Tumor Necrosis Factor Inhibitors Box Warnings

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Tumor Necrosis Factor Inhibitors Box Warnings
Nina Elk, Pharm.D.Internal Medicine Resident
(PGY2)Kingsbrook Jewish Medical
Center Department of Pharmacy Brooklyn, New York
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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

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TNF Inhibitors Box Warnings
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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) v v v v
Bacterial infections (5/2008) v v v v
Hepatosplenic-T-cell lymphoma (5/2008) v
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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.

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TNF Inhibitors Place in Therapy

• Rheumatoid arthritis
• Crohns disease
• Juvenile idiopathic arthritis
• Psoriatic arthritis
• Ankylosing spondylitis
• Plaque psoriasis

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Role of TNF in Inflammation
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Complications Associated with TNF Inhibitors

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

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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

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TNF Inhibitors Cause Severe Infections Evidence
in Literature
Drug Trial Patient Duration Risk of infection
Infliximab 3 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
Certolizumab 200 mg or 400 mg every 2 weeks RAPID 2 619 24 weeks 2 ½ -fold
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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 methotrexate
Reaction 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. 200745(4)366-71. Japanese
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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

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TNF-inhibitors Cause Tuberculosis Infection
Evidence
Adalimumab Clinical trial data Infliximab Postmarketing data Etanercept Postmarketing data
Patients (Patient-years) 2,500 (4900) 198,235 (227,559) gt150,000 (gt230,000)
TB reports US Outside US 13 3 (33) 10 (67) 172 110 (64) 62 (36) 38 34 (90) 4 (10)
Time to onset 3-8 months 36 months 11 months
Certolizumab Pegol
Study Duration Patient TB cases TB onset
RAPID 2 168 days 4,650 5 58 169 days
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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 2007370564
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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

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Trials Reporting TNF Inhibitors and Malignancy
Risk
Infliximab and Adalimumab Placebo
N 3493 N 1512
Odd Ratio 3.3 (95CI, 0-25)
TB et al. JAMA 20062952275-2285
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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
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Non-Small-Cell Lung Cancer Associated with
Infliximab Case Report
Patient 69 y/o female, former smoker X 35 years
Crohns 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 2008359320 - 321
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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

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Recommendations to Prevent Tuberculosis

• Thorough evaluation prior to TNF inhibitor
  treatment
• History of TB
• Risk factors
• Tuberculin skin test (TST) for LTBI gt 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

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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

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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