Title: Tumor Necrosis Factor Inhibitors Box Warnings
1Tumor Necrosis Factor Inhibitors Box Warnings
Nina Elk, Pharm.D.Internal Medicine Resident
(PGY2)Kingsbrook Jewish Medical
Center Department of Pharmacy Brooklyn, New York
2TNF 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
3TNF Inhibitors Box Warnings
4TNF 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
5FDA 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.
6TNF Inhibitors Place in Therapy
- Rheumatoid arthritis
- Crohns disease
- Juvenile idiopathic arthritis
- Psoriatic arthritis
- Ankylosing spondylitis
- Plaque psoriasis
7Role of TNF in Inflammation
8Complications Associated with TNF Inhibitors
- Infections bacterial, viral, fungal
- Mycobacterial infection tuberculosis
- Malignancy
- Injection/infusion reactions
- Induction of autoimmunity
- Demyelinating disease
- Heart failure
9Risk 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
10TNF 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
11Infliximab 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
12Link 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
13TNF-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
14Adalimumab-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
15TNF 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
16Trials 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
17FDA 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
18Non-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
19Recommendations 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
20Recommendations 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
21Recommendations 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
22Take 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