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K r i s t e n T i m p e r m a n , P h a r m D
P G Y 1 H e a l t h W i s e R e s i d e n t
O h i o N o r t h e r n U n i v e r s i t y
E m a i l : k - t i m p e r m a n @ o n u . e d u
Treating Inflammatory Bowel Disease with Biologics
From: http://doccarnahan.blogspot.com/2011/02/help-for-those-suffering-from.html
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Objectives
1) Review epidemiology, proposed causes, and types of inflammatory bowel disease (IBD)
2) Discuss the pharmacology and adverse effect profile of biologics used in IBD
3) Describe the clinical trial evidence supporting biologics used in IBD
4) Identify the role of biologics in pregnant patients with IBD
5) Review important patient counseling information for patients receiving biologics with IBD
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Do you know?
1) Which biologics are currently approved to treat IBD?
I. Natalizumab (Tysabri®)
II. Etanercept (Enbrel®)
III. Infliximab (Remicade®)
IV. Certolizumab pegol (Cimzia®)
V. Adalimumab (Humira®)
a) I, II
b) I, III, IV, V
c) II, III, IV, V
d) All of the above
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Do you know?
2. TNF-α inhibitors are safe to use in pregnancy.
a. True
b. False
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Epidemiology
More common in northern areas
More common in industrialized areas
Incidence: 3.6 to 8.8 per 100,000 persons in the United States
Has increased
Equally affects males and females
Highest age group affected is 20 to 30 year-olds followed by 60 to 80 year-olds
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What is Inflammatory Bowel Disease (IBD)?
Inflammatory bowel disease (IBD)
Types
1. Crohn’s disease
2. Ulcerative colitis
Exact cause is unknown
Inflammatory condition/autoimmune disease
Different from irritable bowel syndrome (IBS)
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Difference Between Ulcerative Colitis and Crohn’s Disease
Ulcerative Colitis
Crohn’s Disease
Disease Location
Mainly colon (may affect terminal ileum)
Any portion of the gastrointestinal tract *Rarely patients have gastroduodenal disease
Lesions Causes continuous lesions
May cause discontinuous lesions
Mucosa Superficial Transmural (affects deeper portions of the mucosa)
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Difference Between Ulcerative Colitis and Crohn’s Disease
A small fraction of patients show symptoms of both diseases
Ulcerative Colitis Crohn’s Disease
Pathologic Crypt abscesses Cobblestone appearance
Complications Fistulas, perforations, strictures, obstructions are LESS common
Fistulas, perforations, strictures, obstructions are MORE common
Systemic Signs and Symptoms
Fever, malaise, and abdominal pain/tenderness are LESS common
Fever, malaise, and abdominal pain/tenderness are MORE common
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Difference Between Ulcerative Colitis and Crohn’s Disease
From: http://medchrome.com
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Difference Between Ulcerative Colitis and Crohn’s Disease
From: http://hopkins-gi.org
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Etiology
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Cause
Exact cause is unknown
Thought to be caused by a combination of:
Abnormal immune response
Thought to be a disorder involving T-cells and increased mature B cells
Leaky gut
Infection
Genetics
Environment
Hygiene hypothesis
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Cause Continued
Normal immune system
Balance of proinflammatory and anti-inflammatory cytokines
Proinflammatory: TNF-α, interferon-γ (IFN-γ), interleukin-1 (IL-1), IL-6, IL-12
Anti-inflammatory: IL-4, IL-10, IL-11
This balance of cytokines is disrupted along with the intestinal epithelial barrier
Leading to destruction of tissue and an activated immune system
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Treatment
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Goals of Treatment
Achieve and maintain clinical remission
Prevent relapses
Reduce exposure to corticosteroids
Decrease need for surgeries and hospitalizations
Improve quality of life
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Pharmacotherapy
5-aminosalicylates: first-line
Mesalamine
Sulfasalazine (Azulfidine®)
Olsalazine (Dipentum®)
Balsalazide (Colazal®, Giazo®)
Immunomodulators
Azathioprine (Imuran®)
Mercaptopurine (Purinethol®)
Methotrexate (Rheumatrex®)
Cyclosporine (Sandimmune®)
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Pharmacotherapy
Antibiotics
Ciprofloxacin
Metronidazole
Corticosteroids
Biologics
TNF-α inhibitors
Leukocyte adhesion and migration inhibitor
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Role of Biologics in Treatment of IBD
Reserved for patients with moderate to severe disease
Role in fistulizing disease
TNF-α inhibitors
Infliximab (Remicade®)
Adalimumab (Humira®)
Certolizumab pegol (Cimzia®)
Alpha-4 integrin inhibitor
Natalizumab (Tysabri®)
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Biologics: TNF-α Inhibitors
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From: Therap Adv Gastroenterol. 2011 November; 4(6): 375–389. which was adapted from Adis Data Information BV [Bourne et al. 2008, 22(5): 331–337]
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Infliximab
From: http://pharmafile.com
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Infliximab (Remicade®)
Drug Class TNF-α inhibitor
MOA Chimeric IgG1 monoclonal antibody •Binds intestinal and soluble TNF-α and neutralizes its effect •Induces T-cell apoptosis in intestinal cells and peripheral blood monocytes
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Infliximab (Remicade®)
FDA Indications
Moderate to severe Crohn’s disease, moderate to severe ulcerative colitis, psoriatic arthritis, rheumatoid arthritis in combination with methotrexate, ankylosing spondylitis, plaque psoriasis
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Infliximab (Remicade®)
Dose
Initial dose: 5 mg/kg at 0, 2, and 6 weeks Maintenance dose: 5 mg/kg every 8 weeks *May increase dose to 10 mg/kg in patients with initial response who lose response (Crohn’s disease labeling)
Duration of Action
Up to 2 months
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Infliximab (Remicade®)
Route Intravenous
Patient Assistance Programs
Available at: http://www.janssenaccessone.com/pages/remicade/patientassist/intro.jsp
Other Pretreat with corticosteroid (oral prednisone day before infusion or IV hydrocortisone 200 mg on day of infusion), acetaminophen, or diphenhydramine 25 mg po to minimize infusion reaction
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Studies Supporting Efficacy in Crohn’s Disease
RCT by Targan, et al. RCT by Rutgerts, et al.
Inclusion Criteria
Moderate to severe Crohn’s disease despite other treatment or failed immunomodulator therapy
Patients who maintained their response after 8 weeks of being treated (73 of the 108 patients initially randomized)
Objective Determine response rate after 4 wks of single-blind infusion
Determine if sustained efficacy and safety with repeat infusions every 8 weeks for 4 additional infusions
Drug Placebo or infliximab 5 mg/kg, 10 mg/kg, 20 mg/kg
Placebo or infliximab 10 mg/kg
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Studies Supporting Efficacy in Crohn’s Disease
RCT by Targan, et al. RCT by Rutgerts, et al.
Results •65% of patients with infliximab had a ≥ 70 point decrease in the CDAI compared to 17% in control group •Highest response rate was with 5 mg/kg (81%) over 10 mg/kg (50%) and 20 mg/kg (64%)
•TREND toward significant response was observed at 44 weeks •Improved QOL and decreased CRP in infliximab group •Significant rates of remission were observed at week 44 between infliximab and control (52.9% vs. 20%, p=0.013)
Conclusion Effective short-term treatment
Repeated dose maintenance therapy may improve remission rates
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Studies Supporting Efficacy in Crohn’s Disease
ACCENT I
Inclusion Criteria
573 patients with a CDAI score of > 220
Design •At week 0, all patients received infliximab 5 mg/kg •Response recorded at week 2 and patients divided into 1 of 3 groups (patients followed until week 46)
•Group I: placebo at weeks 2, 6, and then every 8 weeks •Group II: infliximab 5 mg/kg at weeks 2, 6, then every 8 weeks •Group III: infliximab 5 mg/kg at weeks 2, 6, then 10 mg/kg every 8 weeks thereafter •At week 14, patients in any group if declining and had a response to infliximab could have step-up therapy
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Studies Supporting Efficacy in Crohn’s Disease
ACCENT I
Results •At week 30, 21% (23/110) of group I, 39% (44/113) of group II (p=0.003), and 45% (50/112) of group III were in remission (p=0.0002) •Groups II and III were more likely to sustain clinical remission (odds ratio 2.7, 95% CI 1.6-4.6) •Median time to loss of response was 19 weeks for Group I as compared to 38 weeks for Group II (p=0.002) and 54 weeks for Group III (p=0.002) •Safety: incidence of serious infections was consistent amongst the groups
Conclusion Patients who respond to initial dose are most likely to have a longer response time and sustain response if take infliximab every 8 weeks.
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Studies Supporting Efficacy in Crohn’s Disease
Subanalyses of ACCENT I
Demonstrated superiority of scheduled treatment over episodic treatment in maintaining remission. Scheduled group had significantly less hospitalizations.
Improved mucosal healing in scheduled group over episodic group.
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Studies Supporting Efficacy in Crohn’s Disease
STORI
Inclusion Criteria/ Design
Prospective multicenter cohort evaluating stopping infliximab in patients who had received at least one year of treatment with infliximab and an antimetabolite
Results/ Conclusion
•Approximately ½ of patients relapsed within 1 to 2 yrs after stopping infliximab •Factors associated with a lower risk of relapse: fecal calprotectin < 300 μg/g, hemoglobin >14.5 g/dL, WBC ct ≤ 6 x 109/L, hsCRP < 5 mg/L •Majority of patients retreated with infliximab went back into remission and no patients experienced an infusion reaction = SAFE
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Studies Supporting Efficacy in Crohn’s Disease
Studies by Present et al, Ardizzone et al, and Sands et al point to infliximab’s utility in fistulizing disease
Present et al
68% of the 5 mg/kg group and 56% of the 10 mg/kg group had a > 50% reduction in draining fistulas versus 26% in placebo group (p=0.002 and p=0.02 respectively)
55% of the 5 mg/kg group and 38% of the 10 mg/kg group had closure of all fistulas versus 13% in the placebo group (p=0.001 and p=0.004 respectively)
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Studies Supporting Efficacy in Crohn’s Disease
Studies by Present et al, Ardizzone et al, and Sands et al point to infliximab’s utility in fistulizing disease continued
Ardizzone et al
Approximately 30% of rectovaginal fistulas healed as compared to 60% of perianal fistulas
However, only about 15% of rectovaginal fistulas healed via anal endosonography as compared to about 20% of perianal fissures
Superficial closure of fistulas occurs more easily than deep tract closure
Sands et al
36% of patients in infliximab maintenance group vs. 19% in placebo group had no draining fistulas (p=0.009) at week 54
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Studies Supporting Efficacy in Ulcerative Colitis
ACT 1 ACT 2
Design Randomized moderate to severe ulcerative colitis (UC) patients to placebo, infliximab 5 mg/kg, or infliximab 10 mg/kg at weeks 0, 2, 6, and then every 8 wks thereafter through week 46
Randomized ulcerative colitis patients to placebo, infliximab 5 mg/kg, or infliximab 10 mg/kg at weeks 0, 2, 6, 14, and 22
Results At week 8, significantly higher 5 mg/kg (64%) and 10 mg/kg (61.5%) achieved clinical response versus placebo (37.2%, p<0.001)
At week 8, significantly higher 5 mg/kg (64.5%) and 10 mg/kg (69.2%) achieved clinical response versus placebo (29.3%, p<0.001)
Conclusion Effective in achieving clinical response in UC patients
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Summary: Effectiveness of Infliximab
~60-70% of patients have an initial response to treatment
Increase mucosal healing
Decrease need for surgical interventions and hospitalizations
Role in fistulizing disease
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Adalimumab
From: http://myjourneywithcrohns.com
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Adalimumab (Humira®)
Drug Class TNF-α inhibitor
MOA Humanized monoclonal antibody •Binds TNF-α in the intestinal mucosa and neutralizes its effect •Induces T-cell apoptosis in intestinal cells and peripheral blood monocytes
FDA Indications
Moderate to severe Crohn’s disease, moderate to severe ulcerative colitis, rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, polyarticular juvenile idiopathic arthritis, plaque psoriasis
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Adalimumab (Humira®)
Dose Initial dose: 160 mg (four 40 mg injections on day 1 OR two 40 mg injections per day for 2 consecutive days) Second dose: 80 mg 2 weeks later Maintenance dose: 4o mg every other week (may increase to 40 mg weekly for Crohn’s disease)
Route Subcutaneous
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Adalimumab (Humira®)
Dosage Forms Prefilled syringe or auto-injector pen
Patient Assistance Programs
HUMIRA protection plan and AbbVie Patient Assistance Foundation
Other 40 mg/ 0.8 mL
From: http://www.rxabbvie.com/pdf/humira.pdf
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Studies Supporting Efficacy in Crohn’s Disease
Clinical assessment of adalimumab safety and efficacy studied as induction therapy in Crohn’s disease I (CLASSIC-I) and CLASSIC-II studies: phase III randomized, double-blind, multicenter, placebo-controlled trials
CLASSIC-I: induction trial lasting 4 weeks
CLASSIC-II: maintenance trial lasting 52 weeks
Conclusion: demonstrated safety and efficacy of adalimumab therapy in moderate to severe Crohn’s disease
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Studies Supporting Efficacy in Crohn’s Disease
Crohn’s trial of the fully human antibody adalimumab for remission maintenance (CHARM)
Phase III trial: 56 week, double-blind, multicenter, placebo-controlled assessing safety and efficacy of adalimumab in moderate to severe Crohn’s disease
Open-label induction phase followed by randomization to placebo, adalimumab 40 mg weekly, or adalimumab 40 mg every 2 weeks
Conclusion: adalimumab was safe and effective in maintaining remission in moderate to severe Crohn’s disease in weekly and biweekly dosing
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Studies Supporting Efficacy in Crohn’s Disease
Additional long-term dosing with HUMIRA® to evaluate sustained remission and efficacy in CD (ADHERE)
Long-term, open-label extension of the CHARM trial
Conclusion:
2 years of treatment with adalimumab resulted in decreased hospitalizations, fistula healing, clinical remission, and increased quality of life
A sub-analysis suggests patients with disease onset of < 2 yrs and elevated CRP levels have increased benefit
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Studies Supporting Efficacy In Ulcerative Colitis
Ulcerative colitis long-term remission and maintenance with adalimumab treatment of moderate to severe ulcerative colitis 1 (ULTRA 1) and ULTRA 2
Randomized, double-blind, multicenter, placebo-controlled trials in patients with moderate to severe ulcerative colitis
ULTRA 1 was an 8-week study evaluating induction of clinical remission in those who had not been previously treated with a TNF-α inhibitor and showed adalimumab to be superior to placebo
ULTRA 2 was 52-weeks to gather long-term data and demonstrated improved safety and efficacy of adalimumab in the induction and maintenance of remission along with improved mucosal healing over placebo
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Certolizumab Pegol
From: http://opbmed.blogspot.com
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Certolizumab pegol (Cimzia®)
Drug Class
TNF-α inhibitor
MOA Humanized TNF-α Fab monoclonal antibody conjugated to polyethylene glycol •Binds intestinal and soluble TNF-α and neutralizes its effect •Does NOT induce T-cell apoptosis in intestinal cells and peripheral blood monocytes •Does NOT cause complement activation or antibody-dependent cell-mediated toxicity
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Certolizumab pegol (Cimzia®)
FDA Indications Moderate to severe Crohn’s disease, rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis
Dose Initial dose: 400 mg at weeks 0 and 3 Maintenance dose: 400 mg every 4 wks
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Certolizumab pegol (Cimzia®)
Route Subcutaneous
Dosage Forms Prefilled syringe
Patient Assistance Programs
CIMplicity patient support program
Other 200 mg/ 1 mL
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Studies Supporting Efficacy in Crohn’s Disease
Winter et al
Phase II randomized, placebo-controlled trial
Evaluated safety and efficacy of a single dose of IV certolizumab over a 12 week period as compared to placebo in moderate to severe Crohn’s patients
Randomized into 1.25 mg/kg, 5 mg/kg, 10 mg/kg, or 20 mg/kg of certolizumab or placebo
Conclusion:
The amount of patients achieving a clinical response was not significantly different
The amount of patients achieving clinical remission was superior at week 2 in the 10 mg group (47.1%) as compared to the placebo group (16%, p=0.041)
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Studies Supporting Efficacy in Crohn’s Disease
Schreiber et al
Phase II placebo-controlled study
Moderate to severe Crohn’s patients were randomized to either subcutaneous certolizumab 100 mg, 200 mg, or 400 mg or placebo at weeks 0, 4, and 8
Conclusion: at all time points except 12 weeks, certolizumab was superior in clinical response to placebo
400 mg dose had the highest response rates which was highest at week 10 (52.8% versus 30.1%, p= 0.006)
Patients with CRP levels > 10 mg/L show greater response
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Studies Supporting Efficacy
PRECiSE trials showed previous use of infliximab did not affect response of certolizumab
PRECiSE 2 trial showed a positive impact of certolizumab on the health-related quality of life of Crohn’s disease patients, and treatment started closer to diagnosis leads to improved outcomes
PRECiSE and WELCOME trial showed certolizumab’s positive effect on Crohn’s patients being able to perform activities of daily living and to remain productive
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Studies Supporting Efficacy
WELCOME study
26-week study evaluating patients who had previously lost response with infliximab
Induction phase was open-label followed by randomized, doubled-blind maintenance therapy
At week 26, 40% of patients receiving treatment every 4 weeks and 37% of patients receiving treatment every 2 weeks were in clinical response with 29% and 30% in remission respectively
Demonstrated certolizumab as an effective option for patients failing treatment with infliximab
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Studies Supporting Efficacy
MUSIC trial
Evaluated changes in the intestinal mucosa of patients with active Crohn’s disease who were on long-term therapy with certolizumab
After 10 weeks of therapy, 62% of patients had endoscopic response and 42% had remission
After 54 weeks of therapy, 62% had endoscopic response and 28% had remission
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Loss of Effectiveness with TNF-α Inhibitors
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Loss of Effectiveness with TNF-alpha inhibitors
~40% of patients maintain the response at 1 year or stay in remission
Anti-drug antibodies (ADA) may play a role
Typically are IgG antibodies which bind to biologic proteins decreasing efficacy
May increase clearance of the drug
Contribute to infusion reactions and decreased responsiveness of the medication
Incidence: 10-20% of patients on anti-TNF therapy
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Loss of Effectiveness
If loss of effectiveness to one TNF-α inhibitor, may switch to another medication in the same class, increase dose, or increase dosing frequency
Secondarily, may switch to a non-TNF-α inhibitor medication
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Biologics: Alpha-4 Integrin Inhibitors
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Natalizumab
From: http://www.hcplive.com/articles/Natalizumab-Promising-for-Teens-With-Multiple-Sclerosis
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Natalizumab (Tysabri®)
Drug Class Selective adhesion-molecule inhibitor
MOA Recombinant humanized IgG4 monoclonal antibody •Leukocyte adhesion and migration inhibitor by inhibiting the α4 subunit of integrin
FDA Indication
Moderate to severe Crohn’s disease, multiple sclerosis
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Mechanism of Action
From: http://www.ajnr.org/content/31/9/1588/F2.expansion.html
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Natalizumab (Tysabri®)
Dose 300 mg IV every 4 weeks
Route Intravenous
Other •Only available via the manufacturer’s TOUCH prescribing program •Observe patients during and for 1 hour after the infusion
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Studies Supporting Efficacy
Phase II trials
Demonstrated efficacy of natalizumab IV at doses of 3 mg/kg, 3 mg/kg every 4 wks x 2 doses, and 6 mg/kg every 4 wks x 2 doses
Phase III trials
Natalizumab 300 mg IV every 4 wks for 6 months showed benefit of maintenance treatment greater than 30% over placebo
Patients with an increased CRP level have increased benefit
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Studies Supporting Efficacy
Evaluation of natalizumab in active Crohn’s disease therapy-2 study (ENATC-2)
Randomized, double-blind, placebo-controlled trial, multicenter study
Conclusion: demonstrated ability to taper corticosteroids off while continuing to achieve clinical response and/or remission
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Studies Supporting Efficacy
Has also demonstrated benefit in ulcerative colitis patients
Patients received a single 3 mg/kg infusion
Conclusion: decrease in disease severity
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Safety of Biologics
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Safety: TNF-α Inhibitors
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Contraindications
Infliximab
Doses > 5 mg/kg in moderate to severe heart failure
Hypersensitivity to infliximab or murine protein
Adalimumab
None
Certolizumab pegol
None
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Warnings and Precautions
Serious infections
Invasive fungal infections
Malignancies
Hepatitis B virus reactivation
Hepatotoxicity*
Heart failure
Cytopenias
Hypersensitivity
Demyelinating disease
Lupus-like syndrome
Live vaccines
*Infliximab only
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Class Adverse Effects
Many are due to these products suppressing the immune system
Side effects among the different biologics are similar
Short-term side effects are low
Risk of long-term, more serious side effects is more unclear
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Class Adverse Effects: Black Box Warnings
Serious infection
Increased risk of serious infections leading to hospitalization or death, including TB, bacterial sepsis, invasive fungal infections, and infections due to other opportunistic pathogens.
Discontinue if develop serious infection.
Perform test for latent TB; if positive, start treatment before anti-TNF therapy. Monitor patients for active TB during therapy.
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Class Adverse Effects: Infection Risk
Pneumonia
Sepsis
Tuberculosis
Disseminated coccidiomycosis
Histoplasmosis
Listeriosis
Aspergillosis
Hepatitis B reactivation
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Class Adverse Effects: Black Box Warnings
Malignancy
Lymphoma and other malignancies, some fatal, have been reported in children and other adolescents treated with TNF blockers.
Postmarketing cases of fatal hepatosplenic T-cell lymphoma (HSTCL) have been reported in patients treated with TNF blockers. Majority were adolescent or young adult males. All had received prior concomitant therapy with 6-mercaptopurine or azathioprine.
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Class Adverse Effects: Serious
Heart failure
Lupus-like syndrome: shortness of breath, joint pain, rash on arms or face
Decreased blood cell counts
Nervous system problems: seizures, multiple sclerosis, optic neuritis
Hypersensitivity reactions
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Class Adverse Effects: Less Serious
Hypersensitivity reactions: injection site reactions
Upper respiratory infections
Bladder infection
New or worsening psoriasis
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Safety: Alpha-4 Integrin Inhibitor
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Contraindications & Warnings and Precautions
Contraindications Warnings and Precautions
Current or history of progressive multifocal encephalopathy (PML)
Serious infections including herpes encephalitis and meningitis
Hypersensitivity to natalizumab
Hypersensitivity reactions
Hepatotoxicity
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Adverse Effects: Black Box Warning
Increased risk of progressive multifocal leukoencephalopathy (PML), a viral opportunistic infection of the brain which generally leads to serious disability or death
Risk factors are duration of therapy, anti-JCV antibodies, and prior use of immunosuppressants. Weigh risk versus benefits before starting
Stop treatment at first sign of PML
Only available through restricted distribution program, TOUCH
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Progressive Multifocal Leukoencephalopathy
Caused by the JC virus
Signs and symptoms
Progressive weakness on one side of the body
Loss of control of limbs
Visual changes
Confusion
Personality changes
Death or severe disability typically results in weeks to months
No adequate treatment
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Adverse Effects
Incidence > 10%
Headache
Fatigue
Arthralgia
Diarrhea
Abdominal discomfort
Nausea
Rash
UTI
Lower RTI
Gastroenteritis
Vaginitis
Depression
Pain in the extremity
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Biologics in Pregnancy
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IBD in Pregnancy
Diagnosis is often made during the childbearing years
Goal is to achieve and maintain remission prior to pregnancy
Prior to conception, make sure receiving folate, calcium, and vitamin D supplements
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IBD: Fertility and Trait Inheritance
Fertility
Typically the same as non-IBD patients
Exceptions:
Patients with ileal pouch anal anastomosis (IPAA)
Crohn’s disease patients with inflammation affecting colon, fallopian tubes, or ovaries
Medications do NOT decrease female fertility
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Ileal Pouch Anal Anastomosis
From: http://www.microbiomejournal.com/content/1/1/9/figure/F1
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IBD: Fertility and Trait Inheritance
Risk of passing trait on to children
~7% with Crohn’s and less with ulcerative colitis
~37% if both parents have the disease
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IBD Effects on Pregnancy
Typically disease will be of the same intensity it was when conception occurred
Crohn’s disease may flare in 2nd and 3rd trimesters
Ulcerative colitis may flare in 1st trimester and post-partum period
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IBD Effects on Pregnancy
Typically no adverse effects on fetus
Possible increased risk of preterm delivery and low birth weight
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IBD Effects on Delivery
Most patients can have a normal vaginal delivery
Caesarean section is advised for patients with:
Peri-anal disease
Ileal pouch anal anastomosis
Increased risk of a venous thromboembolism (VTE)
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Biologics in Pregnancy
TNF-α inhibitors: infliximab (Remicade®), adalimumab (Humira®), certolizumab pegol (Cimzia®)
No increased risks of stillbirths, spontaneous abortions, or miscarriages
Does NOT pass into breast milk
Pregnancy category B
Thought to be SAFE
Avoid administration of live vaccines to infants until >6 mo of age
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Biologics in Pregnancy
Alpha-4 integrin inhibitor: natalizumab (Tysabri®)
Pregnancy category C
Limited information
Use when benefit outweighs risk
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Recent News for IBD
Pregnancy in Inflammatory Bowel Disease and Neonatal Outcomes: A National Prospective Registry (PIANO study) Started in August 2007
Enrolled over 1115 patients across the United States (896 delivered)
Objective: to determine whether there is a higher rate of adverse events in a prospective national sample of women from the US with IBD who are being treated with azathioprine/6MP or anti-TNF biologic drugs (infliximab, adalimumab, certolizumab). It compared women on these medications to women on no medications.
Data collection: each trimester of pregnancy, at delivery, and every four months in the first year of the child's life.
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Recent News for IBD
PIANO study continued
Some children will be followed until the age of 4 to look for an infection risk or other adverse effects from taking biologics
Results
IBD meds appear to be safe during pregnancy: not associated with congenital anomalies or altered newborn growth and development
Biologic therapy only: slight increased risk of C-sections and spontaneous abortions
Combination therapy: slight increased risk of preterm birth and infant infections at 12 months
No change in risk of infant infection with breastfeeding
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Patient Counseling Information
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Infection Control
Latent tuberculin skin test prior to treatment
If hepatitis B positive, complete treatment prior to biologic initiation
Ensure vaccine status is up to date
Do not take live vaccines during treatment
Yearly influenza vaccine
Avoid consumption of unpasteurized dairy products
Consider omitting dose of therapy around surgeries due to infection risk
Prosthetic valves
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Nutritional Support
Nutritional deficiencies are common in IBD
Multivitamin
Folic acid and vitamin B 12
Calcium and vitamin D
IBD is a risk factor for osteoporosis along with chronic steroid use
Food diaries
Identify association of food triggers with bowel symptoms
Triggers are unique for each patient
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Probiotics
Conflicting evidence on efficacy
Considered to be safe
VSL #3 has shown to be effective in decreasing flares in patients with pouchitis
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Colonoscopies
Patients are at an increased risk of colon cancer
Additional risk factors
Early age of onset
Disease duration
Extent of involvement
Family history of colorectal cancer
Frequency of colonoscopy depends on the extent and severity of disease
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Stress Reduction
Acupuncture and acupressure
Meditation
Deep breathing exercises
Exercise
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Medications to Avoid
NSAIDs
Increased bleeding risk
Increased risk of disease flares
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Injection Instructions for Subcutaneous Biologics
Injection sites: thigh or stomach
From: http://www.rxabbvie.com/pdf/humira.pdf
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Injection Instructions for Subcutaneous Biologics
Administration:
Check the expiration date before injecting
Do NOT use if the medication is cloudy or has large particles in it
Wipe the injection site with an alcohol swab
Inject at least 2 inches away from the belly button
Do NOT inject in any area that is bruised, red, or swollen
Rotate injection sites
Helpful tip: ice can be used to help numb the area before the injection
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Storage Instructions for Subcutaneous Biologics
Keep in the refrigerator
Do NOT freeze
Store in original package
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Do you know?
1) Which biologics are currently approved to treat IBD?
I. Natalizumab (Tysabri®)
II. Etanercept (Enbrel®)
III. Infliximab (Remicade®)
IV. Certolizumab pegol (Cimzia®)
V. Adalimumab (Humira®)
a) I, II
b) I, III, IV, V
c) II, III, IV, V
d) All of the above
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Answer
1) Which biologics are currently approved to treat IBD?
I. Natalizumab (Tysabri®)
II. Etanercept (Enbrel®)
III. Infliximab (Remicade®)
IV. Certolizumab pegol (Cimzia®)
V. Adalimumab (Humira®)
a) I, II
b) I, III, IV, V
c) II, III, IV, V
d) All of the above
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Do you know?
2. TNF-α inhibitors are safe to use in pregnancy.
a. True
b. False
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Answer
2. TNF-α inhibitors are safe to use in pregnancy.
a. True
b. False
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Questions?
From: http://lynleahz.com
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References
Moss A, Brinks V, Carpenter J. Review article: immunogenicity of anti-TNF biologics in IBD - the role of patient, product and prescriber factors. Alimentary Pharmacology & Therapeutics [serial online]. November 15, 2013;38(10):1188-1197.
Ardizzone S, Porro GB. Biologic therapy for inflammatory bowel disease. Drugs. 2005;65(16):2253-2286.
Targan SR, Hanauer SB, van Deventer SJH, et al. A short-term study of chimeric monoclonal antibody to cA2 to tumor necrosis factor α for Crohn’s disease. N Engl J Med. 1997;337:1029-1035.
Rutgeerts P, Feagan BG, Lichtenstein GR, et al. Comparison of scheduled and episodic treatment strategies of infliximab in Crohn’s disease. Gastroenterology. 2004;126:402-413.
Hanauer SB, Feagan BG, Lichtenstein GR, et al. Maintenance infliximab for Crohn’s disease: the ACCENT I randomized trial. Lancet. 2002;359:1541-1549.
D’Haens G, van Deventer S, van Hogezand R. Endoscopic and histological healing with infliximab anti-tumor necrosis factor antibodies in Crohn’s disease: a European multicenter trial. Gastroenterology. 1999;116:1029-1034.
Present DH, Rutgeerts P, Targan S, et al. Infliximab for the treatment of fistulas in patients with Crohn’s disease. N Engl J Med. 1999;340:1398-1405.
Ardizzone S, Maconi G, Colombo E, et al. Perianal fistulae following infliximab treatment: clinical and endosonographic outcome. Inflamm Bowel Dis. 2004;10:91-96.
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References
Sands BE, Anderson FH, Bernstein CN, et al. Infliximab maintenance therapy for fistulizing Crohn’s disease. N Engl J Med. 2004;350:876-885.
Best WR, Becktel JM, Singleton JW, et al. Development of a Crohn’s disease activity index. National Cooperative Crohn’s Disease Study. Gastroenterology. 1976;70(3):439-444.
Freeman HJ. Use of the Crohn’s disease activity index in clinical trials of biological agents. World J Gastroenterol. 2008;14(26):4127-4130.
Rutgeerts P, Feagan BG, Olson A, et al. A randomised placebo-controlled trial of infliximab therapy for active ulcerative colitis: Act I trial [abstract]. Gastroenterology. 2005;128:A689.
Sandborn WJ, Rachmilewitz D, Hanauer SB, et al. Infliximab induction and maintenance therapy for active ulcerative colitis: the Act 2 trial [abstract]. Gastroenterology. 2005;128:A688.
Schreiber S, Rutgeerts P, Fedorak R, et al. A randomized placebo-controlled trial of certolizumab pegol (CDP870) for treatment of Crohn’s disease. Gastroenterology. 2005;129(3):807-818.
Winter T, Wright J, Ghosh S, et al. Intravenous CDP870, a PEGylated Fab’ fragment of a humanized antitumour necrosis factor antibody, in patients with moderate-to severe Crohn’s disease: an exploratory study. Aliment Pharmacol Ther. 2004;20:1337-1346.
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References
Schreiber S. Certolizumab pegol for the treatment of Crohn’s disease. Therap Adv Gastroenterol. 2011;4(6):375-389.
Pregnancy in gastrointestinal disorders. American College of Gastroenterology. Available from: http://gastro.ucsd.edu/fellowship/Documents/PregnancyMonograph.pdf.
Freeman H. Developments in the treatment of moderate to severe ulcerative colitis: focus on adalimumab. Therapeutics & Clinical Risk Management. November 2013;9:451-456.
Panaccione R, Colombel J, Robinson A, et al. Adalimumab maintains remission of Crohn's disease after up to 4 years of treatment: data from CHARM and ADHERE. Alimentary Pharmacology & Therapeutics. November 15, 2013;38(10):1236-1247.
Louis E, Mary JY, Vernier-Massouille G, et al. Maintenance of remission among patients with Crohn’s disease on antimetabolite therapy after infliximab therapy is stopped. Gastroenterology 2012; 142: 63–70.
Cassinotti A, Ardizzone A, Porro GB. Adalimumab for the treatment of Crohn’s disease. Biologics. 2008;2(4):763-777.
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References
Knutson D, Greenberg G, Cronau H. Management of Crohn’s disease – a practical approach. Am Fam Physician. 2003;68(4):707-715.
Carter MJ, Lobo AJ, Travis SPL. Guidelines for the management of inflammatory bowel disease in adults. British Society of Gastroenterology. Gut. 2004;53:1-16.
Bernstein CN, Fried M, Krabshuis JH, et al. Inflammatory bowel disease: a global perspective. World Gastroenterology Organisation Global Guidelines. June 2009.
Remicade [package insert]. Horsham. PA: Janssen Biotech, Inc; November 2013. Humira [package insert]. North Chicago. IL: AbbVie Inc; January 2013. Cimzia [package insert]. Symrna. GA: UCB, Inc; October 2013. Ozer HTE, Ozbalkan Z. Clinical efficacy of TNF-α Inhibitors: an update. Int J Clin
Rheumatol. 2010;5(1):101-115. Hemstreet BA. Chapter 21. Inflammatory Bowel Disease. In: DiPiro JT, Talbert RL,
Yee GC, Matzke GR, Wells BG, Posey L. eds. Pharmacotherapy: A Pathophysiologic Approach, 9e. New York: McGraw-Hill; 2014. http://0-accesspharmacy.mhmedical.com.polar.onu.edu/content.aspx?bookid=689&Sectionid=45310476.
Tysabri [package insert]. Cambridge. MA: Biogen Idec Inc; December 2013. Mahadevan U, Ng SW. Management of inflammatory bowel disease in pregnancy:
medications. Expert Rev Clin Immunol. 2013;9(1):1-14.
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References
Smith M, Sanderson J. Management of inflammatory bowel disease in pregnancy. Obstetric Medicine (1753-495X). June 2010;3(2):59-64.
Habal F, Huang V. Review article: a decision-making algorithm for the management of pregnancy in the inflammatory bowel disease patient. Alimentary Pharmacology & Therapeutics. March 2012;35(5):501-515.
Lexicomp Database. Hudson (OH): 2012 [cited 2014 February 8]. Available from: http://online.lexi.com
Clinical Pharmacology. Tampa [Fl]: Gold Standard Multimedia Inc.; 2014 [cited 2014 February 8]. Available from: http://www.clinicalpharmacology.com
D'Haens G. Risks and benefits of biologic therapy for inflammatory bowel diseases. Gut. May 2007;56(5):725-732.