Transcript Understanding Contraindications to the Use of

Understanding Contraindications
to the Use of Immunomodulators
and Biologics for Inflammatory
Bowel Disease
Edward V. Loftus, Jr., M.D.
Professor of Medicine
Mayo Clinic
Rochester, Minnesota, USA
Loftus Disclosures (last 12 months)
• Research support • Consultant
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AbbVie
UCB
Bristol-Myers Squibb
Shire
Genentech
Janssen
Amgen
Pfizer
Takeda
GlaxoSmithKline
Robarts Clinical Trials
•AbbVie
•UCB
•Janssen
•Takeda
•Immune Pharmaceuticals
•MedImmune
•Celgene
•Progentec Biosciences
•Theradiag
Overview of Contraindications
• Thiopurines
• Methotrexate
• Calcineurin inhibitors (tacrolimus, cyclosporine)
• Anti-TNF agents
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•
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Infliximab
Adalimumab
Certolizumab pegol
Golimumab
• Anti-integrins
• Natalizumab
• Vedolizumab
Contraindications to Thiopurines
(Azathioprine, Mercaptopurine)
• Known hypersensitivity to drug
• Examples: fever, pancreatitis, influenza-like
symptoms
• Not necessarily nausea/vomiting: half of IBD patients
with nausea on AZA will tolerate 6MP
• Homozygous deficiency to TPMT (1 in 300)
• TPMT testing is recommended in prescribing
information of Purinethol®
• Active untreated infection
• Young male who has negative EBV serology?
• Higher risk of hemophagocytic syndrome if primary EBV
infection occurs while on thiopurine?
©2010 MFMER | slide-4
Possible/Relative Contraindications to
Thiopurines
• Concurrent use of allopurinol (unless dose of
thiopurine is reduced to 25% of normal weightbased dose and CBC is monitored CLOSELY)
• Other possible drug-drug interactions
• Trimethoprim-sulfamethoxazole
• Angiotensin converting enzyme inhibitors
• 5-ASA’s cause partial inhibition of TPMT
©2010 MFMER | slide-5
Contraindications to Methotrexate
• Known hypersensitivity to MTX or an ingredient
in the formulation
• Pregnancy
• Can result in fetal death, embryotoxicity, abortion or
teratogenicity
• Childbearing women, unless they understand
the serious risk to the fetus should they become
pregnant
• Breastfeeding
• Alcoholism, alcoholic liver disease, other
chronic liver disease
©2010 MFMER | slide-6
Relative Contraindications to MTX
• Drug-drug interactions
• Concurrent NSAIDs may potentiate bone marrow
suppression, aplastic anemia, gastrointestinal
toxicity
• Use with caution if there is already a
hematologic abnormality, MTX may cause bone
marrow depression in all cell lines
• Chronic hepatitis B or C infection
• Active infection
©2010 MFMER | slide-7
Contraindications to Anti-TNF Therapies
• Previous severe hypersensitivity reaction to the
drug
• Doses >5mg/kg infliximab in moderate to
severe heart failure
• Active serious infections including invasive
fungal infections (histoplasmosis,
coccidioidomycosis, aspergillosis,
blastomycosis, and pneumocystosis)
• Recent serious histoplasmosis, consider 3 months
prophylaxis itraconazole
• Hepatitis B virus infection
• Chronic or recurrent infection
©2010 MFMER | slide-8
Contraindications to Anti-TNF (cont)
• Latent TB—start treatment for TB before
starting anti-TNF
• Duration of anti-TB treatment before anti-TNF start is
unclear
• Personal history of multiple sclerosis, optic
neuritis, or other demyelinating disease
• Concurrent use of anakinra or abatacept
• “Consider the risks and benefits of TNF-blocker
treatment prior to initiating therapy in patients
with known malignancy other than a
successfully treated non-melanoma skin
cancer”
©2010 MFMER | slide-9
Who Is Most at Risk for Dying From
Sepsis Related to Anti-TNF?
• Older
• Average age = 63 years (systematic review); 67 years
(Mayo first 500 on IFX)
• Multiple co-morbidities
• Concomitant medications (steroids, narcotics)
• Long-standing disease
Young “healthy” patients are not in the
clear, but probably less at risk
Siegel, CGH 2006; Colombel, Gastro 2004; Lichtenstein CGH 2006
Infections and Mortality in the TREAT Registry:
15,000 Patient-Years of Experience
Multivariate Analysis
4.5
Adjusted Odds Ratio
4.0
Mortality
Serious infections
3.5
Steroids
3.0
2.5
2.0
1.5
IFX
IFX
AZA
6-MP
MTX
AZA
6-MP
MTX
Steroids
1.0
P<.001
P=.006
P=.002
0.5
0.0
AZA = azathioprine; IFX = infliximab; MTX = methotrexate.
Lichtenstein GR et al. Am J Gastroenterol. 2012;107:1409-1422..
11
Meta-Analysis of Safety of Anti-TNF
Agents in CD: Placebo-Controlled Trials
• 21 studies, N=5356
• Mortality: no difference
• Malignancy: no difference
• Serious infection: no difference
Peyrin-Biroulet L et al. Clin Gastroenterol Hepatol. 2008;6:644-653.
12
Hospitalization, Follow-up, Abscess Size, and
Recurrence
Medical
Management
n = 55
Median length of hospitalization, days
(range)
Median length of follow-up after
abscess resolution, months (range)
Abscess size, maximum diameter (cm)
Surgical
Management p-value
n = 40
5 (0-36)
16 (2-169)
< 0.001
45 (6-130)
43 (6-120)
0.72
6.9 ± 3.2
7.4 ± 3.7
0.59
17 (31%)
14
3
8 (20%)
5
3
0.25
Abscess recurrence during follow-up
a) Total
b) Within 3 months of resolution
c) After 3 months of resolution
Nguyen DL et al, Clin Gastroenterol Hepatol 2012;10:400-4
Medical Therapy and Abscess Recurrence
Pharmacologic
Therapy* at Abscess
Resolution
(n=95)
Recurrence
(n=25)
Hazard Ratio for Abscess
Reoccurrence (95% CI)
p-value
No therapy
(n=13)
13
1.00 (reference)
Overall
< 0.01
Immunomodulator
monotherapy
(n=44)
10
0.42 (0.17 - 1.03)
0.059
Any anti-TNF therapy
(n=38)
2
0.10 (0.02 - 0.36)
0.001
*Therapy assessed as a time dependent covariate for association with abscess recurrence.
Nguyen DL et al, Clin Gastroenterol Hepatol 2012;10:400-4
Medical Therapy and Abscess Recurrence on
Anti-TNF Therapy
Pharmacologic
Therapy* at Abscess
Resolution
(n=38)
Recurrence
Hazard Ratio for Abscess
Reoccurrence (95% CI)
p-value
Anti-TNF monotherapy
(n=18)
2
0.32 (0.07 - 1.48)
0.14
Combination therapy
(n=20)
0
0.00
< 0.001
*Therapy assessed as a time dependent covariate for association with abscess recurrence.
Nguyen DL et al, Clin Gastroenterol Hepatol 2012;10:400-4
Other Neurologic Side Effects Reported
with Anti-TNF Therapy
• Guillain-Barre syndrome
• Peripheral neuropathy
• Aseptic meningoencephalitis
• Leukoencephalopathy
• Transverse myelitis
• Chronic inflammatory demyelinating
polyneuropathy
• Progressive multifocal leukoencephalopathy
• Posterior reversible encephalopathy syndrome
Singh S et al, Inflamm Bowel Dis 2013; 19:864-72.
Congestive Heart Failure and Anti-TNF
Therapy
• Etanercept trials to treat CHF
were negative
• Infliximab trial of CHF: highest
mortality rate in IFX 10 mg/kg
arm
• Adalimumab: event rate of CHF
<0.26 per 1000 p-y
• Use with caution in patients with
CHF or reduced LVEF
• IFX contraindicated at doses
>5mg/kg in NYHA Class III/IV
• Consider ECHO ± Cards consult
in those with suspected CHF
Mann DL et al, Circulation 2004; Chung ES et al, Circulation 2003; Schiff MH et
al, EULAR 2005; Kent JD et al, ACR 2005.
Hepatotoxicity with Anti-TNF
• Most commonly described with infliximab but
has been describe with all
• PI contains warning
• Hepatocellular > cholestatic injury, often with
autoimmune characteristics
• Slowly improves after drug cessation
• Rare cases of hepatic failure/liver transplant
Ghabril M et al, Clin Gastroenterol Hepatol 2013;11:558-64.
Contraindications to Natalizumab Therapy
• Known hypersensitivity to natalizumab
• Known or suspected progressive multifocal
leukoencephalopathy
• Positive JC virus serology is relative
contraindication
• Concomitant immunosuppressants are not
allowed, and steroids need to tapered within 6
months
©2010 MFMER | slide-19
Natalizumab and PML Risk Based on anti-JC
Virus Antibody Status
Anti-JCV Antibody
Status
Positive (and prior
IS use)
Negative
< 0.11/1000
0-2 years
2/1000 (1 in 500)
2+ years
11/1000
(≈1 in 100)
To ORDER anti-JC Virus antibody test:
Quest Labs test # 90257, JC Virus Antibody with Reflex Inhibition Assay
About 50% of Crohn’s patients will be positive
Bloomgren, et al. NEJM 2012;366.20.
Natalizumab: Adverse Events Beyond
PML
• Headache
• Infusion reactions, generally mild
• Hepatotoxicity
• Rare but severe cholestatic liver injury reported
Contraindications to Vedolizumab
• Known hypersensitivity to vedolizumab
• Active severe infections (until controlled)
• History of recurring severe infections
• Consider screening for TB
• Warning about PML in prescribing info, but no
cases of PML observed
• Discontinue drug in face of rising transaminases
and bilirubin
©2010 MFMER | slide-22
Conclusions
• A wide variety of side effects can occur with our
commonly used medications for IBD
• Many of the contraindications relate to
infectious risks
• Screen for latent TB and chronic viral hepatitis
in all patients starting a biologic