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Gastrointestinal Disorders e. The AHA recommends that ibuprofen be taken at least 30 minutes after or 8 hours before the ingestion of immediate-release low-dose aspirin to prevent the ibuprofen from attenuating the antiplatelet effects of the aspirin. Patient Cases 2. A 68-year-old woman re...

Gastrointestinal Disorders e. The AHA recommends that ibuprofen be taken at least 30 minutes after or 8 hours before the ingestion of immediate-release low-dose aspirin to prevent the ibuprofen from attenuating the antiplatelet effects of the aspirin. Patient Cases 2. A 68-year-old woman referred to a gastroenterologist has intermittent upper abdominal pain with anemia and heme-positive stools. She has a history of hypertension and type 2 diabetes with peripheral neuropathy. She reports no known drug allergies and takes metformin 1000 mg twice daily, aspirin 325 mg daily, lisinopril 20 mg daily, and gabapentin 1000 mg three times daily. In addition, she reports using OTC ketoprofen daily for the past 2 months secondary to uncontrolled pain. The results of a colonoscopy are negative, but endoscopy reveals a 1-cm gastric ulcer with an intact clot. A rapid urease test for CLO is negative. Which treatment is best for this patient’s ulcer? A. Cimetidine 800 mg twice daily for 4 weeks. B. Lansoprazole 30 mg twice daily plus amoxicillin 1000 mg twice daily plus clarithromycin 500 mg twice daily for 10 days. C. Lansoprazole 30 mg/day for 8 weeks. D. Misoprostol 200 mcg twice daily for 8 weeks. 3. A 42-year-old man is in the clinic with the chief concern of sharp epigastric pain for the past 6 weeks. He states that the pain is often worse with eating and that it is present at least 5 days/week. He states that although he initially tried OTC antacids with some relief, the pain returns about 3 hours after each dose. He currently takes no other medications. He reports an allergy to sulfa-containing medications (rash). His practitioner is concerned about a potential peptic ulcer and tests him for H. pylori using a UBT, the result of which is positive. Which treatment for H. pylori is best? A. Amoxicillin 1 g twice daily plus clarithromycin 500 mg twice daily plus omeprazole 20 mg twice daily for 5 days. B. Cephalexin 1 g twice daily plus clarithromycin 500 mg twice daily plus omeprazole 20 mg twice daily for 10 days. C. Bismuth subsalicylate 525 mg four times daily plus tetracycline 500 mg four times daily plus metronidazole 500 mg three times daily plus omeprazole 20 mg twice daily for 14 days. D. Levofloxacin 500 mg once daily plus metronidazole 500 mg twice daily plus omeprazole 20 mg twice daily for 21 days. III. UPPER GI BLEEDING A. Causes of upper GI bleeding 1. Peptic ulcer disease (40%–70%) due to NSAIDs and low-dose aspirin use or H. pylori 2. Esophagitis 3. Erosive disease 4. Esophageal varices 5. Mallory-Weiss tear (longitudinal mucosal lacerations in the lower esophagus or upper stomach) 6. Neoplasm 7. Stress ulcers (critically ill patients) ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-129 Gastrointestinal Disorders B. Clinical Symptoms and Presentation 1. Hematemesis or “coffee-ground” emesis 2. Hematochezia 3. Nausea, vomiting 4. Melena 5. Shock (tachycardia, clammy skin) 6. Hypotension 7. Associated organ dysfunction (renal, hepatic, cardiac, cerebral hypoperfusion) Box 2. Clinical Predictors of Death Associated with Nonvariceal Upper GI Bleeding Advanced age (> 75 yr at highest risk) Blood in gastric aspirate Continued bleeding or rebleeding > 1 comorbid condition Elevated aminotransferases Elevated serum urea Red blood on rectal examination SCr > 150 μmol/L (1.7 mg/dL) Sepsis Shock or hypotension Box 3. Predictors of Persistent or Recurrent Upper GI Bleeding Age > 65 yr Blood in gastric aspirate Coagulopathy Comorbid illness Endoscopic findings: Active bleeding on endoscopy Presence of high-risk stigmata Adherent clot Erratic mental status Gastric or duodenal ulcer Hematemesis Initial hemoglobin < 10 g/dL or hematocrit < 30% Location of ulcer on superior or posterior wall Melena Ongoing bleeding Red blood on rectal examination Shock (systolic blood pressure < 100 mm Hg) Ulcer size ≥ 2 cm C. Management of ulcer-related GI bleeding 1. Volume resuscitation and hemodynamic stabilization a. Placement of one or two large-bore intravenous catheters b. Replacement with crystalloid such as 0.9% normal saline is preferred; colloids such as blood can be given after initial resuscitation in patients with hemoglobin of less than 7 g/dL to maintain a hemoglobin concentration of 8–10 g/dL. 2. Risk stratification a. Clinical signs and symptoms b. Use of clinical scoring scales such as Glasgow-Blatchford scores to determine the risk of early rebleeding and the need for urgent versus nonemergency intervention. Patients with very low risk of rebleeding (Glasgow-Blatchford score of 0–1) can be discharged for outpatient follow-up (conditional recommendation, very-low-quality evidence). c. Placing an NG tube for aspiration can be considered but is not required. d. Endoscopy (within 24 hours if possible, 12 hours with high-risk clinical features) e. Assessment of comorbid illnesses (liver disease, coagulopathies, cardiac status) f. Predictive factors of death with upper GI bleed are listed in Box 2. Predictors of persistent or recurrent GI bleeding are listed in Box 3. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-130 Gastrointestinal Disorders 3. Endoscopic therapy a. Endoscopic therapy is associated with reductions in rebleeding, need for surgery, and mortality. Perform within 24 hours of presentation. b. The combination of injection and coaptive therapy is the most efficacious; the use of either technique plus pharmacotherapy is superior to monotherapy. 4. Pharmacotherapeutic management of nonvariceal upper GI bleeding a. Remove medications that are contributing to bleeding (e.g., NSAIDs). b. PPI therapy i. Use of a pre-endoscopic dose (80-mg intravenous bolus, followed by an 8-mg/hour intravenous infusion) of PPI may be considered. This does not result in reduced mortality, surgery, or rate of rebleeding, but it can reduce the lesion size, the possibility of finding a high-risk lesion, and the need for endoscopic therapy. PPIs may be given if endoscopy will be delayed or cannot be performed. ii. Continuous or intermittent proton pump inhibitor antisecretory therapy is recommended (Am J Gastroenterol 2021;116:899-917). (a) Bolus 80 mg plus a continuous infusion of 8 mg/hour for 72 hours after endoscopic therapy for patients with active bleeding or nonbleeding visible vessel or with adherent clot. Intravenous pantoprazole or esomeprazole can be used; most data are with intravenous omeprazole (used in Europe). (b) Intermittent intravenous or oral PPI therapy (80-mg intravenous bolus followed by 40 mg two to four times daily for 3 days) is safe and effective. iii. Associated with decreases in rebleeding, mortality, and need for surgery in patients with active bleeding who have undergone successful endoscopic intervention. iv. Patients who received endoscopic hemostatic therapy and short-term, high-dose PPI should receive twice-daily PPI therapy for 2 weeks (conditional recommendation, low-quality evidence). v. Oral once-daily PPI therapy can be used for patients with a flat spot or clean-based ulcer. c. The use of H2RAs or somatostatin-octreotide is not recommended. d.  Test for H. pylori and treat if results are positive. If result are negative, then retest. There is no need for a PPI after eradication. e. Assess the need for continued secondary prevention with PPI therapy. If needed, a single daily oral dose of a PPI is recommended. f. Assess the need for NSAID or aspirin use. If NSAID therapy is needed, then use of a COX-2 inhibitor plus a PPI is recommended, barring any significant CV risk. Otherwise, a PPI should be used. g. If the use of low-dose aspirin is required, reinitiate when CV risk is thought to outweigh GI risk. Use a PPI and reinitiate aspirin within 1–3 days, if not within 1 week. Clopidogrel has a higher rate of rebleeding than aspirin. h. Long-term PPI therapy is recommended for ulcers not associated with NSAIDs or H. pylori. D. Prophylaxis of SRMD in critically ill patients 1. Stress-related injury: Superficial diffuse upper GI ulceration 2. Stress ulcer: Deeper mucosal ulceration; may lead to bleeding and hemodynamic compromise 3. Contributing factors to SRMD development a. Hypoperfusion of the GI tract b. Altered susceptibility to gastric acid c. Loss of defense mechanisms: mucous/bicarbonate layer, prostaglandins, cellular renewal d. Alterations in gastric motility; may affect absorption of drugs 4. Pharmacologic prevention a. Not routinely recommended in non–intensive care unit settings ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-131 Gastrointestinal Disorders b. Recommended in patients in an intensive care unit with the risk factors in Box 4. Box 4. Risk Factors for Initiation of Prophylaxis for SRMD in Intensive Care Units Mechanical ventilation > 48 hra Coagulopathy (platelet count < 50,000/mm3, INR > 1.5)a Thermal injury (> 35% BSA) Severe head or spinal cord injury GI bleeding or ulceration within past year Multiple trauma (injury severity score > 16) Perioperative transplant period Low intragastric pH Major surger y (lasting > 4 hr) Acute lung injury Two or more of the following: Sepsis syndrome ICU stay > 1 wk Occult bleeding High-dose corticosteroids (250 mg of hydrocortisone equivalent) Hepatic failure Acute renal insufficiency Hypotension Anticoagulation a Independent risk factors for SRMD. BSA = body surface area; ICU = intensive care unit; INR = international normalized ratio; SRMD = stress-related mucosal disease. 5. Preventive treatment options a. Proton pump inhibitors i. The American Society of Health-System Pharmacists guidelines include minimal recommendations for PPI use because of the lack of data at that time; however, PPIs are commonly used for SRMD prevention. ii. PPIs are similar to H2RAs in safety and efficacy. iii. Oral or intravenous routes may be used and are equally effective for maintaining gastric pH. Alternative formulations exist for patients with difficulty swallowing or with feeding tubes (see section on GERD). iv. In a recent trial, 3298 patients with unplanned intensive care unit admission were randomized to receive either pantoprazole 40 mg intravenously daily or placebo. Mortality at 90 days (primary end point; RR 1.02; 95% CI, 0.91–1.13) and composite event rate, including clinically important GI bleeding, pneumonia, Clostridioides difficile infection, or myocardial infarction (RR 0.96; 95% CI, 0.83–1.11), were similar between groups. Clinically important GI bleeding occurred in 2.5% of patients receiving pantoprazole compared with 4.2% of patients receiving placebo (RR 0.58; 95% CI, 0.4–0.86) (N Engl J Med 2018;379:2199-208). b. H2RAs i. Reduce gastric acid secretion by inhibition of histamine stimulation of the parietal cell; development of tolerance or tachyphylaxis with continued use. ii. Considered efficacious in the prevention of clinically significant bleeding; oral, intravenous intermittent dosing, and continuous infusion are all possible options. High-dose intravenous (cimetidine or famotidine) use can be considered first-line therapy. Cimetidine is the only H2RA that is FDA approved for SRMD prevention. iii. Associated with CNS adverse effects and the rare development of thrombocytopenia; require adjustment for renal dysfunction c. Antacids require several oral doses per day or administration by enteral tube. Diarrhea, constipation, and electrolyte abnormalities are possible. d. Sucralfate i. Provides a direct mucosal barrier; modulates pepsin, mucus activity, bicarbonate secretion, and tissue growth repair ii. Requires many oral doses or administration by enteral tube. May lead to aluminum accumulation and constipation. Possibility of binding to other drugs in GI tract. No effect on platelet count and associated with lower rates of pneumonia development. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-132 Gastrointestinal Disorders IV. INFLAMMATORY BOWEL DISEASE A. Background 1. Inflammatory bowel disease (IBD) includes both UC and CD. In some instances, UC may be indistinguishable from CD, called indeterminate or intermediate colitis. 2. Pathophysiology: The exact cause of continuing inflammation of the GI mucosa is unknown, but it is thought that the inflammation is secondary to an antigen-driven response. 3. Contributing factors a. Defects in the intestinal epithelial barrier and immune system b. There is a definite genetic association; first-degree relatives of affected patients have a 4–20-fold greater risk of developing IBD. c. Environmental i. NSAIDs: Worsen IBD, probably secondary to alteration of epithelial barrier ii. Smoking: Worsens CD; associated with improvement in UC symptoms iii. Luminal bacteria: Endogenous intestinal bacteria thought to be highly involved in stimulating the intestinal inflammatory response observed in IBD iv. Dietary antigens may also contribute to ongoing inflammation. d. Various proinflammatory cytokines, including interleukin-1, interleukin-6, and tumor necrosis factor (TNF), contribute to the ongoing inflammatory process. B. Clinical features 1. Presenting symptoms common to UC and CD include fever, abdominal pain, diarrhea (may be bloody, watery, or mucopurulent), rectal bleeding, and weight loss. Symptoms can vary depending on disease location. See Table 8 for the clinical features of IBD. Table 8. Clinical Features of Inflammatory Bowel Disease Clinical Findings Bowel involvement Perianal involvement Depth of ulceration Continuous inflammation Histology Fistula, perforation, or strictures Development of toxic megacolon Malabsorption or malnutrition Ulcerative Colitis Confined to rectum and colon Terminal ileal involvement (backwash ileitis) in a minority of patients Unlikely Superficial Very common Nontransmural, crypt abscesses Very uncommon Yes Rare Yes May extend to submucosa or deeper Rarely, a patchy, “cobblestone” appearance Transmural lesions, granulomas Yes No Yes, often vitamin deficiencies; possible growth retardation in children Uncommon unless disease affects colon Fairly uncommon Risk factor for colorectal cancer Yes Pseudopolyps Crohn Disease May be anywhere from mouth to anus (66% of cases located in ileum) Common ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-133 Gastrointestinal Disorders 2. 3. Systemic manifestations a. Both UC and CD can present with concurrent systemic manifestations. b. Hepatobiliary: primary sclerosing cholangitis, cholangiocarcinoma, hepatitis, cirrhosis, cholelithiasis, steatosis c. Rheumatologic arthritis, sacroiliitis, ankylosing spondylitis d. Dermatologic: erythema nodosum, aphthous ulcers, pyoderma gangrenosum e. Ocular: iritis or uveitis, episcleritis Gauging clinical severity a. Ulcerative colitis severity can be determined using Table 9 (based on Truelove and Witt criteria) Table 9. Clinical Severity of Ulcerative Colitis Mild ≤4 stools/day (±blood) Moderate > 4 stools/day (±blood) No fever, anemia, or tachycardia Minimal signs of systemic toxicity Normal ESR Severe > 6 stools/day with blood Fulminant > 10 stools/day with Body temperature > 99.5°F continuous blood Body temperature > 99.5°F HR > 90 beats/min ESR > 30 mm/hr Hgb < 75% of normal Abdominal tenderness Bowel wall edema HR > 90 beats/min ESR > 30 mm/hr Transfusions required Abdominal pain Dilated colon ESR = erythrocyte sedimentation rate; Hgb = hemoglobin; HR = heart rate. b. Crohn disease i. Mild-moderate: tolerates oral administration; absence of fever, dehydration, and abdominal tenderness; less than 10% weight loss ii. Moderate-severe: failed treatment of mild-moderate; anemia, nausea and vomiting, or considerable weight loss usually present iii. Severe: no response to outpatient steroids; high temperature, abdominal pain, persistent vomiting; possible obstruction, abscess, cachexia, rebound tenderness 4. General management considerations a. Rule out possible infectious causes of bloody diarrhea, especially C. difficile, in patients with acute symptoms. b. Elevated concentrations of fecal lactoferrin and fecal calprotectin indicate inflammation and help differentiate patients with IBD from those with IBS. These concentrations may also be used to monitor disease activity and therapy response. c. Most patients will undergo colonoscopy to confirm the diagnosis and extent of disease. Computed tomography enterography or magnetic resonance enterography can be considered to evaluate inflammation within the ileum in CD. d. Surgery is a viable option when complications (abscess, fistula, perforation) occur or when fulminant disease is unresponsive to medical treatment. e. Distribution and severity of disease will dictate the initial treatment choice. f. Treatment is generally initiated with induction therapy. These treatments are used to acutely control symptoms and inflammation. Once symptoms are controlled, longer-term maintenance therapy is used to control symptoms and inflammation, together with systemic complications. Most patients will require maintenance therapy because of the high incidence of relapse after induction therapy; the relapse rate is 35%–80% at 2 years for CD and 50%–70% at 1 year for UC. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-134 Gastrointestinal Disorders C. Medical management of IBD: adjunctive therapies 1. Caution in active disease; reduction in motility may precipitate toxic megacolon 2. Loperamide (Imodium) can be useful for proctitis or diarrhea; 2 mg after each loose stool (16 mg/day maximum) 3. Antispasmodics (recommended for short-term use) a. Dicyclomine (Bentyl), 10–40 mg orally four times daily b. Propantheline (Pro-Banthine), 7.5–15 mg orally three times daily c. Hyoscyamine (Levsin), 0.125–0.25 mg orally/slow release every 4 hours as needed 4. Cholestyramine (Questran): for bile salt–induced diarrhea after ileal resection D. Medications used to treat IBD 1. Selection of treatment is based on disease location and severity. 2. Aminosalicylates a. Used for both induction and maintenance of remission b. Sulfasalazine: prototype agent (Azulfidine, Azulfidine-EN) i. Sulfasalazine is cleaved by colonic bacteria to the active portion (5-aminosalicylate) and the inactive carrier molecule sulfapyridine. ii. Efficacy is best in colonic disease because of colonic activation of the drug. iii. Dose-related adverse effects (due to the sulfapyridine portion): GI disturbance, headache, arthralgia, folate malabsorption iv. Idiosyncratic adverse effects: rash, fever, pneumonitis, hepatotoxicity, bone marrow suppression, hemolytic anemia, pancreatitis, decreased sperm production in men v. Avoid in patients with a sulfa allergy. vi. Dosed 2–2.4 g/day orally; available as immediate-release and enteric-coated products. Doses should be titrated beginning at 500–1000 mg once or twice daily to avoid adverse effects. c. 5-Aminosalicylates (non–sulfa containing) i. Generally better tolerated than sulfasalazine; first line in mild-moderate UC and CD ii. Product selection depends on location of disease. Available formulations are listed in Table 10 iii. Olsalazine is associated with secretory diarrhea in up to 25% of patients. iv. Rare instances of nephrotoxicity with use of 5-aminosalicylates Table 10. Aminosalicylate Formulations Drug Trade Names Formulation Strength Daily Dose Range (g) Site of Action Mesalamine Rowasaa Delzicol Asacol HD, Zaldyon Canasa Pentasa Enema Delayed-release capsule Delayed-release tablet 4 g/60 mL 400 mg 800 mg 4 1.6–4.8 Rectum, terminal colon Distal ileum, colon Suppository Controlled-release capsule 1000 mg 250 mg 500 mg 1.2 g 1 2–4 Rectum Small bowel, colon 2.4–4.8 (once daily) 0.375–1.5 (once daily) 1–3 2–6.75 Colon Lialda Apriso Olsalazine Balsalazide a Dipentum Colazal Multimatrix (MMX) delayed-release tablet Intellicor delayed- and extended-release capsule 0.375 g Dimer of mesalamine (capsule) 250 mg Capsule 750 mg Colon Colon Colon Generic mesalamine enema available. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-135 Gastrointestinal Disorders 3. Corticosteroids a. Work quickly to suppress inflammation during acute flares b. They have no role in maintenance therapy; however, more than 50% of patients with severe disease may become steroid-dependent. c. Budesonide is about 15-fold more potent than prednisone; because of its high first-pass metabolism and limited systemic exposure, allow a 2-week overlap when changing from prednisone to budesonide to prevent adrenal insufficiency. It is formulated to release in the terminal ileum and treats only terminal ileal and ascending colonic disease. d. Adverse effects (systemic therapy): adrenal suppression, glucose intolerance, hypertension, sodium/water retention, osteoporosis, cataracts, and impaired wound healing. Systemic adverse effects are minimal with budesonide use. e. Available corticosteroid formulation are listed in Table 11 Table 11. Corticosteroid Preparations Route Oral Agents Prednisone Prednisolone Budesonide capsule (Entocort EC 3 mg) Budesonide tablet (Uceris 9 mg) Intravenous Hydrocortisone Topical (rectal) Methylprednisolone Cortenema Dose 20–60 mg/day 9 mg/day PO; then 6 mg/day Minimal absorption, minimal systemic adverse effects; indicated Can be continued for up to for treatment and maintenance 3 mo of mild-moderate active CD 9 mg/day in the morning for involving terminal ileum or 8 wk ascending colon 100 mg every 8 hr 7- to 10-day course; change to PO when gut is functional 15–48 mg/day 100 mg HS Hydrocortisone-based products 90 mg/day BID Used for patients with distal disease (100 mg/60 mL) Cortifoam Comments Taper as soon as possible (90 mg/applicator) Suppositories; use for proctitis Anucort-HC 25 mg Proctocort 30 mg Uceris rectal foam 25–50 mg PR BID 2 mg BID x 2 wk; then daily For induction of remission of mild x 4 wk to moderate distal UC BID = twice daily; CD = Crohn disease; HS = at bedtime; PO = by mouth; PR = rectally; UC = ulcerative colitis. 4.  Immunomodulators a. Mercaptopurine (Purinethol), azathioprine (Imuran, Azasan; prodrug of mercaptopurine), methotrexate b. Doses: Azathioprine 2–2.5 mg/kg/day orally, mercaptopurine 1–1.5 mg/kg/day orally, methotrexate 15–25 mg/week intramuscularly (CD only) c. Indicated only for maintenance because of long onset of action (3–15 months). d. Use can result in a steroid-sparing effect. e. Azathioprine and mercaptopurine are metabolized by the enzyme thiopurine methyltransferase (TPMT); reduced expression of TPMT can result in slower metabolism and increased toxicity. The TPMT activity or TPMT genotype or phenotype should be determined before initiating therapy. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-136 Gastrointestinal Disorders f. Adverse reactions i. Azathioprine and mercaptopurine: pancreatitis (3%–15%), bone marrow suppression, nausea, diarrhea, rash, possible hepatotoxicity. Risk of hepatosplenic T-cell lymphoma, especially in younger male patients or if combined with a TNFα antagonist. ii. Methotrexate: bone marrow suppression, nausea, diarrhea, rash, pulmonary toxicity, hepatotoxicity, folate deficiency 5. Small molecules: Oral Janus kinase (JAK) inhibitors indicated for moderate to severe UC after one or more TNF antagonist failure or intolerance. a. Tofacitinib (Xeljanz) dosing and outcomes i. Induction dosing: 10 mg orally twice daily for at least 8 weeks ii. Maintenance dosing: 5–10 mg orally twice daily depending on response iii. Discontinue if response is inadequate after 16 weeks of treatment with 10 mg twice daily. iv. Dose adjustments (a) If receiving a strong CYP 3A4 inhibitor or moderate CYP 3A4 inhibitor and a strong CYP 2C19 inhibitor, or if moderate to severe renal impairment or moderate hepatic impairment: Reduce 10 mg twice daily dose to 5 mg twice daily; reduce 5-mg twice-daily dose to 5 mg once daily. (b) If lymphocyte count or absolute neutrophil count is less than 500 cells/mm3, discontinue tofacitinib. (c) If absolute neutrophil count is 500–1000 cells/mm3, reduce dose as earlier and resume previous dose when absolute neutrophil count is greater than 1000 cells/mm3. (d) Interrupt dosing for hemoglobin less than 8 g/dL or a reduction of more than 2 g/dL, and restart dosing when hemoglobin normalizes. (e) Interrupt therapy if patient experiences a serious infection. v. Remission rates in OCTAVE trials (a) In OCTAVE 1, 18.5% and 8.2% of patients achieved remission with tofacitinib 10 mg daily and placebo, respectively (p=0.007) at 8 weeks. (b) In OCTAVE 2, 16.6% and 3.6% achieved remission, respectively (p<0.001) at 8 weeks. (c) OCTAVE Sustain reported remission at 52 weeks in 34.3% of patients receiving 5 mg of tofacitinib twice daily, 40.6% receiving 10 mg twice daily, and 11.1% receiving placebo (p<0.001 both comparisons with placebo). b. Upadacitinib (Rinvoq) dosing and outcomes i. Induction dosing: 45 mg orally once daily for 8 weeks ii. Maintenance dosing: 15 mg orally once daily; 30 mg orally once daily for refractory, severe, or extensive UC. iii. Discontinue if response is inadequate following 30 mg maintenance dose. iv. Dose adjustments: Use reduced dose of 30 mg daily for induction and 15 mg daily maintenance for the following: (a) Creatinine clearance (CrCl) 15–30 mL/min (avoid use in CrCl less than 15 mL/min) (b) Child-Pugh class A or B (avoid use in Child-Pugh class C) (c) Concurrent strong CYP 3A4 inhibitors. (d) Interrupt therapy for severe infection or reduction in absolute neutrophil count less than 1000 cells/mm3; absolute lymphocyte count less than 500 cells/mm3; hemoglobin less than 8 g/dL. v. In two induction studies (U-ACHIEVE and U-ACCOMPLISH), remission at 8 weeks was achieved with upadacitinib 45 mg daily in 26% and 33% of patients compared with placebo (5% and 4%; p<0.0001, both comparisons with placebo). About half the patients enrolled in the trials had experienced failure with at least 1 TNF inhibitor. In the U-ACHIEVE maintenance study, clinical remission at 52 weeks was achieved in 42% with 15 mg daily, 52% with 30 mg daily, and 12% with placebo (p<0.001, both comparisons with placebo). ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-137 Gastrointestinal Disorders c. Janus kinase (JAK) inhibitor adverse effects i. Serious infections include tuberculosis or other opportunistic infections; patients should be screened before starting therapy. ii. Lymphocytopenia, neutropenia, and low hemoglobin can occur. Monitor lymphocyte, neutrophil, and hemoglobin concentrations at baseline and periodically during treatment. iii. Associated malignancies include lymphomas and lung cancers. iv. Other associated adverse effects are higher rates of major adverse cardiovascular events, including cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke, compared with TNF inhibitors. Current and past smokers appear to be at higher risk. Evaluate the risks and benefits before initiating therapy. Discontinue therapy if a suspected cardiovascular event has occurred. iv. Development of deep venous thrombosis, pulmonary embolism, and arterial thrombosis is also associated with JAK inhibitors. Avoid therapy in patients at high risk of thrombosis. Discontinue therapy and evaluate and treat patients with suspected thrombosis. 6. Sphingosine 1-phosphate receptor modulator a. Ozanimod (Zeposia) i. Indicated in moderate to severe active UC in adults ii. Dosing titration: 0.23 mg orally once daily on days 1–4; 0.46 mg orally once daily on days 5–7; then 0.92 mg orally once daily day 8 and thereafter. iii. True North Phase III trial showed 18.4% of patients with UC receiving ozanimod and 6% receiving placebo achieved clinical remission at week 10. Of patients who achieved remission who continued with maintenance therapy, 37% receiving ozanimod and 18.5% receiving placebo were in remission at week 52. iv. Assessments before initiating ozanimod therapy (a) Complete blood count and lymphocyte count (b) Electrocardiogram to assess for prolonged QTc, bradycardia, or heart block because ozanimod may reduce heart rate and cause conduction delays liver function tests (c) Ophthalmic assessment in patients at risk for macular edema (d) Varicella zoster immunity (per vaccination or history of infection) documentation v. Contraindications (a) Within the past 6 months: myocardial infarction, unstable angina, stroke, transient ischemic attack, decompensated heart failure requiring hospitalization, or class III or IV heart failure (b) Mobitz type II second-degree or third-degree atrioventricular (AV) block, sick sinus syndrome, or sinoatrial block unless a functioning pacemaker is present (c) Severe untreated sleep apnea (d) Concurrent monoamine oxidase inhibitor 7. Biologic agents: TNF inhibitors (infliximab, adalimumab, certolizumab, golimumab); integrin inhibitors (natalizumab, vedolizumab); anti-interleukin 12 and anti-interleukin 23 (ustekinumab) a. Baseline evaluation before biologic agent use: comprehensive metabolic panel, liver function tests, complete blood cell count; viral hepatitis screening; tuberculosis screening b. Infliximab (Remicade) i. Chimeric monoclonal antibody against TNFα, intravenous infusion ii. Indicated for induction and maintenance of remission in moderate to severe active UC or CD or in fistulizing CD iii. Dosing: Moderate to severe active disease or fistulizing disease: 5 mg/kg as single dose, followed by 5 mg/kg at 2 and 6 weeks; then every 8 weeks as maintenance. Patients who experience a loss of response over time can be treated with a 10 mg/kg dose. iv. Therapeutic drug monitoring: Minimal “therapeutic” target trough concentration of infliximab is 7.5 mcg/mL or greater according to the guidelines. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-138 Gastrointestinal Disorders c. Adalimumab (Humira) i. Fully humanized antibody to TNFα; therefore, theoretically, the risk of antibody development is reduced ii. Indicated for both induction and maintenance therapy for moderate to severe active CD and UC in patients unresponsive to conventional therapy; also indicated for patients who no longer respond to infliximab iii. Dosing (a) Induction: 160 mg subcutaneously on day 1 (given as four separate 40-mg injections) or two 40-mg/day injections for 2 consecutive days, followed by 80 mg subcutaneously 2 weeks later (day 15) (b) Starting on day 29 of therapy, decrease dose to 40 mg subcutaneously every other week (maintenance therapy dose). iv. Therapeutic drug monitoring: Minimal “therapeutic” trough concentration of adalimumab is 5 mcg/mL or greater d. Certolizumab (Cimzia) i. Humanized monoclonal antibody fragment to TNFα linked to polyethylene glycol, with murine-complimentary determining regions ii. Indicated for maintenance therapy for moderate to severe active CD in patients unresponsive to conventional therapy iii. Dosing (a) Induction: 400 mg subcutaneously; then 400 mg subcutaneously at weeks 2 and 4 (b) Maintenance: 400 mg subcutaneously every 4 weeks iv. Therapeutic drug monitoring: Evidence is sparse; however, suggested minimal “therapeutic” target trough concentration is 20 mcg/mL or greater. e.  Golimumab (Simponi) i. Human IgG1κ monoclonal antibody directed against TNFα ii. Indicated for moderate to severe UC in patients intolerant of previous therapies or requiring continuous steroid therapy iii. Dosing: 200 mg subcutaneously at week 0, 100 mg at week 2; then 100 mg every 4 weeks thereafter f. TNF antagonists adverse reactions i. Infusion related: hypotension, fever, chills, urticaria, pruritus; infuse over at least 2 hours (may pretreat with acetaminophen and/or antihistamine) ii. Delayed hypersensitivity: fever, rash, myalgia, headache, or sore throat 3–10 days after administration. iii. Infection: reactivation of latent infections (bacterial, including disseminated tuberculosis, fungal, and sepsis); do not give to patients with active infections. Tuberculosis should be ruled out before any biologic agents are initiated. iv. Heart failure exacerbations: contraindicated in New York Heart Association class III/IV heart failure; do not exceed 5-mg/kg dose in other patients with chronic heart failure. v. Antibody induction: Up to 50% of patients receiving infliximab may develop antinuclear antibodies; 19% may develop anti-double-stranded DNA antibodies. vi. Bone marrow suppression (pancytopenia) vii. Black box warning applies to all TNFα antagonists. Unusual cancers have been reported in children and teenage patients taking TNF blockers. Hepatosplenic T-cell lymphoma has occurred mostly in teenaged or young adult males with CD or UC who were taking infliximab and azathioprine or mercaptopurine. viii. Hepatitis, with reactivation of hepatitis B virus (HBV) or autoimmune hepatitis; discontinue use if liver function tests increase to more than 5 times the upper limit of normal (ULN). ix. Vasculitis with CNS involvement ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-139 Gastrointestinal Disorders g. Natalizumab (Tysabri) i. Humanized monoclonal antibody that antagonizes integrin heterodimers and inhibits α4 integrin-mediated leukocyte adhesion ii. Indicated for induction and maintenance of remission of moderate to severe active CD after an inadequate response to, or intolerance of, conventional therapies and inhibitors of TNFα. John Cunningham (JC) virus serum antibody test should be completed before and every 6 months during natalizumab therapy. Treatment should be discontinued if the result is positive. iii. Dosing: Must enroll in the TOUCH program before the drug is dispensed because of its association with progressive multifocal leukoencephalopathy. Induction and maintenance doses are both 300 mg intravenously every 4 weeks. If there is no effect after 12 weeks or an inability to discontinue steroids within 6 months of beginning therapy, discontinue natalizumab. iv. Adverse effects: progressive multifocal leukoencephalopathy. Monitor for mental status changes during treatment. Consider magnetic resonance imaging and lumbar puncture if mental status changes or weakness is observed. Monitor for hepatotoxicity, jaundice or other signs of liver disease. Monitor for infection. Observe patients for 1 hour after infusion for infusion reaction. Do not combine with TNFα inhibitors or immunosuppressants. h. Vedolizumab (Entyvio) i. Humanized monoclonal antibody that targets α4β7-integrin–mediated leukocyte adhesion ii. Indicated for induction and maintenance of UC and CD after failure of other therapies, including TNFα antagonists. iii. Induction and maintenance doses are both 300 mg intravenously given at 0, 2, and 6 weeks and then every 8 weeks. Discontinue if there is no evidence of improvement at 14 weeks. iv. Safety profile is similar to natalizumab, with a lower risk of progressive multifocal leukoencephalopathy because the mechanism of vedolizumab is more specific for gut-based integrin; no prescribing program is required for vedolizumab. i.  Ustekinumab (Stelara) i. Monoclonal antibody to the p40 subunit of interleukin 12 and interleukin 23 (anti-IL-12/23) ii. Indicated for moderate to severely active CD and UC after the failure of corticosteroids, thiopurines, methotrexate, or TNF inhibitors iii. Dosing, intravenous: (a) Induction dosing is based on weight at week 0: 260 mg for less than 55 kg, 390 mg for more than 55–85 kg, and 520 mg more than 85 kg (b) Maintenance dosing: 90 mg subcutaneously every 8 weeks iv. Adverse effects (a) Common adverse effects: vomiting with induction therapy; nasopharyngitis, injection-site erythema, vulvovaginal candidiasis, bronchitis, pruritus, urinary tract infection, and sinusitis with maintenance treatment (b) As with other biologic therapies, serious infections include tuberculosis; therefore, screening for tuberculosis is recommended before starting therapy. E. Medical management of UC: Treatment is selected according to disease location and severity. 1. Guideline definitions of UC distribution a. Distal disease: Distal to splenic flexure (may use oral/systemic or topical [rectal] therapy) b. Extensive disease: Proximal to splenic flexure (requires systemic/oral therapy) 2. Mildly active UC a. Topical aminosalicylates are recommended for induction of remission for ulcerative proctitis (strong recommendation, high-quality evidence) and left-sided colitis (strong recommendation, moderate-quality evidence). An oral aminosalicylate in combination with a topical aminosalicylate ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-140