to the safety profile seen in HUMIRA Studies RA I to RA IV. In this study, deaths occurred in 5 of 542 (0.92%) HUMIRA-treated patients compared to 1 of 257 (0.39%) methotrexate-treated patients. The rate of deaths in both treatment arms is less than expected in the normal population with a Standardized Mortality Ratio of 0.57 (0.18, 1.32; 95% CI) in the adalimumab group and 0.22 (0.00, 1.23; 95% CI) in the methotrexate group.
HUMIRA has also been studied in 395 patients with psoriatic arthritis in two placebo-controlled studies and in an open-label extension study, in 393 patients with ankylosing spondylitis in two placebo-controlled studies and in over 1400 patients with Crohn’s disease in four placebo controlled and two open-label extension studies. The safety profile for patients with psoriatic arthritis treated with HUMIRA 40 mg every other week was similar to the safety profile seen in patients with rheumatoid arthritis, HUMIRA Studies RA I to RA V. During the controlled period of the psoriatic arthritis studies, no deaths occurred in the HUMIRA-treated or placebo-treated patients. During the psoriatic arthritis open-label study 2 deaths occurred in 382 patients with 795.7 patient-years of exposure. The rate of deaths is less than expected in the normal population with a Standardized Mortality Ratio (SMR) of 0.39 (0.04, 1.43; 95% CI).
Indications and Clinical Use
Evidence from clinical studies and experience suggests that use of adalimumab in the geriatric population is not associated with differences in safety or effectiveness. A brief discussion can be found under Warnings and Precautions, Special Populations, Geriatrics (>65 years of age).
reducing signs and symptoms and inducing and maintaining clinical remission in adult patients with moderately to severely active Crohn’s disease who have had an inadequate response to conventional therapy, including corticosteroids and/or immunosuppressants. HUMIRA is indicated for reducing signs and symptoms and inducing clinical remission in these patients if they have also lost response to or are intolerant to infliximab.
reducing signs and symptoms in patients with active ankylosing spondylitis who have had an inadequate response to conventional therapy.
Safety and effectiveness in pediatric patients have not been established.
treatment of adult patients with chronic moderate to severe psoriasis who are candidates for systemic therapy. For patients with chronic moderate plaque psoriasis, HUMIRA should be used after phototherapy has been shown to be ineffective or inappropriate.
reducing the signs and symptoms of active arthritis and inhibiting the progression of structural damage and improving the physical function in adult psoriatic arthritis patients. HUMIRA can be used in combination with methotrexate (MTX) in patients who do not respond adequately to methotrexate alone.
reducing the signs and symptoms, inducing major clinical response and clinical remission, inhibiting the progression of structural damage and improving physical function in adult patients with moderately to severely active rheumatoid arthritis. HUMIRA can be used alone or in combination with methotrexate (MTX) or other Disease-Modifying Anti-rheumatic Drugs (DMARDs).
When used as first-line treatment in recently diagnosed patients who have not been previously treated with methotrexate (MTX), HUMIRA should be given in combination with MTX. HUMIRA can be given as monotherapy in case of intolerance to MTX or when treatment with MTX is contraindicated.
Overdosage
For management of a suspected drug overdose, CPhA recommends that you contact your regional Poison Control Centre. See the eCPS Directories section for a list of Poison Control Centres.
The maximum tolerated dose of HUMIRA (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 Forms, Composition and Packaging
Each mL of sterile solution for subcutaneous administration contains: adalimumab 50 mg. Nonmedicinal ingredients: citric acid monohydrate, dibasic sodium phosphate dihydrate, mannitol, monobasic sodium phosphate dihydrate, polysorbate 80, sodium citrate, sodium chloride, sodium hydroxide (added as necessary to adjust pH) and water for injection. Cartons containing two dose trays and two alcohol pads. Each dose tray consists of a single-use pen containing 1 mL pre-filled glass syringe with a fixed 27 gauge ½ inch needle, providing 40 mg adalimumab dissolved in 0.8 mL sterile solution (50 mg/mL).
Each mL of sterile solution for subcutaneous administration contains: adalimumab 50 mg. Nonmedicinal ingredients: citric acid monohydrate, dibasic sodium phosphate dihydrate, mannitol, monobasic sodium phosphate dihydrate, polysorbate 80, sodium citrate, sodium chloride, sodium hydroxide (added as necessary to adjust pH) and water for injection. Cartons containing two dose trays: in addition to one alcohol pad, each dose tray consists of a single-dose, 1 mL pre-filled glass syringe with a fixed 27 gauge ½ inch needle, providing 40 mg adalimumab dissolved in 0.8 mL sterile solution (50 mg/mL).
Warnings and Precautions
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, Adverse Drug Reaction Overview, Autoantibodies).
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-E. coli (Ames) assay, respectively.
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.
However, for HUMIRA, the occurrence of lymphoma was rare, and the follow-up period of placebo patients was shorter than for patients receiving TNF-antagonist therapy. The size of the control group and limited duration of the controlled portions of studies precludes the ability to draw firm conclusions. Furthermore, there is an increased background lymphoma risk in rheumatoid arthritis patients with long-standing, highly active, inflammatory disease, which complicates the risk estimation.
In combining the controlled and uncontrolled open-label portions of these clinical trials with a median duration of approximately 1.7 years, including 6539 patients and over 16 000 patient-years of therapy, the observed rate of lymphomas is approximately 0.11/100 patient-years. This is approximately 3.0 fold higher than expected in the general population.
During the long-term open label trials with HUMIRA, the overall standard incidence ratio (SIR) of malignancies was 0.99 (95% CI; 0.81-1.20). With current knowledge in this area, a possible risk for development of lymphomas or other malignancies in patients treated with a TNF-antagonist cannot be excluded.
No studies have been conducted that include patients with a history of malignancy or that continue treatment in patients who develop malignancy while receiving HUMIRA. Additional caution should be exercised when considering HUMIRA treatment in these patients.
Very rare cases of Hepatitis B virus (HBV) reactivation have been associated with anti-TNF therapy. Clinically active HBV infection occurred following a latency period ranging from 3 to 20 months after initiation of therapy. In the majority of cases, patients were also taking other immunosuppressive drugs, including methotrexate, azathioprine, and/or corticosteroids. Hence, establishing a causal relationship to anti-TNF agents is confounded by the presence of these other medications. Where outcome information was provided, most patients were reported to have improved after antiviral treatment and/or discontinuation of the anti-TNF agent. However, fatal outcomes have also occurred in reported cases. Patients at risk of HBV infection should be evaluated for prior evidence of HBV infection before initiating anti-TNF therapy. Those identified as chronic carriers (i.e., surface antigen positive) should be monitored for signs and symptoms of active HBV infection throughout the course of therapy and for several months following discontinuation of therapy. Reactivation of HBV is not unique to anti- TNF-alpha agents and has been reported with other immunosuppressive drugs.
Use of TNF blocking agents, including HUMIRA, has been associated with rare cases with new onset or exacerbation of clinical symptoms and/or radiographic evidence of demyelinating disease, including multiple sclerosis. Prescribers should exercise caution in considering the use of adalimumab in patients with preexisting or recent-onset central nervous system demyelinating disorders.
The possibility exists for TNF blocking agents, including HUMIRA, to affect host defences against infections and malignancies since TNF mediates inflammation and modulates cellular immune responses. In a study of 64 patients with rheumatoid arthritis who were 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 Precautions and Adverse Reactions, Adverse Drug Reaction Overview, Infections and Malignancies).
As observed with other TNF blocking agents, tuberculosis (frequently disseminated or extrapulmonary at clinical presentation) associated with the administration of HUMIRA in clinical trials has been reported (see Warnings and Precautions, Serious Warnings and Precautions, Infections). 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.
Before initiation, during and after treatment with HUMIRA, patients should be evaluated for active or latent tuberculosis infection with a tuberculin skin test. Treatment of latent tuberculosis infections should be initiated prior to therapy with HUMIRA. When tuberculin skin testing is performed for latent tuberculosis infection, an induration size of 5 mm or greater should be considered positive, even if vaccinated previously with Bacille Calmette-Guerin (BCG).
The possibility of undetected latent tuberculosis should be considered especially in patients who have immigrated from or traveled to countries with a high prevalence of tuberculosis or who had close contact with a person with active tuberculosis. If latent infection is diagnosed, appropriate prophylaxis in accordance with the Canadian Tuberculosis Standards and Centers for Disease Control and Prevention guidelines should be instituted. Anti-tuberculosis therapy prior to initiating HUMIRA should also be considered in patients who have a negative test for latent tuberculosis but have risk factors for TB infection. The decision to initiate anti-tuberculosis therapy in these patients should only be made after taking into account both the risk for latent tuberculosis infection and the risks of anti-tuberculosis therapy. If necessary, consultation should occur with a physician with expertise in the treatment of tuberculosis. Active tuberculosis has developed in patients receiving HUMIRA whose screening for latent tuberculosis infection was negative, and some patients who have previously received treatment for latent or active tuberculosis have developed active tuberculosis while being treated with TNF blocking agents.
Patients receiving HUMIRA should be monitored for signs and symptoms of active tuberculosis, particularly because tests for latent tuberculosis infection may be falsely negative. The risk of false negative tuberculin skin test results should be considered especially in patients who are severely ill or immunocompromised. 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, and physicians should monitor for signs and symptoms of active tuberculosis, including patients who are tuberculosis skin test negative.
Safety and effectiveness in pediatric patients have not been established.
The extent of exposure in pregnancy during clinical trials is very limited, consisting only of individual cases.
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 adalimumab subcutaneously with methotrexate every week, or 373 times when given 40 mg adalimumab subcutaneously without methotrexate) 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.
A total of 519 rheumatoid arthritis patients 65 years of age and older, including 107 patients 75 years and older, received adalimumab in clinical studies RA I to RA IV. No overall differences in effectiveness were 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 the age of 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.
There are no known effects of adalimumab on labor or delivery.
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 HUMIRA. HUMIRA 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 HUMIRA in patients who have heart failure and monitor them carefully.
In a randomized, double-blind, placebo-controlled study in 226 adult rheumatoid arthritis patients treated with HUMIRA, antibody responses to concomitant pneumococcal and influenza vaccines were assessed. Protective antibody levels to the pneumococcal antigens were achieved by 86% of patients in the HUMIRA group compared to 82% in the placebo group. A total of 37% of HUMIRA-treated subjects and 40% of placebo-treated subjects achieved at least a 2-fold increase in antibody titer to at least three out of five pneumococcal antigens. In the same study, 98% of patients in the HUMIRA group and 95% in the placebo group achieved protective antibody levels to the influenza antigens. A total of 52% of HUMIRA-treated subjects and 63% of placebo-treated subjects achieved at least a 4-fold increase in antibody titer to at least two out of three influenza antigens.
Patients on HUMIRA may receive concurrent vaccinations, except for live vaccines. No data are available on the secondary transmission of infection by live vaccines in patients receiving HUMIRA.
Allergic reactions (e.g., allergic rash, anaphylactoid reaction, fixed drug reaction, non-specified drug reaction, urticaria) have been observed in approximately 1% of patients receiving HUMIRA in clinical trials (see Adverse Reactions). Serious allergic reactions, including anaphylaxis, have been reported very rarely following post-marketing HUMIRA administration. If an anaphylactic reaction or other serious allergic reactions occur, administration of adalimumab should be discontinued immediately and appropriate therapy initiated.
The needle cover of the syringe contains dry natural rubber (latex). This may cause severe allergic reactions in patients sensitive to this substance (see Dosage and Administration, Administration, Pre-filled Syringe or Pre-filled Pen).
HUMIRA has not been studied in these patient populations.
Failure to respond to treatment for Crohn’s disease may indicate the presence of fixed fibrotic stricture that may require surgical treatment. Available data suggest that HUMIRA does not worsen or cause strictures.
In the controlled portions of clinical trials of some TNF-blocking agent, including HUMIRA, more cases of malignancies have been observed among patients receiving those TNF blockers compared to control patients.
In the controlled and uncontrolled open-label portions of clinical trials of HUMIRA, the more frequently observed malignancies, other than lymphoma and non-melanoma skin cancer, were breast, colon, prostate, lung and melanoma.
There is no known interference between adalimumab and laboratory tests.
Rare reports of pancytopenia, including aplastic anemia, have been reported with TNF blocking agents. Adverse events of the hematologic system, including medically significant cytopenia (e.g., thrombocytopenia, leukopenia) have been infrequently reported with HUMIRA. The causal relationship of these reports to HUMIRA remains unclear. All patients should be advised to seek immediate medical attention if they develop signs and symptoms suggestive of blood dyscrasias (e.g., persistent fever, bruising, bleeding, pallor) while on HUMIRA. Discontinuation of HUMIRA therapy should be considered in patients with confirmed significant hematologic abnormalities.
Serious infections were seen in clinical studies with concurrent use of anakinra (an interleukin-1 antagonist) and another TNF blocking agent, etanercept, with no added benefit compared to etanercept alone. Because of the nature of the adverse events seen with the combination of etanercept and anakinra, similar toxicities may also result from the combination of anakinra and other TNF-blocking agents. Therefore, the combination of adalimumab and anakinra is not recommended (see Drug Interactions, Drug-Drug Interactions).
During the controlled portions of HUMIRA trials in patients with rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn’s disease, and psoriasis, malignancies, other than lymphoma and non-melanoma skin cancer, were observed at a rate (95% confidence interval) of 0.6 (0.4, 1.0)/100 patient-years among 3853 HUMIRA-treated patients versus a rate of 0.4 (0.2,1.0)/100 patient-years among 2183 control patients (median duration of treatment of 5.5 months for HUMIRA-treated patients and 3.9 months for control-treated patients).
During the controlled portions of HUMIRA rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn’s disease, and psoriasis trials, the rate (95% confidence interval) of non-melanoma skin cancers was 0.9 (0.57, 1.35)/100 patient-years among HUMIRA-treated patients and 0.3 (0.08, 0.80)/100 patient-years among control patients. Of these skin cancers, squamous cell carcinomas occurred at rates (95% confidence interval) of 0.2 (0.1, 0.6) per 100 patient-years among HUMIRA-treated patients and 0 per 100 patient-years among control patients. The rate (95% confidence interval) of lymphomas was 0.1 (0.02, 0.33) per 100 patient-years among HUMIRA treated patients and 0.1 (0.01, 0.61) per 100 patient-years among control patients.
In combining the controlled and uncontrolled open-label portions of these clinical trials with a median duration of approximately 1.7 years, including 6539 patients and over 16 000 patient-years of therapy, the observed rate of malignancies, other than lymphoma and non-melanoma skin cancers is approximately 1.0 per 100 patient years. The observed rate of non-melanoma skin cancers is approximately 0.9 per 100 patient-years.
All patients, and in particular psoriasis patients with a medical history of extensive immunosuppressant therapy or psoriasis patients with a history of Psoralen Ultra Violet A (PUVA) treatment should be examined for the presence of non-melanoma skin cancer prior to and during treatment with HUMIRA.
Opportunistic infections, including invasive fungal infections, have been observed in patients receiving HUMIRA. These infections are not consistently recognized in patients taking TNF-blockers and this has resulted in delays in appropriate treatment, sometimes resulting in fatal outcomes.
Patients taking TNF-blockers are more susceptible to serious fungal infections such as histoplasmosis, coccidioidomycosis, blastomycosis, aspergillosis, candidiasis, and other opportunistic infections. Those who develop fever, malaise, weight loss, sweats, cough, dyspnea, and/or pulmonary infiltrates, or other serious systemic illness with or without concomitant shock should promptly seek medical attention for a diagnostic evaluation.
For patients who reside or travel in regions where mycoses are endemic, invasive fungal infections should be suspected if they develop the signs and symptoms of possible systemic fungal infection. Patients are at risk of histoplasmosis and other invasive fungal infections and hence clinicians should consider empiric antifungal treatment until the pathogen(s) are identified. Antigen and antibody testing for histoplasmosis may be negative in some patients with active infection. When feasible, the decision to administer empiric antifungal therapy in these patients should be made in consultation with a physician with expertise in the diagnosis and treatment of invasive fungal infections and should take into account both the risk for severe fungal infection and the risks of antifungal therapy. Patients who develop a severe fungal infection are also advised to stop the TNF-blocker until infections are controlled.
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.
Storage and Stability
HUMIRA (adalimumab) must be refrigerated at 2-8°C. Store in original carton until time of administration. Do not freeze. Protect from light. Do not use beyond the expiration date.
Action and Clinical Pharmacology
Methotrexate (MTX) reduced adalimumab apparent clearance after single and multiple doses by 29% and 44%, respectively in patients with rheumatoid arthritis.
Adalimumab concentrations in the synovial fluid from five rheumatoid arthritis patients ranged from 31 to 96% of those in serum.
The single-dose pharmacokinetics of adalimumab in rheumatoid arthritis (RA) patients were determined in several studies with intravenous doses ranging from 0.25 to 10.0 mg/kg. The distribution volume (Vss) 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. The pharmacokinetics of adalimumab were linear over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose.
Adalimumab mean steady-state trough concentrations of approximately 5 µg/mL and 8 to 9 µg/mL, were observed in rheumatoid arthritis patients 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 in patients with rheumatoid arthritis revealed that there was a trend toward higher apparent clearance of adalimumab in the presence of anti-adalimumab antibodies.
In patients with psoriatic arthritis, adalimumab mean steady-state trough concentrations of adalimumab of 8.5-12 µg/mL and 6-10 µg/mL were observed in patients with and without methotrexate, respectively.
In patients with Crohn’s disease, the loading dose of 160 mg HUMIRA on Week 0 followed by 80 mg HUMIRA on Week 2 achieves mean serum adalimumab trough concentrations of approximately 12 µg/mL at Week 2 and Week 4. Mean steady-state trough levels of approximately 7 µg/mL were observed at Week 24 and Week 56 in Crohn’s disease patients who received a maintenance dose of 40 mg HUMIRA every other week.
Population pharmacokinetic analysis in patients with Crohn’s disease revealed a lower apparent clearance of HUMIRA as compared to patients with RA.
In patients with psoriasis, the mean steady-state trough concentration was 5 µg/mL during adalimumab 40 mg every other week monotherapy treatment.
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 subcutaneous administration of adalimumab 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.
Population pharmacokinetic analyses in patients with rheumatoid arthritis revealed that 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. Population pharmacokinetic analyses predicted minor increases in apparent clearance 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.
After treatment with HUMIRA (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. A rapid decrease in CRP levels was also observed in patients with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that produce tissue remodeling responsible for cartilage destruction were also decreased after adalimumab administration.
The serum adalimumab concentration-efficacy relationship as measured by the American College of Rheumatology response criteria (ACR 20) appears to follow the Hill Emax equation as shown in Figure 1.
Adalimumab has not been studied in children.
Population pharmacokinetic analyses in patients with rheumatoid arthritis revealed that there was a trend toward lower clearance with increasing age in patients aged 40 to >75 years.
No pharmacokinetic data are available in patients with hepatic impairment.
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, psoriatic arthritis and ankylosing spondylitis patients and play an important role in both pathologic inflammation and joint destruction that are hallmarks of these diseases. Increased levels of TNF are also found in psoriasis plaques, which contribute to the inflammatory response, to the proliferation and decreased maturation of keratinocytes and to the associated vascular damages that are characteristic of the disease.
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).
EC50 estimates ranging from 0.8 to 1.4 μg/mL were obtained through pharmacokinetic/pharmacodynamic modelling of swollen joint count, tender joint count and ACR 20 response from patients participating in Phase II and III trials.
No formal studies have been conducted to evaluate the metabolism and excretion of adalimumab. However, as adalimumab is an IgG1 antibody of entirely human sequences, it is expected that its metabolism and excretion would follow the course of other IgG molecules.
No differences in immunoglobulin clearance would be expected among races. From limited data in non-Caucasians, no important kinetic differences were observed for adalimumab.
No pharmacokinetic data are available in patients with renal impairment.
Contraindications
Patients with known hypersensitivity to adalimumab or any of its components. For a complete listing, see Dosage Forms, Composition and Packaging.
