INFLAMMATORY BOWEL DISEASE. Brittany Palasik, PharmD, BCPS University of North Texas System College of Pharmacy

Transcription

1 INFLAMMATORY BOWEL DISEASE Brittany Palasik, PharmD, BCPS University of North Texas System College of Pharmacy

2 Pharmacist learning objectives By the end of this presentation, the pharmacist should be able to: Differentiate signs and symptoms, clinical presentation, and disease severity for ulcerative colitis and Crohn s disease. Identify the role in therapy for systemic corticosteroids, immunosuppressants, and monoclonal antibodies in the treatment of IBD. Construct an appropriate monitoring plan for evaluating the efficacy and toxicity of drug therapies for inflammatory bowel disease.

3 Technician learning objectives By the end of this presentation, the technician should be able to: Describe safe handling practices for all hazardous medications to treat inflammatory bowel disease. Identify storage criteria for medications to treat inflammatory bowel disease. Apply hazardous drug information to determine how to properly dispose of medications to treat inflammatory bowel disease.

4 Disclosures Most pharmacologic agents discussed have FDA approved indications for Inflammatory Bowel Disease Agents that are not mentioned in Inflammatory Bowel Disease Guidelines Golimumab (Simponi ) Tofacitinib (Xeljanz ) Lichtenstein et al. Am J Gastroenterol 2018;113:

5 Introduction Inflammatory Bowel Disease (IBD) Inflammatory condition of various regions of the GI tract Chronic, idiopathic, refractory disease Types Ulcerative Colitis (UC) Crohn s disease (CD) Intermediate colitis *Note: IBD is not related to irritable bowel syndrome Lichtenstein et al. Am J Gastroenterol 2018;113:

6 Etiology Genetic Infectious Lifestyle, dietary, medications Immunologic Psychological Friedman S, Blumberg RS. Inflammatory Bowel Disease. In: Jameson J, Fauci AS, Kasper DL, Hauser SL, Longo DL, Loscalzo J. eds. Harrison's Principles of Internal Medicine, 20e New York, NY: McGraw-Hill; Accessed January 11, Lichtenstein et al. Am J Gastroenterol 2018;113:

7 Immunologic etiology Everything is working well! Friedman S, Blumberg RS. Inflammatory Bowel Disease. In: Jameson J, Fauci AS, Kasper DL, Hauser SL, Longo DL, Loscalzo J. eds. Harrison's Principles of Internal Medicine, 20e New York, NY: McGraw-Hill; Accessed January 11, Lichtenstein et al. Am J Gastroenterol 2018;113:

8 Immunologic etiology Friedman S, Blumberg RS. Inflammatory Bowel Disease. In: Jameson J, Fauci AS, Kasper DL, Hauser SL, Longo DL, Loscalzo J. eds. Harrison's Principles of Internal Medicine, 20e New York, NY: McGraw-Hill; Accessed January 11, Lichtenstein et al. Am J Gastroenterol 2018;113:

9 Clinical presentation of IBD Abdominal pain or cramps** Diarrhea** Anemia Fatigue Weight loss Lichtenstein et al. Am J Gastroenterol 2018;113:

10 Differences in clinical features Crohn s Disease = transmural Friedman S, Blumberg RS. Inflammatory Bowel Disease. In: Jameson J, Fauci AS, Kasper DL, Hauser SL, Longo DL, Loscalzo J. eds. Harrison's Principles of Internal Medicine, 20e New York, NY: McGraw-Hill; Accessed January 11, 2019.

11 Ulcerative colitis Differences in clinical features Stomach Small Intestine Large intestine Crohn s Disease Distal Colon Rectum Friedman S, Blumberg RS. Inflammatory Bowel Disease. In: Jameson J, Fauci AS, Kasper DL, Hauser SL, Longo DL, Loscalzo J. eds. Harrison's Principles of Internal Medicine, 20e New York, NY: McGraw-Hill; Accessed January 11, Lichtenstein et al. Am J Gastroenterol 2018;113:

12 Differences in clinical features Clinical Features UC CD Rectal bleeding Transmural Cobblestone appearance Systemic symptoms Stricture/Fistula/ Abdominal Mass/ Granuloma Rare Absent Uncommon Rare Friedman S, Blumberg RS. Inflammatory Bowel Disease. In: Jameson J, Fauci AS, Kasper DL, Hauser SL, Longo DL, Loscalzo J. eds. Harrison's Principles of Internal Medicine, 20e New York, NY: McGraw-Hill; Accessed January 11, Lichtenstein et al. Am J Gastroenterol 2018;113:

13 Case Question 1 SJ is a 32-year old woman who presents to the ED with a 14-day history of cramping, abdominal pain, fever, fatigue, continuous vomiting and bloody stools/day. She has lost 9 kg (normal weight 78 kg). On physical exam, she has a small fistula. She is maintained on mesalamine 250mg 4 capsules BID. On admission, she is febrile, has a HR of 110 bmp and RR of 21 breaths/min. Which symptom of her IBD is most specific for Crohn s disease? A) Diarrhea B) Bloody stools C) Abdominal pain D) Fistula

14 Ulcerative colitis severity Severity Category Stools per day Blood Systemic toxicity Mild < 4 + or - None None Moderate or - Minimal None Other Lab Markers, Signs and Symptoms Severe Abdominal tenderness, bowel wall edema, ESR >30 Fulminant >10 Continuous (requires transfusions) + Abdominal pain, colon dilation, ESR >30 + = positive - = negative Systemic toxicity = anemia, fever, tachycardia ESR = erythrocyte sedimentation rate Kornbluth A, et al. Am J Gastroenterol 2010;105:

15 Crohn s disease severity Severity Category Mild- Moderate Moderate- Severe Severe- Fulminant CDAI Localized symptoms Weight loss Systemic toxicity Other Signs and Symptoms - <10% None Tolerates PO, no dehydration + >10% + Intermittent nausea and vomiting, anemia >450 + >10% + Abscess, cachexia, persistent vomiting, intestinal obstruction Treatment failure CDAI = Crohn s Disease Activity Index + = positive - = negative PO = by mouth Localized symptoms = abdominal tenderness Systemic toxicity = fever, rigors Lichtenstein et al. Am J Gastroenterol 2018;113:

16 Case Question 2 SJ is a 32-year old woman who presents to the ED with a 14-day history of cramping, abdominal pain, fever, fatigue, continuous vomiting and bloody stools/day. She has lost 9 kg (normal weight 78 kg). On physical exam, she has a small fistula. She is maintained on mesalamine 250mg 4 capsules BID. On admission, she is febrile, has a HR of 110 bmp and RR of 21 breaths/min. Which severity category does SJ fit into? A) Mild-moderate B) Moderate-severe C) Severe-fulminant

17 Treatment goals Non-curative disease Inducing remission within 3 months Maintaining remission (>3 months) Reducing steroid burden Improving QOL Preventing complications Lichtenstein et al. Am J Gastroenterol 2018;113:

18 General treatment approach Induction Treats a disease flare Typically 4-8 weeks of therapy, up to 16 weeks Commonly requires higher doses of medications Maintenance Preventing relapse of disease Taper drugs to the lowest effective doses Lichtenstein et al. Am J Gastroenterol 2018;113:

19 Monitoring Response to therapy Expected improvement: 2-4 weeks Maximal improvement: weeks Key points Monitor adverse effects closely Continue induction until remission or failure to improve Failure to improve: choose alternate therapy or advance to different treatment Lichtenstein et al. Am J Gastroenterol 2018;113:

20 Treatment options 5-ASA Antibiotics Immunomodulators Steroids Anti-TNF Leukocyte trafficking target + anti-p40

21 Aminosalicylates (5-ASAs) MOA: Localized inflammation: leukotrienes, free radical scavenging, inhibits TNF-α Examples: Mesalamine (many products on market) Pro-drugs: Sulfasalazine (sulfa allergy), Balsalazide Formulations Oral (all available as delayed release tablets) Topical (enema or suppository) ADEs Dose-dependent: N/V/D, anorexia, headache Dose-independent: fever, skin rash, agranulocytosis Lexi-Comp Online [Internet]. Hudson, Ohio: Lexi-Comp, Inc [cited 2019 Nov 19]. Lichtenstein et al. Am J Gastroenterol 2018;113:

22 Release sites for 5-ASAs Stomach Small Intestine Jejunum and below: Pentasa Terminal ileum and below: Asacol HD Large intestine Rectum: suppositories Proximal colon and below: Colazal (basalazide) Dipentum (olsalazine), Apriso, Lialda, Delzicol Rectum and distal colon: enemas Pharmacotherapy of Inflammatory Bowel Disease. In: Hilal-Dandan R, Brunton LL. eds. Goodman and Gilman's Manual of Pharmacology and Therapeutics, 2e New York, NY: McGraw-Hill

23 Handling of 5-ASAs Special storage criteria: Mesalamine delayed release products Delzicol - dispense with desiccant pouch inside Asacol HD : only good for 6 months after desiccant removed Lexi-Comp Online [Internet]. Hudson, Ohio: Lexi-Comp, Inc [cited 2019 Nov 19].

24 Topical (enema or suppository) E.g. Budesonide (Uceris ) 2 mg rectal foam For maintenance in mild to moderate disease in the colon Fact Sheet: Recently Approved Treatments (2018, June). Retrieved from: Lexi-Comp Online [Internet]. Hudson, Ohio: Lexi-Comp, Inc [cited 2019 Nov 19]. Lichtenstein et al. Am J Gastroenterol 2018;113: Corticosteroids MOA: blocks migration of leukocytes to reduce inflammation Oral (Budesonide CIR 9mg/day) High first pass metabolism (10-20% bioavailability) Site of action: distal ileum and ascending colon only Less systemic adverse effects than prednisone

25 Lexi-Comp Online [Internet]. Hudson, Ohio: Lexi-Comp, Inc [cited 2019 Nov 19]. Lichtenstein et al. Am J Gastroenterol 2018;113: Immunomodulators: Thiopurines MOA: metabolites incorporated into replicating DNA and halt replication Azathioprine (pro-drug) 6-mercaptopurine (6-MP) Adverse effects Allergic reactions, nausea Myelosuppression/infections, malignancy, hepatotoxicity, pancreatitis May take 3-6 months for efficacy Reduces immunogenicity against biologics

26 TPMT testing of thiopurines Enzymatic TPMT testing must be done PRIOR TO therapy initiation Guides dosing of thiopurines to prevent bone marrow suppression Thiopurines: TPMT testing Normal enzymatic activity = empiric weight-based dosing Intermediate enzymatic activity = consider 50% dose reduction Low enzymatic activity = 0-10% of normal dose or do not use medication Lexi-Comp Online [Internet]. Hudson, Ohio: Lexi-Comp, Inc [cited 2019 Nov 19]. Lichtenstein et al. Am J Gastroenterol 2018;113: Thiopurine Methyltransferase Testing TPMT. (2018, September) Retrieved from:

27 Lexi-Comp Online [Internet]. Hudson, Ohio: Lexi-Comp, Inc [cited 2019 Nov 19]. Lichtenstein et al. Am J Gastroenterol 2018;113: Immunomodulator: Methotrexate MOA: blocks dihydrofolate reductase, which DNA synthesis/ repair May take 3-6 months for efficacy Adverse effects Hepatic fibrosis/cirrhosis supplement with folic acid if cumulative dose >1.5g Bone marrow suppression Skin (SJS, TEN) N/V/D Pulmonary toxicity Teratogenicity (men and women)

28 Handling of Immunomodulators Safe handling: Methotrexate and azathioprine Injectable preparation: double gloving, protective gowns, ventilation control, controlled system transfer devices 6-mercaptopurine Receiving, handling: single gloving Preparing oral suspension: double gloving, protective gowns, controlled device preparation Special storage Injections: store 20-25⁰C, protect from light 6-mercaptopurine: tablets 20-25⁰C, suspension 15-25⁰C Lexi-Comp Online [Internet]. Hudson, Ohio: Lexi-Comp, Inc [cited 2019 Nov 19].

29 Lexi-Comp Online [Internet]. Hudson, Ohio: Lexi-Comp, Inc [cited 2019 Nov 19]. Lichtenstein et al. Am J Gastroenterol 2018;113: Monoclonal Antibodies: TNF-α inhibitors Options: infliximab IV (Remicade ), adalimumab SQ (Humira, certolizumab SQ (Cimzia ), golimumab SQ (Simponi ) Benefits shown within 2 weeks Before initiation: assess for latent/active TB, latent opportunistic infections, viral hepatitis Give appropriate vaccinations: pneumococcal, varicella, HPV, hepatitis A, inactivated flu, herpes zoster

30 Adverse effects of TNF-α inhibitors Common: headache, abdominal pain, nausea, hepatotoxicity, infection, infusion-related reactions Serious Antibody development (most with infliximab) Demyelinating diseases Heart failure Pancytopenia HBV reactivation Hypersensitivity BBW: risk of infection (~30%), risk lymphomas/other malignancies, risk tuberculosis Lexi-Comp Online [Internet]. Hudson, Ohio: Lexi-Comp, Inc [cited 2019 Nov 19]. Lichtenstein et al. Am J Gastroenterol 2018;113:

31 Biosimilars Biosimilars: cannot produce exact replica of a biologic Amino acid sequences are the same Potentially differences in drug properties and immunogenicity Ability for pharmacies to substitute biosimilars is determined by each state board of pharmacy Infliximab: Inflectra, Renflexis, Remsima, Ixifi Adalimumab: Cyltezo, Amjevita (available in 2023) Fact Sheet: Recently Approved Treatments (2018, June). Retrieved from: Lexi-Comp Online [Internet]. Hudson, Ohio: Lexi-Comp, Inc [cited 2019 Nov 19]. Lichtenstein et al. Am J Gastroenterol 2018;113:

32 Poll Question Would you substitute a biosimilar product for the brand name? Yes No

33 Therapeutic drug monitoring TNF-α inhibitors Performed during induction or maintenance All evidence is for induction AGA recommendation: use trough concentrations to help guide treatment changes in active IBD Infliximab trough: 5 mcg/ml Adalimumab trough: 7.5 mcg/ml Certolizumab pegol trough: 20 mcg/ml Gastroenterology 2017;S (17) Lichtenstein et al. Am J Gastroenterol 2018;113:

34 Types of treatment failure (TDM) Mechanistic Failure: choose another agent or class Adequate trough No antibody development Reason: inflammatory mediators not being blocked by current therapy Non-immune mediated PK failure: increase dose, shorten dosing interval, or add immunomodulator Low trough No antibody development Reason: rapid drug clearance Immune-mediated PK failure: choose another agent or class Trough low or undetectable Antibody development Reason: immune-mediated formation of antibodies against the drug Gastroenterology 2017;S (17) Lichtenstein et al. Am J Gastroenterol 2018;113:

35 Handling of TNF-α inhibitors All Maintain vials 2-8C Protect from light (except infliximab) Infliximab (Remicade ) Can store at room temp up to 6 months Certolizumab Prefilled syringes 25 C for 7 days Do not freeze Golimumab Do not freeze Room temperature for 30 days Adalimumab (Humira ) Can keep at room temp <25⁰C for 14 days Do not freeze Lexi-Comp Online [Internet]. Hudson, Ohio: Lexi-Comp, Inc [cited 2019 Nov 19].

36 Monoclonal antibodies: leukocyte adhesion/migration inhibitors Natalizumab (Tysabri ) and Vedolizumab (Entyvio ) Natalizumab (α4 subunit of integrin) Vedolizumab (α4β7 subunit of integrin) Contraindicated with immunosuppressants and TNF-α inhibitors Progressive Multifocal Leukoencephalopathy caused by JC virus Test for JC virus every 6 months Natalizumab REMS TOUCH Program Vedolizumab (lower risk, no REMS) Discontinue if no effect after 12 weeks (Natalizumab) and 14 weeks (vedolizumab) Lexi-Comp Online [Internet]. Hudson, Ohio: Lexi-Comp, Inc [cited 2019 Nov 19]. Lichtenstein et al. Am J Gastroenterol 2018;113:

37 Other monoclonal antibodies Ustekinumab (Stelara ) MOA: cytokines, IL-12/23, TNF-α Adverse effects: Posterior leukoencephalopathy syndrome (PLS), carcinoma, TB Tofacitinib (Xeljanz ) MOA: inhibition of Janus kinase (JAK) enzymes (affects gene expression related to cytokines) Only approved for adult ulcerative colitis Not recommended with TNF-alpha inhibitors or thiopurines Adverse effects: bone marrow suppression, prolonged PR interval, GI perforation, interstitial lung disease, dyslipidemia BBW: malignancy and TB Fact Sheet: Recently Approved Treatments (2018, June). Retrieved from: Lexi-Comp Online [Internet]. Hudson, Ohio: Lexi-Comp, Inc [cited 2019 Nov 19].

38 Monoclonal antibody adverse effects Antibody development Hepatotoxicity Herpes infection/increased infection risk Hypersensitivity Lexi-Comp Online [Internet]. Hudson, Ohio: Lexi-Comp, Inc [cited 2019 Nov 19]. Lichtenstein et al. Am J Gastroenterol 2018;113:

39 Handling of monoclonal antibodies Natalizumab (IV) and ustekinumab (IV) 2-8 ⁰C, do not freeze, protect from light, do not shake Vedolizumab (IV) 2-8 ⁰C, protect from light Tofacitinib (oral) Receiving, handling: single gloving Lexi-Comp Online [Internet]. Hudson, Ohio: Lexi-Comp, Inc [cited 2019 Nov 19].

40 Crohn s disease (CD) treatment New 2018 Guidelines New treatments added New treatment schematics Addressing therapeutic drug monitoring of TNF-α inhibitors Treatment based on disease severity, location of disease, and extra-intestinal activity Steroid-dependent vs. steroid-refractory Lichtenstein et al. Am J Gastroenterol 2018;113:

41 CD: mild-moderate Category General Principles 5-ASA Corticosteroids Induction Outpatient management Non-pharmacologic: optimize nutrition Symptoms: loperamide No benefit as monotherapy or added to steroids Only budesonide CIR for disease limited to ileum and colon Maintenance No great options No benefit Not effective long term Budesonide CIR loses efficacy after 4 months Lichtenstein et al. Am J Gastroenterol 2018;113:

42 CD: moderate-severe induction Remission: Taper prednisone Tapering: Prednisone by 5 mg/week until 20 mg Then by mg/ week until discontinuation Do not exceed 3 months total Prednisone mg/day Wait and see (1-2 weeks) Not in remission? Add MTX or thiopurine Add TNF-α Switch to monoclonal Steroids are associated with abscesses and fistulas 1 in 5 patients will be refractory to corticosteroids Lichtenstein et al. Am J Gastroenterol 2018;113:

43 CD: moderate-severe maintenance Use whichever agent worked to induce remission as maintenance Steroid-induced remission = methotrexate or thiopurine Remission: Taper prednisone Prednisone mg/day Wait and see (1-2 weeks) Not in remission? Add MTX or thiopurine Add TNF-α Switch to monoclonal Lichtenstein et al. Am J Gastroenterol 2018;113:

44 Severe-fulminant CD IV steroids Remission: Change to prednisone PO If no response to IV steroids: start anti-tnf-α Slowly taper prednisone Reintroduce maintenance Remission: maintenance therapy IV methylprednisolone mg/day (7 days) Patients may need bowel rest Lichtenstein et al. Am J Gastroenterol 2018;113:

45 Case Question 3 SJ is a 32-year old woman who presents to the ED with a 14-day history of cramping, abdominal pain, fever, fatigue, continuous vomiting and bloody stools/day. She has lost 9 kg (normal weight 78 kg). On physical exam, she has a small fistula. She is maintained on mesalamine 250mg 4 capsules BID. On admission, she is febrile, has a HR of 110 bmp and RR of 21 breaths/min. Which therapy is most appropriate? A) Increase mesalamine dose to 4g/day B) Administer cyclosporine 4mg/hr by continuous infusion C) Obtain surgery consult for an immediate colectomy D) Administer methylprednisolone IV E) Start prednisone 40mg PO daily

46 Case Question 4 SJ responded to IV methylprednisolone and has gone into remission. Which of the following agents should be initiated for maintenance therapy? A) Prednisone 40 mg PO daily B) Adalimumab (Humira ) C) Mesalamine oral tablet D) Methotrexate

47 Case Question 5 How should the pharmacy technician handle methotrexate? What should the pharmacist tell SJ about handling her methotrexate?

48 Ulcerative colitis (UC) Located in the rectum and colon Extensive disease!!! must give oral therapy Colon Rectum Distal Disease Kornbluth A, et al. Am J Gastroenterol 2010;105:

49 Mild-moderate UC Distal disease Induction Rectal mesalamine preferred* Optional: combination with oral 5-ASAs and/or topical steroids If refractory: oral prednisone or infliximab Maintenance Rectal +/- oral 5-ASA If refractory: thiopurines, infliximab No topical or systemic steroids* Extensive disease Induction Oral 5-ASA +/- rectal If refractory: systemic steroids If refractory to steroids and 5- ASAs: Thiopurines or infliximab Maintenance Oral 5-ASA +/- rectal 5-ASA If refractory: thiopurines, infliximab No topical or systemic steroids* Kornbluth A, et al. Am J Gastroenterol 2010;105:

50 Severe or fulminant UC Induction IV steroids No response in 3-5 days (Steroid failure) IV cyclosporine Possibly infliximab Colectomy- last line Maintenance options (if respond to IV steroids or IV cyclosporine) Thiopurine Anti-TNF-α +/- thiopurine Vedolizumab +/- immunomodulator Maintenance options (if respond to infliximab) Infliximab +/- thiopurine Kornbluth A, et al. Am J Gastroenterol 2010;105:

51 Summary Inflammatory bowel disease is a chronic inflammatory condition Refractory disease typically fluctuating between active disease and remission Therapeutic drug monitoring can help properly adjust TNF-α inhibitors Pharmacists can help select appropriate treatments for IBD based on patient and agent-related factors

52 INFLAMMATORY BOWEL DISEASE Brittany Palasik, PharmD, BCPS University of North Texas System College of Pharmacy