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Adalimumab


Adalimumab

Article Author:
Carter Ellis
Article Editor:
Chaudhary Ehtsham Azmat
Updated:
11/4/2020 11:25:31 AM
For CME on this topic:
Adalimumab CME
PubMed Link:
Adalimumab

Indications

The FDA first approved the original molecule of adalimumab for the treatment of rheumatoid arthritis. It was the third tumor necrosis factor (TNF) alpha inhibitor to be approved by the FDA after infliximab and etanercept. Subsequently, the FDA has approved adalimumab for the following indications:[1][2]

  • Rheumatoid arthritis
  • Ankylosing spondylitis
  • Crohn disease
  • Ulcerative colitis
  • Hidradenitis suppurativa
  • Juvenile idiopathic arthritis
  • Plaque psoriasis
  • Psoriatic arthritis
  • Uveitis

The off label uses of adalimumab include:

  • Neutrophilic dermatosis – pyoderma gangrenosum, Behcet disease
  • Wegeners granulomatosis
  • Sarcoidosis
  • Pemphigus
  • Multicentric reticulohistiocytosis
  • Alopecia areata.

Several biosimilar molecules have now been developed, for, eg. ABP 501, BI 695501, and SB5.[3]

Mechanism of Action

Adalimumab is a fully human, high-affinity, recombinant immunoglobulin G (IgG) anti-TNF alpha monoclonal antibody. It is a molecule comprising 1330 amino acids and has a molecular weight of approximately 148 kDa.[4] It inhibits the binding of TNF alpha (both soluble and membrane-bound). It inhibits its interaction with p55 (TNFR1) and p75 (TNFR2) cell surface TNF receptors, which in turn interferes with cytokine-driven inflammatory processes. It is identical in structure and function to the naturally occurring human IgG1, and thus has high selectivity for TNF alpha, and has low immunogenic potential.[5][6]

It does not affect or bind to other cytokines like lymphotoxin or interleukins. Its efficacy in various arthritis owes to its potent osteogenic action. TNF mediates activation of NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) ligand (RANKL) receptors on stromal or osteoblast cells. TNF blockade thus inhibits subsequent destruction of cartilage and bone. TNF also plays a role in osteoclast maturation and activation, which remains in check with TNF blockade. Anti-TNF agents also downregulate serum matrix metalloproteinases 1 and 3 (MMP-1 and MMP-3). All of these factors contribute to the efficacy of TNF inhibitors in arthritis.[6]

Administration

Administer injection subcutaneously at separate sites in the thigh or lower abdomen (avoid areas within 2 inches of the navel); rotate injection sites; may leave at room temperature for 15 to 20 minutes prior to use; do not remove cap or cover while allowing the product to reach room temperature; not for administration to the skin which is red, tender, bruised, hard, or that scars, stretch marks, or psoriasis plaques.[7][1]

The recommended doses for each indication are:

  • Rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis: 40 mg every other week.[6]
  • Juvenile idiopathic arthritis or pediatric uveitis[8]:
    • 10 kg to less than 15 kg: 10 mg every other week
    • 5 kg to less than 30 kg: 20 mg every other week
    • Greater than 30 kg: 40 mg every other week

  • Adult Crohn disease and ulcerative colitis[9]:
    • Initial dose (day 1): 160 mg
    • The second dose is two weeks later (day 15): 80 mg
    • Two weeks later (day 29): Start a maintenance dose of 40 mg every other week.
    • For patients with ulcerative colitis only: Continue adalimumab in only the patients who have shown evidence of clinical remission by eight weeks (Day 57) of therapy.

  • Plaque psoriasis or adult uveitis[10][11]:
    • 80 mg initial dose, followed by 40 mg every other week, starting one week after the initial dose.

  • Hidradenitis suppurativa[12]:
    • Initial dose (day 1): 160 mg
    • The second dose is two weeks later (day 15): 80 mg
    • Third (day 29) and the subsequent doses: 40 mg every week.

The injection is available as a pre-filled glass syringe or pen, or as a single-use glass vial in doses of 10 mg, 20 mg, 40 mg or 80 mg. Patients may use the adalimumab pen as self-administration. The vial is for institutional use only.

Following a single 40 mg subcutaneous dose, the pharmacokinetics of adalimumab are as follows:[6]

  • Absolute bioavailability: 64%
  • Time to peak concentration: 131 +/- 56 h
  • Maximum serum concentration: 4.7 +/- 1.6 mcg/ml
  • The volume of distribution: 4.7- 6 L
  • Steady-state concentration:
    • Without concomitant methotrexate: 5 mcg/ml
    • With concomitant methotrexate: 8 to 9 mcg/ml
  • Systemic clearance: 12 ml/hr
  • Terminal half-life: 2 weeks

Adverse Effects

The most common adverse effects of adalimumab are:

  • Injection site reactions
  • Headache
  • Skin rash
  • Risk of serious infections, in particular, reactivation of latent tuberculosis.
  • Other infections such as deep fungal infections, histoplasmosis, listeriosis, pulmonary aspergillosis, and Pneumocystis carinii pneumonia may occur.
  • Antibody development
  • Elevated creatinine phosphokinase and transaminases
  • Worsening or initiation of congestive heart failure
  • Lupus-like syndrome
  • Lymphoma
  • Pancytopenia
  • Worsening or initiation of multiple sclerosis/neurological disease.[5]

Contraindications

Although the manufacturers have listed no contraindications, adalimumab has not been adequately studied in patients who are younger than four years of age and weighing less than 15 kg. CLinicians should avoid using it in this age group as a precautionary measure.[13]

Clinicians must also avoid adalimumab in cases of hypersensitivity, patients with underlying foci of infection, congestive cardiac failure, or hepatic dysfunction.

Concomitant administration of live vaccines is contraindicated. Also, the risk of serious infections increases significantly in the co-administration of abatacept and anakinra.

Monitoring

  • Complete blood count, liver function tests, serum urea, and electrolytes: At baseline, then monthly for three months, and subsequently every three months
  • Screen for latent tuberculosis before initiating therapy with a chest X-ray and Mantoux test
  • Screening for viral markers before initiating therapy
  • dsDNA- screen yearly
  • Signs/symptoms/worsening of heart failure
  • signs and symptoms of hypersensitivity reactions
  • signs/symptoms of malignancy, including periodic skin examination.[14]
  • Newer studies recommend maintaining therapeutic drug monitoring for serum levels of adalimumab at between 5 to 8 mg/ml, and subsequent maintenance and tapering of the drug guided by these levels.[15]

Toxicity

Long term human or animal studies on adalimumab have not been conducted, leaving the toxicity profile mostly unknown. It has not demonstrated to be mutagenic in vitro or in vivo studies.[16]

The FDA categorizes adalimumab as a pregnancy category B drug. There is no conclusive published evidence of poor pregnancy outcomes or specific pattern of defects in infants exposed prenatally to adalimumab.[17]

Enhancing Healthcare Team Outcomes

The administration of TNF alpha antagonists such as adalimumab requires thorough knowledge and working experience with these drugs. A few points to be kept in mind are:

  • Ensure that the agent is truly indicated in the situation.
  • Thorough investigations for fitness at baseline need to be performed, with a complete blood count, liver, and renal function tests. Ensure the patient is not in or at risk of congestive cardiac failure.
  • It is essential to rule out any underlying infections, as these are known to flare up after therapy with TNF alpha antagonists. In tuberculosis-endemic countries, the risk of flaring up of a quiescent focus of tuberculosis is very common. Thus a chest X-ray and a Mantoux test is of great value before starting therapy.
  • Monitoring the patient throughout treatment to follow up and track the development of any side effects is paramount.

References

[1] Adalimumab 2012;     [PubMed PMID: 31643860]
[2] Traczewski P,Rudnicka L, Adalimumab in dermatology. British journal of clinical pharmacology. 2008 Nov;     [PubMed PMID: 18754844]
[3] Kaushik VV, Review of Biosimilars of Adalimumab. The Journal of the Association of Physicians of India. 2017 May;     [PubMed PMID: 28836746]
[4] Vena GA,Cassano N, Drug focus: adalimumab in the treatment of moderate to severe psoriasis. Biologics : targets     [PubMed PMID: 19707319]
[5] Scheinfeld N, Adalimumab: a review of side effects. Expert opinion on drug safety. 2005 Jul;     [PubMed PMID: 16011443]
[6] Mease PJ, Adalimumab in the treatment of arthritis. Therapeutics and clinical risk management. 2007 Mar;     [PubMed PMID: 18360621]
[7] Bang LM,Keating GM, Adalimumab: a review of its use in rheumatoid arthritis. BioDrugs : clinical immunotherapeutics, biopharmaceuticals and gene therapy. 2004;     [PubMed PMID: 15046527]
[8] Marzan KA, Role of adalimumab in the management of children and adolescents with juvenile idiopathic arthritis and other rheumatic conditions. Adolescent health, medicine and therapeutics. 2012;     [PubMed PMID: 24600289]
[9] Asgharpour A,Cheng J,Bickston SJ, Adalimumab treatment in Crohn's disease: an overview of long-term efficacy and safety in light of the EXTEND trial. Clinical and experimental gastroenterology. 2013 Aug 30;     [PubMed PMID: 24039442]
[10] Alwawi EA,Mehlis SL,Gordon KB, Treating psoriasis with adalimumab. Therapeutics and clinical risk management. 2008 Apr;     [PubMed PMID: 18728850]
[11] Ming S,Xie K,He H,Li Y,Lei B, Efficacy and safety of adalimumab in the treatment of non-infectious uveitis: a meta-analysis and systematic review. Drug design, development and therapy. 2018;     [PubMed PMID: 30013320]
[12] Kyriakou A,Trigoni A,Galanis N,Sotiriadis D,Patsatsi A, Efficacy of adalimumab in moderate to severe hidradenitis suppurativa: Real life data. Dermatology reports. 2018 Oct 1;     [PubMed PMID: 30370041]
[13] Kingsbury DJ,Bader-Meunier B,Patel G,Arora V,Kalabic J,Kupper H, Safety, effectiveness, and pharmacokinetics of adalimumab in children with polyarticular juvenile idiopathic arthritis aged 2 to 4 years. Clinical rheumatology. 2014;     [PubMed PMID: 24487484]
[14] Emer JJ,Frankel A,Zeichner JA, A practical approach to monitoring patients on biological agents for the treatment of psoriasis. The Journal of clinical and aesthetic dermatology. 2010 Aug;     [PubMed PMID: 20877538]
[15] Mulleman D,Balsa A, Adalimumab concentration-based tapering strategy: as good as the recommended dosage. Annals of the rheumatic diseases. 2018 Apr;     [PubMed PMID: 29306871]
[16] Gerriets V,Khaddour K, Tumor Necrosis Factor (TNF) Inhibitors 2019 Jan;     [PubMed PMID: 29494032]
[17] Burmester GR,Landewé R,Genovese MC,Friedman AW,Pfeifer ND,Varothai NA,Lacerda AP, Adalimumab long-term safety: infections, vaccination response and pregnancy outcomes in patients with rheumatoid arthritis. Annals of the rheumatic diseases. 2017 Feb;     [PubMed PMID: 27338778]