These highlights do not include all the information needed to use HUMIRA safely and effectively. See full prescribing information for HUMIRA.HUMIRA (adalimumab) Injection, Solution for Subcutaneous useInitial U.S. Approval: 2002
Humira Information
Company Name Abbott Laboratories
Humira (Adalimumab) Dosage And Administration
Humira (Adalimumab) is administered by subcutaneous injection.
The recommended dose of Humira (Adalimumab) for pediatric patients 4 to 17 years of age with polyarticular juvenile idiopathic arthritis (JIA) is based on weight as shown below. MTX, glucocorticoids, NSAIDs, and/or analgesics may be continued during treatment with Humira (Adalimumab) .
Limited data are available for Humira (Adalimumab) treatment in pediatric patients with a weight below 15 kg.
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The recommended Humira (Adalimumab) dose regimen for adult patients with Crohn’s disease is 160 mg initially on Day 1 (given as four 40 mg injections in one day or as two 40 mg injections per day for two consecutive days), followed by 80 mg two weeks later (Day 15). Two weeks later (Day 29) begin a maintenance dose of 40 mg every other week. Aminosalicylates and/or corticosteroids may be continued during treatment with Humira (Adalimumab) . Azathioprine, 6-mercaptopurine (6-MP) [] or MTX may be continued during treatment with Humira (Adalimumab) if necessary.
Humira (Adalimumab) is intended for use under the guidance and supervision of a physician. A patient may self-inject Humira (Adalimumab) if a physician determines that it is appropriate, and with medical follow-up, as necessary, after proper training in subcutaneous injection technique.
The solution in the Humira (Adalimumab) Pen or prefilled syringe 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 (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 Humira (Adalimumab) Pen or prefilled syringe should be instructed to inject the full amount in the syringe (0.8 mL), which provides 40 mg of Humira (Adalimumab) , according to the directions provided in the Patient Instructions for Use
Patients (15 kg to
Injection sites should be rotated and injections should never be given into areas where the skin is tender, bruised, red or hard.
Humira (Adalimumab) Dosage Forms And Strengths
A single-use pen (Humira (Adalimumab) Pen), containing a 1 mL prefilled glass syringe with a fixed 27 gauge ½ inch needle, providing 40 mg (0.8 mL) of Humira (Adalimumab) .
A single-use, 1 mL prefilled glass syringe with a fixed 27 gauge ½ inch needle, providing 40 mg (0.8 mL) of Humira (Adalimumab) .
A single-use, 1 mL prefilled glass syringe with a fixed 27 gauge ½ inch needle, providing 20 mg (0.4 mL) of Humira (Adalimumab) .
Humira (Adalimumab) Contraindications
None.
Humira (Adalimumab) Adverse Reactions
The most serious adverse reactions were:
The most common adverse reaction with Humira (Adalimumab) was injection site reactions. In placebo-controlled trials, 20% of patients treated with Humira (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 reactions during the double-blind, placebo-controlled portion of Studies RA-I, RA-II, RA-III and RA-IV was 7% for patients taking Humira (Adalimumab) and 4% for placebo-treated patients. The most common adverse reactions leading to discontinuation of Humira (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.
In the controlled portions of the 32 global Humira (Adalimumab) clinical trials in adult patients with RA, PsA, AS, CD and Ps, the rate of serious infections was 4.7 per 100 patient-years in 6694 Humira (Adalimumab) -treated patients versus a rate of 2.7 per 100 patient-years in 3749 control-treated patients. Serious infections observed included pneumonia, septic arthritis, prosthetic and post-surgical infections, erysipelas, cellulitis, diverticulitis, and pyelonephritis
In 45 global controlled and uncontrolled clinical trials in RA, PsA, AS, CD and Ps that included 22,026 Humira (Adalimumab) -treated patients, the rate of reported active tuberculosis was 0.22 per 100 patient-years and the rate of positive PPD conversion was 0.07 per 100 patient-years. In a subgroup of 8940 U.S. and Canadian Humira (Adalimumab) -treated patients, the rate of reported active TB was 0.07 per 100 patient-years and the rate of positive PPD conversion was 0.06 per 100 patient-years. These trials included reports of miliary, lymphatic, peritoneal, and pulmonary TB. Most of the TB cases occurred within the first eight months after initiation of therapy and may reflect recrudescence of latent disease. In these global clinical trials, cases of serious opportunistic infections have been reported at an overall rate of 0.07 per 100 patient-years. Some cases of serious opportunistic infections and TB have been fatal
In the rheumatoid arthritis controlled trials, 12% of patients treated with Humira (Adalimumab) and 7% of placebo-treated patients that had negative baseline ANA titers developed positive titers at week 24. Two patients out of 3046 treated with Humira (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 Humira (Adalimumab) on the development of autoimmune diseases is unknown.
There have been reports of severe hepatic reactions including acute liver failure in patients receiving TNF-blockers. In controlled Phase 3 trials of Humira (Adalimumab) (40 mg SC every other week) in patients with RA, PsA, and AS with control period duration ranging from 4 to 104 weeks, ALT elevations ≥ 3 x ULN occurred in 3.5% of Humira (Adalimumab) -treated patients and 1.5% of control-treated patients. Since many of these patients in these trials were also taking medications that cause liver enzyme elevations (e.g., NSAIDS, MTX), the relationship between Humira (Adalimumab) and the liver enzyme elevations is not clear. In controlled Phase 3 trials of Humira (Adalimumab) (initial doses of 160 mg and 80 mg, or 80 mg and 40 mg on Days 1 and 15, respectively, followed by 40 mg every other week) in patients with Crohn’s disease with control period duration ranging from 4 to 52 weeks, ALT elevations ≥ 3 x ULN occurred in 0.9% of Humira (Adalimumab) -treated patients and 0.9% of control-treated patients. In controlled Phase 3 trials of Humira (Adalimumab) (initial dose of 80 mg then 40 mg every other week) in patients with plaque psoriasis with control period duration ranging from 12 to 24 weeks, ALT elevations ≥ 3 x ULN occurred in 1.8% of Humira (Adalimumab) -treated patients and 1.8% of control-treated patients.
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 Humira (Adalimumab) developed low-titer antibodies to adalimumab at least once during treatment, which were neutralizing . Patients treated with concomitant methotrexate had a lower rate of antibody development than patients on Humira (Adalimumab) monotherapy (1% versus 12%). No apparent correlation of antibody development to adverse reactions 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 (Adalimumab) is unknown.
In patients with juvenile idiopathic arthritis, adalimumab antibodies were identified in 16% of Humira (Adalimumab) -treated patients. In patients receiving concomitant methotrexate, the incidence was 6% compared to 26% with Humira (Adalimumab) monotherapy.
In patients with ankylosing spondylitis, the rate of development of antibodies to adalimumab in Humira (Adalimumab) -treated patients was comparable to patients with rheumatoid arthritis. In patients with psoriatic arthritis, the rate of antibody development in patients receiving Humira (Adalimumab) monotherapy was comparable to patients with rheumatoid arthritis; however, in patients receiving concomitant methotrexate the rate was 7% compared to 1% in rheumatoid arthritis. In patients with Crohn's disease, the rate of antibody development was 3%. In patients with plaque psoriasis, the rate of antibody development with Humira (Adalimumab) monotherapy was 8%. However, due to the limitation of the assay conditions, antibodies to adalimumab could be detected only when serum adalimumab levels were
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. The observed incidence of antibody (including neutralizing antibody) positivity in an assay is highly dependent on several factors including assay sensitivity and specificity, assay methodology, 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.
The data described below reflect exposure to Humira (Adalimumab) in 2468 patients, including 2073 exposed for 6 months, 1497 exposed for greater than one year and 1380 in adequate and well-controlled studies (Studies RA-I, RA-II, RA-III, and RA-IV). Humira (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 Humira (Adalimumab) every other week.
Table 1 summarizes reactions reported at a rate of at least 5% in patients treated with Humira (Adalimumab) 40 mg every other week compared to placebo and with an incidence higher than placebo. In Study RA-III, the types and frequencies of adverse reactions in the second year open-label extension were similar to those observed in the one-year double-blind portion.
Other infrequent serious adverse reactions that do not appear in the Warnings and Precautions or Adverse Reaction sections that occurred at an incidence of less than 5% in Humira (Adalimumab) -treated patients in RA studies were:
Body As A Whole:
Cardiovascular System:
Digestive System:
Endocrine System:
Hemic And Lymphatic System:
Metabolic And Nutritional Disorders:
Musculo-Skeletal System:
Neoplasia:
Nervous System:
Respiratory System:
Special Senses:
Thrombosis:
Urogenital System:
In general, the adverse reactions in the Humira (Adalimumab) -treated pediatric patients in the juvenile idiopathic arthritis (JIA) trial were similar in frequency and type to those seen in adult patients . Important findings and differences from adults are discussed in the following paragraphs.
Humira (Adalimumab) was studied in 171 pediatric patients, 4 to 17 years of age, with polyarticular JIA. Severe adverse reactions reported in the study included neutropenia, streptococcal pharyngitis, increased aminotransferases, herpes zoster, myositis, metrorrhagia, appendicitis. Serious infections were observed in 4% of patients within approximately 2 years of initiation of treatment with Humira (Adalimumab) and included cases of herpes simplex, pneumonia, urinary tract infection, pharyngitis, and herpes zoster.
A total of 45% of children experienced an infection while receiving Humira (Adalimumab) with or without concomitant MTX in the first 16 weeks of treatment. The types of infections reported in Humira (Adalimumab) -treated patients were generally similar to those commonly seen in JIA patients who are not treated with TNF blockers. Upon initiation of treatment, the most common adverse reactions occurring in the pediatric population treated with Humira (Adalimumab) were injection site pain and injection site reaction (19% and 16%, respectively). A less commonly reported adverse event in children receiving Humira (Adalimumab) was granuloma annulare which did not lead to discontinuation of Humira (Adalimumab) treatment.
In the first 48 weeks of treatment, non-serious hypersensitivity reactions were seen in approximately 6% of children and included primarily localized allergic hypersensitivity reactions and allergic rash.
Isolated mild to moderate elevations of liver aminotransferases (ALT more common than AST) were observed in children with JIA exposed to Humira (Adalimumab) alone; liver enzyme test elevations were more frequent among those treated with the combination of Humira (Adalimumab) and MTX than those treated with Humira (Adalimumab) alone. In general, these elevations did not lead to discontinuation of Humira (Adalimumab) treatment.
In the JIA trial, 10% of patients treated with Humira (Adalimumab) who had negative baseline anti-dsDNA antibodies developed positive titers after 48 weeks of treatment. No patient developed clinical signs of autoimmunity during the clinical trial.
Approximately 15% of children treated with Humira (Adalimumab) developed mild-to-moderate elevations of creatine phosphokinase (CPK). Elevations exceeding 5 times the upper limit of normal were observed in several patients. CPK levels decreased or returned to normal in all patients. Most patients were able to continue Humira (Adalimumab) without interruption.
Humira (Adalimumab) has been studied in 395 patients with psoriatic arthritis (PsA) in two placebo-controlled trials and in an open label study and in 393 patients with ankylosing spondylitis (AS) in two placebo-controlled studies. The safety profile for patients with PsA and AS treated with Humira (Adalimumab) 40 mg every other week was similar to the safety profile seen in patients with RA, Humira (Adalimumab) Studies RA-I through IV.
Humira (Adalimumab) has been studied in 1478 patients with Crohn’s disease in four placebo-controlled and two open-label extension studies. The safety profile for patients with Crohn’s disease treated with Humira (Adalimumab) was similar to the safety profile seen in patients with RA.
Humira (Adalimumab) has been studied in 1696 patients with plaque psoriasis in placebo-controlled and open-label extension studies. The safety profile for patients with plaque psoriasis treated with Humira (Adalimumab) was similar to the safety profile seen in patients with RA with the following exceptions. In the placebo-controlled portions of the clinical trials in plaque psoriasis patients, Humira (Adalimumab) -treated patients had a higher incidence of arthralgia when compared to controls (3% 1%).
Adverse reactions have been reported during post-approval use of Humira (Adalimumab) . Because these reactions 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 Humira (Adalimumab) exposure.
Gastrointestinal disorders: Diverticulitis, large bowel perforations including perforations associated with diverticulitis and appendiceal perforations associated with appendicitis, pancreatitis
Respiratory disorders: Interstitial lung disease, including pulmonary fibrosis
Skin reactions: Stevens Johnson Syndrome, cutaneous vasculitis, erythema multiforme, new or worsening psoriasis (all sub-types including pustular and palmoplantar)
Vascular disorders: Systemic vasculitis
Humira (Adalimumab) Use In Specific Populations
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 subcutaneously with methotrexate every week or 373 times human AUC when given 40 mg 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 (Adalimumab) should be used during pregnancy only if clearly needed.
Safety and efficacy of Humira (Adalimumab) in pediatric patients for uses other than juvenile idiopathic arthritis (JIA) have not been established.
Juvenile Idiopathic Arthritis
In the JIA trial, Humira (Adalimumab) was shown to reduce signs and symptoms of active polyarticular JIA in patients 4 to 17 years of age . Humira (Adalimumab) has not been studied in children less than 4 years of age, and there are limited data on Humira (Adalimumab) treatment in children with weight
The safety of Humira (Adalimumab) in pediatric patients in the JIA trial was generally similar to that observed in adults with certain exceptions .
Post-marketing cases of malignancies, some fatal, have been reported among children, adolescents, and young adults who received treatment with TNF-blockers including Humira (Adalimumab) .
Humira (Adalimumab) Overdosage
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.
Humira (Adalimumab) Description
Humira (Adalimumab) is a recombinant human IgG1 monoclonal antibody specific for human tumor necrosis factor (TNF). Humira (Adalimumab) 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. 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 (Adalimumab) is supplied as a sterile, preservative-free solution of adalimumab for subcutaneous administration. The drug product is supplied as either a single-use, prefilled pen (Humira (Adalimumab) Pen) or as a single-use, 1 mL prefilled glass syringe. Enclosed within the pen is a single-use, 1 mL prefilled glass syringe. The solution of Humira (Adalimumab) is clear and colorless, with a pH of about 5.2.
Each prefilled syringe delivers 0.8 mL (40 mg) of drug product. Each 0.8 mL of Humira (Adalimumab) 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.
Each pediatric prefilled syringe delivers 0.4 mL (20 mg) of drug product. Each 0.4 mL of Humira (Adalimumab) contains 20 mg adalimumab, 2.47 mg sodium chloride, 0.34 mg monobasic sodium phosphate dihydrate, 0.61 mg dibasic sodium phosphate dihydrate, 0.12 mg sodium citrate, 0.52 mg citric acid monohydrate, 4.8 mg mannitol, 0.4 mg polysorbate 80, and Water for Injection, USP. Sodium hydroxide added as necessary to adjust pH.
Humira (Adalimumab) Clinical Pharmacology
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 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, including juvenile idiopathic arthritis, psoriatic arthritis, and ankylosing spondylitis patients and play an important role in both the pathologic inflammation and the joint destruction that are hallmarks of these diseases. Increased levels of TNF are also found in psoriasis (Ps) plaques. In plaque psoriasis, treatment with Humira (Adalimumab) may reduce the epidermal thickness and infiltration of inflammatory cells. The relationship between these pharmacodynamic activities and the mechanism(s) by which Humira (Adalimumab) exerts its clinical effects is unknown.
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 IC of 1-2 X 10M).
The maximum serum concentration (C) and the time to reach the maximum concentration (T) were 4.7 ± 1.6 µg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of Humira (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.
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 mg/kg. The distribution volume (V) 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 to 96% of those in serum.
In RA patients receiving 40 mg Humira (Adalimumab) every other week, 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. MTX reduced adalimumab apparent clearance after single and multiple dosing by 29% and 44% respectively, in patients with RA. Mean 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.
Adalimumab mean steady-state trough concentrations were slightly higher in psoriatic arthritis patients treated with 40 mg Humira (Adalimumab) every other week (6 to 10 µg/mL and 8.5 to 12 µg/mL, without and with MTX, respectively) compared to the concentrations in RA patients treated with the same dose.
The pharmacokinetics of adalimumab in patients with ankylosing spondylitis were similar to those in patients with RA.
In patients with Crohn’s disease, the loading dose of 160 mg Humira (Adalimumab) on Week 0 followed by 80 mg Humira (Adalimumab) on Week 2 achieves mean serum adalimumab trough levels 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 after receiving a maintenance dose of 40 mg Humira (Adalimumab) every other week.
In patients with plaque psoriasis, the mean steady-state trough concentration was approximately 5 to 6 µg/mL during adalimumab 40 mg every other week monotherapy treatment.
Population pharmacokinetic analyses in patients with RA 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 RA patients receiving doses lower than the recommended dose and in RA 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.
In subjects with juvenile idiopathic arthritis (4 to 17 years of age), the mean steady-state trough serum adalimumab concentrations for subjects weighing
Humira (Adalimumab) Clinical Studies
The efficacy and safety of Humira (Adalimumab) were assessed in five randomized, double-blind studies in patients ≥18 years of age with active rheumatoid arthritis diagnosed according to American College of Rheumatology (ACR) criteria. Patients had at least 6 swollen and 9 tender joints. Humira (Adalimumab) was administered subcutaneously in combination with methotrexate (MTX) (12.5 to 25 mg, Studies RA-I, RA-III and RA-V) or as monotherapy (Studies RA-II and RA-V) or with other disease-modifying anti-rheumatic drugs (DMARDs) (Study RA-IV).
Study RA-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 (Adalimumab) or placebo were given every other week for 24 weeks.
Study RA-II evaluated 544 patients who had failed therapy with at least one DMARD. Doses of placebo, 20 or 40 mg of Humira (Adalimumab) were given as monotherapy every other week or weekly for 26 weeks.
Study RA-III evaluated 619 patients who had an inadequate response to MTX. Patients received placebo, 40 mg of Humira (Adalimumab) every other week with placebo injections on alternate weeks, or 20 mg of Humira (Adalimumab) weekly for up to 52 weeks. Study RA-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 Humira (Adalimumab) was administered every other week for up to 5 years.
Study RA-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 (Adalimumab) or placebo every other week for 24 weeks.
Study RA-V evaluated 799 patients with moderately to severely active rheumatoid arthritis of less than 3 years duration who were ≥18 years old and MTX naïve. Patients were randomized to receive either MTX (optimized to 20 mg/week by week 8), Humira (Adalimumab) 40 mg every other week or Humira (Adalimumab) /MTX combination therapy for 104 weeks. Patients were evaluated for signs and symptoms, and for radiographic progression of joint damage. The median disease duration among patients enrolled in the study was 5 months. The median MTX dose achieved was 20 mg.
The percent of Humira (Adalimumab) treated patients achieving ACR 20, 50 and 70 responses in Studies RA-II and III are shown in Table 2.
The results of Study RA-I were similar to Study RA-III; patients receiving Humira (Adalimumab) 40 mg every other week in Study RA-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
The results of the components of the ACR response criteria for Studies RA-II and RA-III are shown in Table 3. ACR response rates and improvement in all components of ACR response were maintained to week 104. Over the 2 years in Study RA-III, 20% of Humira (Adalimumab) patients receiving 40 mg every other week (EOW) achieved a major clinical response, defined as maintenance of an ACR 70 response over a 6-month period. ACR responses were maintained in similar proportions of patients for up to 5 years with continuous Humira (Adalimumab) treatment in the open-label portion of Study RA-III.
The time course of ACR 20 response for Study RA-III is shown in Figure 1.
In Study RA-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 RA-I and Study RA-II were similar.
Figure 1. Study RA-III ACR 20 Responses over 52 Weeks
In Study RA-IV, 53% of patients treated with Humira (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
In Study RA-V with MTX naïve patients with recent onset rheumatoid arthritis, the combination treatment with Humira (Adalimumab) plus MTX led to greater percentages of patients achieving ACR responses than either MTX monotherapy or Humira (Adalimumab) monotherapy at Week 52 and responses were sustained at Week 104 (see Table 4).
At Week 52, all individual components of the ACR response criteria for Study RA-V improved in the Humira (Adalimumab) /MTX group and improvements were maintained to Week 104.
In Study RA-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 5. Humira (Adalimumab) /MTX treated patients demonstrated less radiographic progression than patients receiving MTX alone at 52 weeks.
In the open-label extension of Study RA-III, 77% of the original patients treated with any dose of Humira (Adalimumab) were evaluated radiographically at 2 years. Patients maintained inhibition of structural damage, as measured by the TSS. Fifty-four percent had no progression of structural damage as defined by a change in the TSS of zero or less. Fifty-five percent (55%) of patients originally treated with 40 mg Humira (Adalimumab) every other week have been evaluated radiographically at 5 years. Patients had continued inhibition of structural damage with 50% showing no progression of structural damage defined by a change in the TSS of zero or less.
In Study RA-V, structural joint damage was assessed as in Study RA-III. Greater inhibition of radiographic progression, as assessed by changes in TSS, erosion score and JSN was observed in the Humira (Adalimumab) /MTX combination group as compared to either the MTX or Humira (Adalimumab) monotherapy group at Week 52 as well as at Week 104 (see Table 6).
In studies RA-I through IV, Humira (Adalimumab) showed significantly greater improvement than placebo in the disability index of Health Assessment Questionnaire (HAQ-DI) 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 RA-III, the mean (95% CI) improvement in HAQ-DI from baseline at week 52 was 0.60 (0.55, 0.65) for the Humira (Adalimumab) patients and 0.25 (0.17, 0.33) for placebo/MTX (p
In Study RA-V, the HAQ-DI and the physical component of the SF-36 showed greater improvement (p
The safety and efficacy of Humira (Adalimumab) were assessed in a multicenter, randomized, withdrawal, double-blind, parallel-group study in 171 children (4 to 17 years of age) with polyarticular juvenile idiopathic arthritis (JIA). In the study, the patients were stratified into two groups: MTX-treated or non-MTX-treated. All subjects had to show signs of active moderate or severe disease despite previous treatment with NSAIDs, analgesics, corticosteroids, or DMARDS. Subjects who received prior treatment with any biologic DMARDS were excluded from the study.
The study included four phases: an open-label lead in phase (OL-LI; 16 weeks), a double-blind randomized withdrawal phase (DB; 32 weeks), an open-label extension phase (OLE-BSA; up to 136 weeks), and an open-label fixed dose phase (OLE-FD; 16 weeks). In the first three phases of the study, Humira (Adalimumab) was administered based on body surface area at a dose of 24 mg/m up to a maximum total body dose of 40 mg subcutaneously (SC) every other week. In the OLE-FD phase, the patients were treated with 20 mg of Humira (Adalimumab) SC every other week if their weight was less than 30 kg and with 40 mg of Humira (Adalimumab) SC every other week if their weight was 30 kg or greater. Patients remained on stable doses of NSAIDs and or prednisone (≤0.2 mg/kg/day or 10 mg/day maximum).
Patients demonstrating a Pediatric ACR 30 response at the end of OL-LI phase were randomized into the double blind (DB) phase of the study and received either Humira (Adalimumab) or placebo every other week for 32 weeks or until disease flare. Disease flare was defined as a worsening of ≥30% from baseline in ≥3 of 6 Pediatric ACR core criteria, ≥2 active joints, and improvement of >30% in no more than 1 of the 6 criteria. After 32 weeks or at the time of disease flare during the DB phase, patients were treated in the open-label extension phase based on the BSA regimen (OLE-BSA), before converting to a fixed dose regimen based on body weight (OLE-FD phase).
At the end of the 16-week OL-LI phase, 94% of the patients in the MTX stratum and 74% of the patients in the non-MTX stratum were Pediatric ACR 30 responders. In the DB phase significantly fewer patients who received Humira (Adalimumab) experienced disease flare compared to placebo, both without MTX (43% 71%) and with MTX (37% 65%). More patients treated with Humira (Adalimumab) continued to show pediatric ACR 30/50/70 responses at Week 48 compared to patients treated with placebo. Pediatric ACR responses were maintained for up to two years in the OLE phase in patients who received Humira (Adalimumab) throughout the study.
The safety and efficacy of Humira (Adalimumab) was assessed in two randomized, double-blind, placebo controlled studies in 413 patients with psoriatic arthritis. Upon completion of both studies, 383 patients enrolled in an open-label extension study, in which 40 mg Humira (Adalimumab) was administered every other week.
Study PsA-I enrolled 313 adult patients with moderately to severely active psoriatic arthritis (>3 swollen and >3 tender joints) who had an inadequate response to NSAID therapy in one of the following forms: (1) distal interphalangeal (DIP) involvement (N=23); (2) polyarticular arthritis (absence of rheumatoid nodules and presence of plaque psoriasis) (N=210); (3) arthritis mutilans (N=1); (4) asymmetric psoriatic arthritis (N=77); or (5) ankylosing spondylitis-like (N=2). Patients on MTX therapy (158 of 313 patients) at enrollment (stable dose of ≤30 mg/week for >1 month) could continue MTX at the same dose. Doses of Humira (Adalimumab) 40 mg or placebo every other week were administered during the 24-week double-blind period of the study.
Compared to placebo, treatment with Humira (Adalimumab) resulted in improvements in the measures of disease activity (see Tables 7 and 8). Among patients with psoriatic arthritis who received Humira (Adalimumab) , the clinical responses were apparent in some patients at the time of the first visit (two weeks) and were maintained up to 88 weeks in the ongoing open-label study. Similar responses were seen in patients with each of the subtypes of psoriatic arthritis, although few patients were enrolled with the arthritis mutilans and ankylosing spondylitis-like subtypes. Responses were similar in patients who were or were not receiving concomitant MTX therapy at baseline.
Patients with psoriatic involvement of at least three percent body surface area (BSA) were evaluated for Psoriatic Area and Severity Index (PASI) responses. At 24 weeks, the proportions of patients achieving a 75% or 90% improvement in the PASI were 59% and 42% respectively, in the Humira (Adalimumab) group (N=69), compared to 1% and 0% respectively, in the placebo group (N=69) (p
Similar results were seen in an additional, 12-week study in 100 patients with moderate to severe psoriatic arthritis who had suboptimal response to DMARD therapy as manifested by ≥3 tender joints and ≥3 swollen joints at enrollment.
Radiographic changes were assessed in the psoriatic arthritis studies. Radiographs of hands, wrists, and feet were obtained at baseline and Week 24 during the double-blind period when patients were on Humira (Adalimumab) or placebo and at Week 48 when all patients were on open-label Humira (Adalimumab) . A modified Total Sharp Score (mTSS), which included distal interphalangeal joints (i.e., not identical to the TSS used for rheumatoid arthritis), was used by readers blinded to treatment group to assess the radiographs.
Humira (Adalimumab) -treated patients demonstrated greater inhibition of radiographic progression compared to placebo-treated patients and this effect was maintained at 48 weeks (see Table 9).
In Study PsA-I, physical function and disability were assessed using the HAQ Disability Index (HAQ-DI) and the SF-36 Health Survey. Patients treated with 40 mg of Humira (Adalimumab) every other week showed greater improvement from baseline in the HAQ-DI score (mean decreases of 47% and 49% at Weeks 12 and 24 respectively) in comparison to placebo (mean decreases of 1% and 3% at Weeks 12 and 24 respectively). At Weeks 12 and 24, patients treated with Humira (Adalimumab) showed greater improvement from baseline in the SF-36 Physical Component Summary score compared to patients treated with placebo, and no worsening in the SF-36 Mental Component Summary score. Improvement in physical function based on the HAQ-DI was maintained for up to 84 weeks through the open-label portion of the study.
The safety and efficacy of Humira (Adalimumab) 40 mg every other week was assessed in 315 adult patients in a randomized, 24 week double-blind, placebo-controlled study in patients with active ankylosing spondylitis (AS) who had an inadequate response to glucocorticoids, NSAIDs, analgesics, methotrexate or sulfasalazine. Active AS was defined as patients who fulfilled at least two of the following three criteria: (1) a Bath AS disease activity index (BASDAI) score ≥4 cm, (2) a visual analog score (VAS) for total back pain ≥ 40 mm, and (3) morning stiffness ≥ 1 hour. The blinded period was followed by an open-label period during which patients received Humira (Adalimumab) 40 mg every other week subcutaneously for up to an additional 28 weeks.
Improvement in measures of disease activity was first observed at Week 2 and maintained through 24 weeks as shown in Figure 2 and Table 10.
Responses of patients with total spinal ankylosis (n=11) were similar to those without total ankylosis.
Figure 2. ASAS 20 Response By Visit, Study AS-I
At 12 weeks, the ASAS 20/50/70 responses were achieved by 58%, 38%, and 23%, respectively, of patients receiving Humira (Adalimumab) , compared to 21%, 10%, and 5% respectively, of patients receiving placebo (p
A greater proportion of patients treated with Humira (Adalimumab) (22%) achieved a low level of disease activity at 24 weeks (defined as a value
A second randomized, multicenter, double-blind, placebo-controlled study of 82 patients with ankylosing spondylitis showed similar results.
Patients treated with Humira (Adalimumab) achieved improvement from baseline in the Ankylosing Spondylitis Quality of Life Questionnaire (ASQoL) score (-3.6 -1.1) and in the Short Form Health Survey (SF-36) Physical Component Summary (PCS) score (7.4 1.9) compared to placebo-treated patients at Week 24.
The safety and efficacy of multiple doses of Humira (Adalimumab) were assessed in adult patients with moderately to severely active Crohn’s disease (Crohn’s Disease Activity Index (CDAI) ≥ 220 and ≤ 450) in randomized, double-blind, placebo-controlled studies. Concomitant stable doses of aminosalicylates, corticosteroids, and/or immunomodulatory agents were permitted, and 79% of patients continued to receive at least one of these medications.
Induction of clinical remission (defined as CDAI
In the second induction study, Study CD-II, 325 patients who had lost response to, or were intolerant to, previous infliximab therapy were randomized to receive either 160 mg Humira (Adalimumab) at Week 0 and 80 mg at Week 2, or placebo at Weeks 0 and 2. Clinical results were assessed at Week 4.
Maintenance of clinical remission was evaluated in Study CD-III. In this study, 854 patients with active disease received open-label Humira (Adalimumab) , 80 mg at week 0 and 40 mg at Week 2. Patients were then randomized at Week 4 to 40 mg Humira (Adalimumab) every other week, 40 mg Humira (Adalimumab) every week, or placebo. The total study duration was 56 weeks. Patients in clinical response (decrease in CDAI ≥70) at Week 4 were stratified and analyzed separately from those not in clinical response at Week 4.
A greater percentage of the patients treated with 160/80 mg Humira (Adalimumab) achieved induction of clinical remission versus placebo at Week 4 regardless of whether the patients were TNF blocker naïve (CD-I), or had lost response to or were intolerant to infliximab (CD-II) (see Table 11).
In Study CD-III at Week 4, 58% (499/854) of patients were in clinical response and were assessed in the primary analysis. At Weeks 26 and 56, greater proportions of patients who were in clinical response at Week 4 achieved clinical remission in the Humira (Adalimumab) 40 mg every other week maintenance group compared to patients in the placebo maintenance group (see Table 12). The group that received Humira (Adalimumab) therapy every week did not demonstrate significantly higher remission rates compared to the group that received Humira (Adalimumab) every other week.
Of those in response at Week 4 who attained remission during the study, patients in the Humira (Adalimumab) every other week group maintained remission for a longer time than patients in the placebo maintenance group. Among patients who were not in response by Week 12, therapy continued beyond 12 weeks did not result in significantly more responses.
The safety and efficacy of Humira (Adalimumab) were assessed in randomized, double-blind, placebo-controlled studies in 1696 adult patients with moderate to severe chronic plaque psoriasis who were candidates for systemic therapy or phototherapy.
Study Ps-I evaluated 1212 patients with chronic plaque psoriasis with ≥10% body surface area (BSA) involvement, Physician’s Global Assessment (PGA) of at least moderate disease severity, and Psoriasis Area and Severity Index (PASI) ≥12 within three treatment periods. In period A, patients received placebo or Humira (Adalimumab) at an initial dose of 80 mg at Week 0 followed by a dose of 40 mg every other week starting at Week 1. After 16 weeks of therapy, patients who achieved at least a PASI 75 response at Week 16, defined as a PASI score improvement of at least 75% relative to baseline, entered period B and received open-label 40 mg Humira (Adalimumab) every other week. After 17 weeks of open label therapy, patients who maintained at least a PASI 75 response at Week 33 and were originally randomized to active therapy in period A were re-randomized in period C to receive 40 mg Humira (Adalimumab) every other week or placebo for an additional 19 weeks. Across all treatment groups the mean baseline PASI score was 19 and the baseline Physician’s Global Assessment score ranged from “moderate” (53%) to “severe” (41%) to “very severe” (6%).
Study Ps-II evaluated 99 patients randomized to Humira (Adalimumab) and 48 patients randomized to placebo with chronic plaque psoriasis with ≥10% BSA involvement and PASI ≥12. Patients received placebo, or an initial dose of 80 mg Humira (Adalimumab) at Week 0 followed by 40 mg every other week starting at Week 1 for 16 weeks. Across all treatment groups the mean baseline PASI score was 21 and the baseline PGA score ranged from “moderate” (41%) to “severe” (51%) to “very severe” (8%).
Studies Ps-I and II evaluated the proportion of patients who achieved “clear” or “minimal” disease on the 6-point PGA scale and the proportion of patients who achieved a reduction in PASI score of at least 75% (PASI 75) from baseline at Week 16 (see Table 13 and 14).
Additionally, Study Ps-I evaluated the proportion of subjects who maintained a PGA of “clear” or “minimal” disease or a PASI 75 response after Week 33 and on or before Week 52.
Additionally, in Study Ps-I, subjects on Humira (Adalimumab) who maintained a PASI 75 were re-randomized to Humira (Adalimumab) (N = 250) or placebo (N = 240) at Week 33. After 52 weeks of treatment with Humira (Adalimumab) , more patients on Humira (Adalimumab) maintained efficacy when compared to subjects who were re-randomized to placebo based on maintenance of PGA of “clear” or “minimal” disease (68% 28%) or a PASI 75 (79% 43%).
A total of 347 stable responders participated in a withdrawal and retreatment evaluation in an open-label extension study. Median time to relapse (decline to PGA “moderate” or worse) was approximately 5 months. During the withdrawal period, no subject experienced transformation to either pustular or erythrodermic psoriasis. A total of 178 subjects who relapsed re-initiated treatment with 80 mg of Humira (Adalimumab) , then 40 mg eow beginning at week 1. At week 16, 69% (123/178) of subjects had a response of PGA “clear” or “minimal”.
Humira (Adalimumab) How Supplied/storage And Handling
Humira (Adalimumab) is supplied in prefilled syringes as a preservative-free, sterile solution for subcutaneous administration. The following packaging configurations are available.
Humira (Adalimumab) is dispensed in a carton containing two alcohol preps and two dose trays. Each dose tray consists of a single-use pen, containing a 1 mL prefilled glass syringe with a fixed 27 gauge ½ inch needle, providing 40 mg (0.8 mL) of Humira (Adalimumab) . The NDC number is 0074-4339-02.
Humira (Adalimumab) is dispensed in a carton containing 6 alcohol preps and 6 dose trays (Crohn’s Disease Starter Package). Each dose tray consists of a single-use pen, containing a 1 mL prefilled glass syringe with a fixed 27 gauge ½ inch needle, providing 40 mg (0.8 mL) of Humira (Adalimumab) . The NDC number is 0074-4339-06.
Humira (Adalimumab) is dispensed in a carton containing 4 alcohol preps and 4 dose trays (Psoriasis Starter Package). Each dose tray consists of a single-use pen, containing a 1 mL prefilled glass syringe with a fixed 27 gauge ½ inch needle, providing 40 mg (0.8 mL) of Humira (Adalimumab) . The NDC number is 0074-4339-07.
Humira (Adalimumab) is dispensed in a carton containing two alcohol preps and two dose trays. Each dose tray consists of a single-use, 1 mL prefilled glass syringe with a fixed 27 gauge ½ inch needle, providing 40 mg (0.8 mL) of Humira (Adalimumab) . The NDC number is 0074-3799-02.
Humira (Adalimumab) is supplied for pediatric use only 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 ½ inch needle, providing 20 mg (0.4 mL) of Humira (Adalimumab) . The NDC number is 0074-9374-02.
Humira (Adalimumab) Patient Counseling Information
See FDA-approved patient labeling (Medication Guide).
Patients or their caregivers should be provided the Humira (Adalimumab) “Medication Guide” and provided an opportunity to read it and ask questions prior to initiation of therapy. The healthcare provider should ask the patient questions to determine any risk factors for treatment. Patients developing signs and symptoms of infection should seek medical evaluation immediately.
Humira (Adalimumab)
Humira (Adalimumab)
