Remicade in GI Patients (Nursing In-Service)

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Provided to the general surgery nursing staff at St Paul's Hospital, Vancouver, British Columbia on August 20 and 22, 2013.

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  • TNF-α is a cytokine that is expressed by cells such as macrophages, monocytes, and T cells evokes two types of responses in cells: (1) proinflammatory effects, and (2) induction of apoptotic cell death The proinflammatory effects upregulation of adhesion molecule expression induction of secondary cytokines and chemokines (3) overexpression contributes to chronic inflammatory processes Infliximab is a chimeric human-murine immunoglobulin G 1  kappa (IgG 1  kappa) monoclonal antibody linked variable regions of mouse antihuman TNF MAb to human IgG1 has high affinity for and binds to soluble and transmembrane forms of TNF-α inhibits binding of TNF to cell surface TNF receptors effectively neutralizes TNF-α and blocks pro-inflammatory mechanism, although it's full mechanism of action is not well-understood may also cause cytotoxicity and apoptosis of T lymphoctes and monocytes, and down-regulation of other proinflammatory cytokines (4) to cause immunosuppression
  • chronic inflammatory diseases (which also include rheumatoid arthritis, and psoriasis) more specific to this ward, we see GI patients who may have come in for Crohn's Disease or Ulcerative Colitis exacerbation/resection it's beyond the scope of this presentation to discuss the diseases in detail, but Crohn’s disease (has specific SPA request form with pharmacare, must have failed 5-ASA + glucocorticoid + one of the immunosuppressants) Induce and maintain clinical remission in adults and pediatric patients with moderately to severely active disease with inadequate response to conventional therapies Reduce the number of draining enterocutaneous and rectovaginal fistulas Maintain fistula closure in adults with fistulising Crohn’s Ulcerative Colitis (approved by pharmacare on case-by-case basis, first dose must be trialed) in patients with moderately to severely active ulcerative colitis who have had an inadequate response to conventional therapies reduce the signs and symptoms of the disease induce and maintain clinical remission in adults and pediatric patients eliminate use of corticosteroids induce and maintain mucosal healing in adults.(1)
  • Infections: due to body now having impairment of immune response; particularly worry about reactivation of latent tuberculosis (350/400,000 patients, highest risk within 2 months after first infusion)(4) Latient TB treatment should be initiated before starting infliximab. TB appears to occur more frequently than other opportunistic infections (legionellosis or listeriosis; hepatitis B virus reactivation may also occur rarely.(5) Anti-infliximab antibodies possibly associated with occurrence of infusion reactions and decreased by concomitant immunosuppressive therapy.(6) Acute infusion reactions occur within 24 hours and delayed ones develop 2–14 days after initiation of treatment. Acute reactions can be true allergic, namely IgE-mediated type I reactions (anaphylactic reactions), including hypotension, bronchospasm, wheezing and/or urticaria. However, the great majority of infusion reactions reported during infliximab treatment are characterized by more nonspecific symptoms and are often classified as anaphylactoid ones (i.e. probably nonallergic) [5]. A range of symptoms including headache, nausea, fever or chills, dizziness, flush, pruritus, and chest or back pain have been described in relation to infusions Antinuclear antibodies (antibodies targeted against cell nuclei): Cases of lupus-like syndrome have been reported, but in the majority of patients the appearance of ANAs did not have any clinical significance (6) Heart failure: use with caution in mild NYHA Class I or II HF, doses >5mg/kg should not be administered in patients with mod-severe HF (III or IV) The ATTACH trial (anti-TNFα therapy against chronic heart failure) enrolled 150 patients with CHF to investigate the impact of treatment with infliximab, a chimeric (mouse/human) IgG1 monoclonal antibody that binds both soluble and membrane bound TNFα.27 It is administered intravenously. Like RENAISSANCE and RECOVER, this study was designed in a multicentre, randomised, double blind, placebo controlled fashion.27 It has also been stopped prematurely. However, when analysing the data from ATTACH it is noteworthy that the plasma values of infliximab achieved in the patients were many times higher than expected. This may account for the increased risk of death in the group receiving the higher dose of infliximab (10 mg/kg body weight) observed in this study (RR 2.84, 95% CI 1.01 to 7.97; p < 0.05). There was no adverse risk associated with 5 mg/kg body weight infliximab (RR 0.80, 95% CI 0.22 to 2.99) and in fact in patients receiving this dose LVEF improved (p < 0.05).27 (7,8) Further studies needed to clarify regarding: malignancies (possible increased risk in non-Hodgkin's lymphoma, reported in 3 patients treated for CD), demyelinization disorders (multiple sclerosis, optic neuritis)(4), but they are serious enough conditions that we should keep them in mind
  • + other drugs that affect the immune system: Echinacea: May diminish the therapeutic effect of Immunosuppressants.  Risk D: Consider therapy modification Leflunomide: Immunosuppressants may enhance the adverse/toxic effect of Leflunomide. Specifically, the risk for hematologic toxicity such as pancytopenia, agranulocytosis, and/or thrombocytopenia may be increased. Management: Consider not using a leflunomide loading dose in patients receiving other immunosuppressants. Patients receiving both leflunomide and another immunosuppressant should be monitored for bone marrow suppression at least monthly.  Risk D: Consider therapy modification Tacrolimus (Topical): May enhance the adverse/toxic effect of Immunosuppressants.  Risk X: Avoid combination + vaccines: Inactivated: Immunosuppressants may diminish the therapeutic effect of Vaccines (Inactivated).  Risk C: Monitor therapy Live: Immunosuppressants may enhance the adverse/toxic effect of Vaccines (Live). Vaccinial infections may develop. Immunosuppressants may diminish the therapeutic effect of Vaccines (Live). Management: live-attenuated vaccines should not be given for at least 3 months after immunosuppressants.  
  • Physicians and Pharmacists will usually take care of this, but keep in mind that the following must be checked before a patient can be initiated on infliximab:
  • Crohn's disease:  I.V.: 5 mg/kg at 0, 2, and 6 weeks, followed by 5 mg/kg every 8 weeks thereafter; dose may be increased to 10 mg/kg in patients who respond but then lose their response. If no response by week 14, consider discontinuing therapy. Ulcerative colitis:  I.V.: 5 mg/kg at 0, 2, and 6 weeks, followed by 5 mg/kg every 8 weeks thereafter Follow Initial Infliximab Infusion Orders (PPO) Infuse at 20 mL/hr x15mins, 80 mL/hr x15mins, 125 mL/hr until complete Compatibility  Stable in NS; do not infuse with other agents (uptodate)
  • Monitoring and Management of Side Effects: Vitals prior, q30 minutes during infusion, 1 hr post-infusion Sn/sx: headache, vasodilatation, flushing, pruritis, rash, hives, respiratory distress (wheeze or stridor), swelling of lips or larynx, hypotension, abdominal pain, hypoxemia, flu-like symptoms If mild infusion reactions (no resp distress or vascular instability): Stop infusion May give APAP 650mg po, diphenhydramine 25-50mg, hydrocortisone 200mg IV or prednisone 40mg po Call Dr If symptoms clear, restart infusion at ½ previous rate Continue monitoring minimum 6 hours If anaphylactic reaction: Stop infusion Give 0.5 mL aqueous adrenaline 1:1000 sc Give NS 1L bolus Give Salbutamol 5mg via nebulizer q15min prn if respiratory wheeze prominent May give diphenhydramine 25-50mg May give hydrocortisone 200mg IV or prednisone 40mg PO Carry out other emergency/resuscitative measures as necessary Continue monitoring minimum 24-48 hours
  • Remicade in GI Patients (Nursing In-Service)

    1. 1. NURSING IN-SERVICE: REMICADE®(INFLIXIMAB) IN GI PATIENTS 10A/B Surgery Ward, St. Paul’s Hospital August 20 & 22, 2013 Joan Ng, B. Sc. Pharm, Pharmacy Resident 1
    2. 2. Outline 2 1. Introduction 2. Pharmacology 3. Indications 4. Side Effects 5. Contraindications 6. Drug Interactions 7. Practical Considerations 8. Question & Answer
    3. 3. What is Remicade®? 3  Generic drug name: Infliximab  Manufacturer: Janssen Inc.  Formulation: 100 mg/vial powder for solution (reconstituted by pharmacy), to be administered as an IV infusion  Drug Class: tumor necrosis factor alpha (TNF- α) inhibitor Reference: 2
    4. 4. Pharmacology 4  TNF-α = pro-inflammatory cytokine  Infliximab = chimeric human-murine IgG MAb  Infliximab binds to TNF-α  Neutralizes TNF-α, blocks inflammation  Apoptosis of T-lymphocytes and monocytes  Down-regulation of other pro-inflammatory cytokines Reference: 2-5
    5. 5. Indications (focus: GI) 5  Chronic inflammatory diseases  Crohn’s Disease (Moderate-Severe)  Ulcerative Colitis (Moderate-Severe)  For patients with inadequate response to conventional therapies  Induce and maintain remission  Maintain fistula closure (in fistulizing Crohn’s)  Induce and maintain mucosal healing (UC) Reference: 2
    6. 6. Side Effects / Safety Concerns 6 Resp Upper respiratory tract infection (32%) GI Nausea (21%) Abdominal pain (12%; Crohn’s 26%) Misc Antinuclear antibodies (~50%) Infection (36%) Infusion reactions (20%; severe <1%) Malignancies (<5%) Reference: 5-9
    7. 7. Contraindications 7  Hypersensitivity to infliximab, any component of the formulation  Doses >5 mg/kg in patients with moderate or severe heart failure (NYHA Class III/IV)  Severe infections  Sepsis, Abscesses  Tuberculosis  Opportunistic infections Reference: 6
    8. 8. Drug Interactions 8  Other drugs that stimulate/suppress immune system  Vaccines  Inactivated  Live Reference: 6
    9. 9. Practical: Screening/Preparation 9  TB Skin Test and follow-up CXR if (+)  Hepatitis B virus evaluation  Rule out infection/abscesses (C. diff, T, WBC)  Arrange for 1-to-1 nursing  Crohn's: Pharmacare Special Authority must be applied before start ($3000 per dose!)  Ulcerative Colitis: hospital provides first dose; if respond to first dose, then we submit to SA Reference: 10
    10. 10. Practical: Drug Administration 10  I.V.: 5 mg/kg at 0, 2, and 6 weeks, followed by 5 mg/kg every 8 weeks thereafter  MD present for first 10 minutes of first dose  Follow Initial Infliximab Infusion Orders (PPO) Infuse at 20 mL/hr x15mins, 80 mL/hr x15mins, 125 mL/hr until complete  Compatibility: Stable in NS; do not infuse with other agents Reference: 6
    11. 11. Practical: Monitoring & SE Management 11  Vitals prior to start, q30 minutes during infusion, and at least 1 hour post-infusion  Monitor signs/symptoms of infusion reaction:  headache, flushing, pruritis, rash, hives, respiratory distress, swelling of lips or larynx, hypotension, abdominal pain, hypoxemia, flu-like symptoms  Follow PPO for management of acute reactions  Mild infusion reactions: monitor for min 6h  Anaphylactic reaction: monitor for min 24-48h
    12. 12. Questions? 12
    13. 13. References 1. Government of Canada HC. Drug Product Database Online Query [Internet]. 2012 [cited 2012 Sep 17]. Available from: http://webprod3.hc-sc.gc.ca/dpd-bdpp/dispatch-repartition.do?lang=eng 2. Infliximab: AHFS Drug Information [Internet]. [cited 2013 Aug 14]. Available from: http://www.medicinescomplete.com 3. Järnerot G, Hertervig E, Friis-Liby I, Blomquist L, Karlén P, Grännö C, et al. Infliximab as Rescue Therapy in Severe to Moderately Severe Ulcerative Colitis: A Randomized, Placebo-Controlled Study. Gastroenterology. 2005 Jun;128(7):1805–11. 4. AccessMedicine | Tumor Necrosis Factor: The Other Primary Cytokine [Internet]. [cited 2013 Aug 14]. Available from: http://www.accessmedicine.com.ezproxy.library.ubc.ca 5. Poggioli G, Laureti S, Campieri M, Pierangeli F, Gionchetti P, Ugolini F, et al. Infliximab in the treatment of Crohn’s disease. Ther Clin Risk Manag. 2007 Jun;3(2):301–8. 6. AccessMedicine | InFLIXimab [Internet]. [cited 2013 Aug 15]. Available from: http://www.accessmedicine.com.ezproxy.library.ubc.ca 7. Kapetanovic MC, Larsson L, Truedsson L, Sturfelt G, Saxne T, Geborek P. Predictors of infusion reactions during infliximab treatment in patients with arthritis. Arthritis Res Ther. 2006 Jul 26;8(4):R131. 8. Anker SD, Haehling S von. Inflammatory mediators in chronic heart failure: an overview. Heart. 2004 Apr 1;90(4):464–70. 9. Chung ES, Packer M, Lo KH, Fasanmade AA, Willerson JT. Randomized, Double-Blind, Placebo-Controlled, Pilot Trial of Infliximab, a Chimeric Monoclonal Antibody to Tumor Necrosis Factor-α, in Patients With Moderate-to-Severe Heart Failure Results of the Anti-TNF Therapy Against Congestive Heart failure (ATTACH) Trial. Circulation. 2003 Jul 1;107(25):3133–40. 10. Mowat C, Cole A, Windsor A, Ahmad T, Arnott I, Driscoll R, et al. Guidelines for the management of inflammatory bowel disease in adults. Gut. 2011 May 1;60(5):571–607. 13

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