AMJEVITA (adalimumab-atto) injection for subcutaneous use
Biosimilar to HUMIRA (adalimumab
INDICATIONS:
Rheumatoid Arthritis : Reducing signs and symptoms, inducing major clinical response, inhibiting the progression of structural damage, and improving physical function
Juvenile Idiopathic Arthritis: Reducing signs and symptoms of moderately to severely active polyarticular juvenile idiopathic arthritis
Psoriatic Arthritis: Reducing signs and symptoms, inhibiting the progression of structural damage, and improving physical function in adult patients with active psoriatic arthritis
Ankylosing Spondylitis : Reducing signs and symptoms in adult patients with active ankylosing spondylitis
Adult Crohn’s Disease: Reducing signs and symptoms and inducing and maintaining clinical remission
Ulcerative Colitis: Inducing and sustaining clinical remission in adult patients with moderately to severely active ulcerative colitis who have had an inadequate response to immunosuppressants
Plaque Psoriasis: Treatment of adult patients with moderate to severe chronic plaque psoriasis who are candidates for systemic therapy or phototherapy
| Mechanism of Action | Adalimumab products bind specifically to TNF-alpha and block its interaction with the p55 and p75 cell surface TNF (tumor necrosis factors) receptors. Adalimumab products also lyse surface TNF expressing cells in vitro in the presence of complement. Adalimumab products do 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 patients with RA (Rheumatoid Arthritis), JIA (Juvenile Idiopathic Arthritis), PsA (Psoriatic Arthritis), and AS (Ankylosing Spondylitis) and play an important role in both the pathologic inflammation and the joint destruction. Increased levels of TNF are also found in psoriasis plaques (Ps). In Ps, treatment with AMJEVITA may reduce the epidermal thickness and infiltration of inflammatory cells. The relationship between these pharmacodynamic activities and the mechanism(s) by which adalimumab products exert their clinical effects is unknown. Adalimumab products also modulate 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 X10-10 M). |
| Pharmacodynamics (PD) | After treatment with adalimumab, a 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 RA. A decrease in CRP levels was also observed in patients with Crohn’s disease (CD) and ulcerative colitis (UC). Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that produce tissue remodeling responsible for cartilage destruction were also decreased after adalimumab administration. |
| Pharmacokinetics (PK) | The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) with adalimumab treatment 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 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 RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 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. 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 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 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 AS were similar to those in patients with RA. In patients with CD, the loading dose of 160 mg adalimumab on Week 0 followed by 80 mg 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 CD patients after receiving a maintenance dose of 40 mg adalimumab every other week. In patients with UC, the loading dose of 160 mg adalimumab on Week 0 followed by 80 mg 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 level of approximately 8 μg/mL was observed at Week 52 in UC patients after receiving a dose of 40 mg adalimumab every other week, and approximately 15 μg/mL at Week 52 in UC patients who increased to a dose of 40 mg adalimumab every week. In patients with Ps, the mean steady-state trough concentration was approximately 5 to 6 μg/mL during adalimumab 40 mg every other week monotherapy treatment. 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. |
| PK-PD Analysis | No reported. |
| Population PK | 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.
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| Special Populations | 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 study with polyarticular JIA patients who were 4 to 17 years of age, the mean steady-state trough serum adalimumab concentrations for patients weighing < 30 kg receiving 20 mg adalimumab subcutaneously every other week as monotherapy or with concomitant MTX were 6.8 μg/mL and 10.9 μg/mL, respectively. The mean steady-state trough serum adalimumab concentrations for patients weighing ≥30 kg receiving 40 mg adalimumab subcutaneously every other week as monotherapy or with concomitant MTX were 6.6 μg/mL and 8.1 μg/mL, respectively. |
| PD Interactions | In RA patients, increased risk of serious infections has been seen with the combination of TNF blockers with anakinra or abatacept, with no added benefit
Higher rate of serious infections RA patients treated with rituximab with subsequent treatment with a TNF blocker The formation of CYP450 enzymes may be suppressed. |
Source: http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/761024lbl.pdf