Infliximab

Mechanism of Action

Infliximab is a type of biological therapy/immunotherapy designed to stimulate our body's immune system and treat certain diseases. Infliximab is a purified, recombinant DNA-derived chimeric IgG monoclonal antibody protein that contains both murine and human components that inhibit tumor necrosis factor-alpha (TNF-a).[6] TNF-a is a signaling protein involved in acute phase reaction and systemic inflammation. It is produced by macrophages, CD4+ lymphocytes, NK cells, neutrophils, mast cells, eosinophils, and neurons. This inhibition of TNF-a stops the cascade of the inflammatory reaction, leading to improved disease conditions (psoriasis, Crohn disease, etc.). It has been shown to have a half-life of 7 to 12 days in adults.[7]

Infliximab has a high affinity for TNF-alpha and does not inhibit TNF-beta. TNF-alpha is responsible for a number of physiological responses, including inducing proinflammatory cytokines (e.g., IL-1 and IL-6), increasing adhesion molecule release, and enhancing the migration of leukocytes from blood vessels into the surrounding tissue (via increased endothelial permeability.)[8]

Administration

Infliximab is administered via an intravenous route. It has been shown to cause type I and type III hypersensitivity reactions in the studies conducted.

A variety of strategies are used to prevent infliximab-induced infusion reactions, including the following:

• Administering antihistamine and acetaminophen 90 minutes before the infusion
• Using a test dose of infliximab
• Patients with a prior history of an anaphylactic reaction to infliximab should receive prednisone, antihistamine, and acetaminophen before infusion.

Dosage Adjustments

• No dosage adjustment is necessary for patients with mild heart failure (NYHA class I/II), but caution and monitoring are essential.
• In patients with severe heart failure (NYHA Class III/IV), dosage adjustment is necessary, such that the dose is kept less than or equal to 5 mg/kg.
• As of this writing, no dosage adjustments have been recommended in patients with renal or hepatic impairment.[9][10]

Adverse Effects

Infliximab is a generally safe and well-tolerated medication, but as the dose or the age of the patient (greater than 60 years) increases, there are heightened chances of side effects; some o these adverse events can be life-threatening and are common in the TNF-alpha-inhibitor class of drugs.[11]

• Reports of infections are more common in patients taking additional immunosuppressive therapy. (Black Box warning; prescribers are warned to perform very thorough patient screening.)
• Infusion-related reactions (fever, pruritis, anaphylaxis, etc.)
• Headache
• Nausea
• Abdominal pain
• ALT elevation
• Dyspepsia
• Diarrhea
• Constipation
• Hepatotoxicity - There have been reported cases severe enough to be fatal and to necessitate a liver transplant.
• Heart failure
• Hypertension
• Anemia, leukopenia, neutropenia, thrombocytopenia - patients should seek immediate medical care if they develop symptoms of an infection.
• Demyelination disease
• Paradoxical reaction
• Tuberculosis reactivation
• Malignancy - half of the cases reported are lymphomas.
• Reactivation of hepatitis B
• Psoriasis
• Lupus-like syndrome
• Vitiligo or other autoimmune disorders - antinuclear antibody has been positive in patients taking infliximab with normal baseline levels.
• Transient vision loss - has been reported within 2 hours of the infusion; stopping the drug is advisable if serious.

Infliximab has been shown to cross the placenta and is present in the serum of babies whose mothers were given infliximab during pregnancy for up to 6 months. Clinicians have seen agranulocytosis and reactions to live vaccines in these infants.[12] Therefore, a wait of 6 or more months is recommended in exposed infants before administering live vaccines.[13]

Patients have developed antibodies (human anti-chimeric antibodies) against infliximab, which lowers the efficacy of the drug and causes infusion reactions. To reduce this risk, co-administration of other immunosuppressors like methotrexate should be a consideration.

Contraindications

Infliximab can be administered with care in certain conditions, but the following conditions are defined as a contraindication to infliximab administration:

• Heart failure (NYHA class III/IV) - According to the American Heart Association, TNF inhibitors may cause myocardial toxicity or exacerbate the underlying myocardial dysfunction.
• Previous hypersensitivity reaction to infliximab
• Current severe infection (sepsis, tuberculosis)
• Active infection

Use Infliximab with Caution in the Following Conditions

• Preexisting demyelinating disease
• Mild to moderate heart failure (NYHA class I/II)
• History of seizures
• Patients over age 65
• Uncontrolled diabetes mellitus
• Moderate to severe COPD

It is known to cause a cross-reaction with some drugs (e.g., abatacept, adalimumab, etanercept), so care is administered when the patient is on another medicine. Infliximab is contraindicated in patients who have or will require live vaccines such as cholera vaccine, live virus MMR vaccine, smallpox vaccine (live vaccinia virus), etc. Generally, vaccination should occur more than four weeks before or over three months following immunosuppressive therapy with infliximab.[14]

Monitoring

Before administering infliximab following tests are recommendations; patients should have testing for the following:

Tuberculosis: A thorough screening for tuberculosis (TB) is necessary with: 

• A detailed history of previous exposure/infection AND one of the following
• Negative purified protein derivative (PPD less than 5 mm) testing
• Negative interferon-gamma release assay test
• Positive TB screening but negative chest X-ray with infectious disease consultation
• At least four weeks post-initiation of isoniazid therapy for latent TB
• Standard drug therapy for active TB with infectious disease consultation

Hepatitis B: A negative hepatitis screen (particularly Hep B surface antigen) is required.

Heart Failure: Careful monitoring is necessary with serial echocardiograms to avoid heart failure exacerbations. Therapy should immediately discontinue if the patient has frequent or worsening heart failure exacerbations.

Others: Detailed history should be taken to evaluate the patient for any recent or active infection, any recent or upcoming surgery, or live virus vaccination. Avoid live vaccine administration should in patients taking infliximab.

Toxicity

Infliximab is usually administered by healthcare personnel in a medical setting. Toxicity is very rare. Therefore, there is no specific treatment for infliximab toxicity. The best treatment if such an event occurs is supportive treatment.

Enhancing Healthcare Team Outcomes

Infliximab is an effective drug for a number of chronic inflammatory disorders. However, all interprofessional healthcare team members (clinicians, nurses, pharmacists) should work together to ensure that the patient has had a proper workup for tuberculosis, hepatitis B, and cardiac status evaluated prior to administering the drug. Close monitoring of the patient by a specialty-trained nurse is necessary, as the drug does have mild to moderate adverse effects. A clinical pharmacist can also provide valuable input on dosing, and drug-drug interactions and answer patient questions about the medication. The best outcomes will be achieved by an interprofessional team approach to the use of infliximab, which can optimize therapeutic outcomes and prevent adverse events. [Level 5]