Tumor Necrosis Factor Inhibitors Box Warnings

Nina Elk, Pharm.D.Internal Medicine Resident (PGY2)Kingsbrook Jewish Medical Center

Department of Pharmacy Brooklyn, New York

TNF Inhibitors Available on the Market

• Etanercept (Enbrel®) – soluble TNF receptor fusion protein

• Infliximab (Remicade®) – chimeric anti-TNF-alpha antibody

• Adalimumab (Humira®) – human monoclonal anti-TNF-alpha antibody

• Certolizumab pegol (Cimzia®) – antigen-binding fragment of humanized monoclonal antibody coupled to polyethylene glycol

TNF Inhibitors Box Warnings

TNF Inhibitors Box Warnings Box Warnings Infliximab

(Remicade®) August 1998

Etanercept (Enbrel®)

November 1998

Adalimumab (Humira®)

January 2002

Certolizumab (Cimzia®)April 2008

Fungal infections (9/2008)

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Bacterial infections (5/2008)

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Hepatosplenic-T-cell lymphoma (5/2008)

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FDA MedWatch Warning Malignancy Association with TNF Inhibitors

“ [Posted 06/03/2008] FDA issued an Early Communication About an Ongoing Safety Review to inform healthcare professionals that the Agency is investigating a possible association between the use of Tumor Necrosis Factor (TNF) blockers and the development of lymphoma and other cancers in children and young adults. Until the evaluation is completed, healthcare providers, parents, and caregivers should be aware of the possible risk of lymphoma and other cancers in children and young adults when deciding how to best treat these patients.”

TNF Inhibitors Place in Therapy

• Rheumatoid arthritis• Crohn’s disease• Juvenile idiopathic arthritis • Psoriatic arthritis• Ankylosing spondylitis• Plaque psoriasis

Role of TNF in Inflammation

Complications Associated with TNF Inhibitors

• Infections – bacterial, viral, fungal• Mycobacterial infection – tuberculosis• Malignancy • Injection/infusion reactions• Induction of autoimmunity • Demyelinating disease• Heart failure

Risk of Serious Infections Mechanism

• TNF important component of immune system– Enhanced endothelial cell activation – Inflammatory cell recruitment – Procoagulant role (infection spread limited)– Activates macrophages for phagocytosis

• Inhibition of TNF can cause serious infections

TNF Inhibitors Cause Severe Infections Evidence in Literature

Drug Trial Patient #

Duration Risk of infection

Infliximab3 mg/kg or 6 mg/kg

Every 8 weeks

ASPIRE 1049 54 weeks 2-fold

Adalimumab 40 mg

every other week

PREMIER 799 2 years 2-fold

Etanercept Retrospective case review

23,733 N/A 2-fold

Certolizumab200 mg or 400 mg every

2 weeks

RAPID 2 619 24 weeks 2 ½ -fold

Infliximab – Induced Pneumocystis Jiroveci Pneumonia Case Report

Patient 69 y/o female with PMH: RA X 5 years, diabetes mellitus, no history of infection

RA treatment Infliximab + methotrexateReaction onset 3 weeks after infliximab initiation (infliximab 3

doses received)Reaction Exertional dyspnea and fever. Broncho-alveolar

lavage detected Pneumocystosis jiroveci

Management Trimethoprim/sulfamethoxazole started and condition improved within 1 week

NK et. al. 2007;45(4):366-71. Japanese

Link Between TNF Inhibitors and Tuberculosis

• Patients with latent tuberculosis infection (LTBI) have Mycobacterium tuberculosis (Mtb) bacilli contained in granulomas

• TNF is required for maintenance of granuloma structure – Macrophages, multinucleated giant cells

• Tumor necrosis factors inhibit TNF which sets Mtb bacilli free

• Latent tuberculosis transforms into active tuberculosis

TNF-inhibitors Cause Tuberculosis Infection Evidence

AdalimumabClinical trial data

InfliximabPostmarketing data

EtanerceptPostmarketing data

Patients(Patient-years)

2,500(4900)

198,235(227,559)

>150,000(>230,000)

TB reports:•US

•Outside US

133 (33%)10 (67%)

172110 (64%)62 (36%)

3834 (90%)4 (10%)

Time to onset 3-8 months 3–6 months 11 months

Study Duration Patient # TB cases TB onset

RAPID 2 168 days 4,650 5 58 – 169 days

Certolizumab Pegol

Adalimumab-Induced Disseminated Tuberculosis Case Report

Patient 71 y/o woman PMH: COPD, sleep apnea, osteoporosis

RA treatment Adalimumab 40 mg sq every other week

Reaction onset 18 months after treatment initiation

Reaction Ascites, asthenia, anorexia, miliary nodules of peritoneal surfaces

Management Rifampin, isoniazid, pyrazinamide

RA The Lancet 2007;370:564

TNF Inhibitors and Malignancy • Patients with RA at risk for malignancy

– Autoimmune dysfunction – Chronic inflammation

• TNF induces apoptosis of tumor cells• Medications used concomitantly increase risk of cancer

– Methotrexate– Azathioprine– Cyclophosphamide

Trials Reporting TNF Inhibitors and Malignancy Risk

Odd Ratio 3.3 (95%CI, 0%-25%)

Infliximab and Adalimumab Placebo

N = 3493 N = 1512

TB et al. JAMA 2006;295:2275-2285

FDA Investigates TNF Inhibitors Risk of Malignancy• 30 cancer cases reported to FDA from 1998 – 2008

– Infliximab– Adalimumab – Etanercept

• Ten year study planned for Certolizumab to evaluate long term risks

www.fda.gov/medwAtch/safety/2008

Non-Small-Cell Lung Cancer Associated with Infliximab Case Report Patient 69 y/o female, former smoker X 35 years

Crohn’s disease management

MTX + Infliximab (2000 – 2004), adalimumab (2004 – 2006)

Reaction Non-small cell lung cancer with TNF receptors

Management Discontinuation of adalimumab and complete resolution of symptoms

NEJM 2008;359:320 - 321

Recommendations to Prevent Serious Infections

• Routine screening – Histoplasmosis, coccidiosis, listeria monocytogenes

• Avoid unpasteurized products and undercooked meat

• Educate patients to self report fever, respiratory problems

• Routine CBC test to check for left shift

Recommendations to Prevent Tuberculosis• Thorough evaluation prior to TNF inhibitor treatment

– History of TB– Risk factors

• Tuberculin skin test (TST) for LTBI > 5mm positive • Immunocompromised patients false (+)ve TST results • Chest X-ray prior to treatment• BCG vaccination yield (+)ve TST

– T-SPOT TB test more sensitive to LTBI • Positive for LTBI begin treatment

– Isoniazid 300 mg daily X 9 months– Rifampicin 600 mg +/- isoniazid 300 mg X 4 months– Monitor LFTs baseline and monthly

Recommendations to Reduce Risk of Malignancy • Evaluate patient risk for malignancy prior to TNF

inhibitors initiation • Review medications which can further increase risk

of malignancy • Evaluate malignancy risk and benefit from

immunosuppressants

Take Home Message

• TNF inhibitors possess risk on – Infections – Tuberculosis– Malignancy

• Vigilant monitoring for signs and symptoms of adverse reactions

• Patient education related to risk of malignancy and serious infections

• Keep abreast with FDA warnings due to ongoing investigations with TNF inhibitors