Tumor Necrosis Factor Inhibitors Box Warnings Nina Elk, Pharm.D. Internal Medicine Resident (PGY2)...
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Transcript of Tumor Necrosis Factor Inhibitors Box Warnings Nina Elk, Pharm.D. Internal Medicine Resident (PGY2)...
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)
√ √ √ √
Bacterial infections (5/2008)
√ √ √ √
Hepatosplenic-T-cell lymphoma (5/2008)
√
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