Drugs for inflammatory bowel disease

Treatment Guidelines from The Medical Letter® Published by The Medical Letter, Inc • 145 Huguenot Street, New Rochelle, NY 10801 • A Nonprofit Publication IN THIS ISSUE (starts on next page) Drugs for Inflammatory Bowel Disease p 19 Important Copyright Message The Medical Letter® publications are protected by US and international copyright laws Forwarding, copying or any distribution of this material is prohibited Sharing a password with a non-subscriber or otherwise making the contents of this site available to third parties is strictly prohibited By accessing and reading the attached content I agree to comply with US and international copyright laws and these terms and conditions of The Medical Letter, Inc For further information click: Subscriptions, Site Licenses, Reprints or call customer service at: 800-211-2769 FORWARDING OR COPYING IS A VIOLATION OF US AND INTERNATIONAL COPYRIGHT LAWS The Medical Letter publications are protected by US and international copyright laws Forwarding, copying or any other distribution of this material is strictly prohibited For further information call: 800-211-2769 Treatment Guidelines from The Medical Letter® Published by The Medical Letter, Inc • 145 Huguenot Street, New Rochelle, NY 10801 • A Nonprofit Publication Volume 10 (Issue 115) March 2012 www.medicalletter.org Take CME exams Tables Drugs for Inflammatory Bowel Disease Drugs for Crohn’s Disease Drugs for Ulcerative Colitis Pages 20-21 Page 23 Page 24 Drugs for Inflammatory Bowel Disease RECOMMENDATIONS Ulcerative Colitis – An aminosalicylate is generally used first for treatment and maintenance of remission Mercaptopurine or azathioprine is often used in patients with moderate to severe disease Prednisone can be used to treat severe relapses Patients with treatment-refractory disease may respond to a TNF inhibitor, such as infliximab Crohn’s Disease – Prednisone can be used to induce remission Azathioprine or mercaptopurine is often used for maintenance of remission Moderate to severe Crohn’s disease that has not responded to other drugs may respond to a TNF inhibitor, such as infliximab Some clinicians would use a TNF inhibitor alone or in combination with azathioprine for initial treatment of moderate to severe disease Metronidazole or ciprofloxacin may be helpful in some patients Methotrexate is an alternative for patients with steroid-resistant or steroid-dependent disease Inflammatory bowel disease (IBD) is generally classified as either Crohn’s disease (CD) or ulcerative colitis (UC) More detailed guidelines on their treatment are available from the American College of Gastroenterology.1,2 AMINOSALICYLATES The active moiety of all the aminosalicylates used to treat IBD is 5-aminosalicylate (5-ASA), also called mesalamine MECHANISM OF ACTION — 5-ASA has antiinflammatory, antimicrobial and antioxidant effects The anti-inflammatory effect is probably due to inhibition of leukotriene production and reduction in interleukin-1 (IL-1) and tumor necrosis factor alpha (TNF-) signaling 5-ASA also activates a colonocyte differentiation factor and has other antiproliferative effects, which may protect against colorectal cancer.3 FORMULATIONS — Oral mesalamine is absorbed in the small intestine and does not reach the colon Pentasa is an ethylcellulose-coated formulation that releases mesalamine gradually throughout the gastrointestinal tract Asacol and Asacol HD tablets are coated with a pH-sensitive film that dissolves at the higher pH of the terminal ileum and proximal colon, releasing the drug Lialda and Apriso both delay the release of the drug until it reaches the distal ileum and colon.4,5 Sulfasalazine (Azulfidine, and others), balsalazide (Colazal, and others) and olsalazine (Dipentum) are prodrugs; mesalamine is azo-bonded to a second moiety and released in the colon following bacterial cleavage of the bond Mesalamine is also available as an enema (Rowasa, and others) and as a rectal suppository (Canasa) EFFICACY — In clinical trials, use of aminosalicylates generally achieved remission in about 35-50% of patients with mild or moderate UC and maintained the remission for months or more in about 55-75% of patients In distal UC and proctitis, mesalamine suppositories or enemas may be more effective than oral formulations both at inducing and maintaining remission Combination therapy with oral and rectal mesalamine has been reported to be more effective than either alone.6 In CD, aminosalicylates are only modestly more effective than placebo in inducing remission, and those that are released in the colon are ineffective for CD of the small intestine Data are insufficient to support use of these drugs for maintenance of remission in CD.7 ADVERSE EFFECTS — The most common adverse effects of mesalamine have been nausea, vomiting, Federal copyright law prohibits unauthorized reproduction by any means and imposes severe fines 19 Drugs for Inflammatory Bowel Disease Table Drugs for Inflammatory Bowel Disease Some Formulations Drug Indications Aminosalicylates Mesalamine – delayed- or extended-release Apriso (Salix) 375 mg extended-release caps Asacol (Warner Chilcott) 400 mg delayed-release tabs Asacol HD (Warner Chilcott) Lialda (Shire) Pentasa (Shire) Mesalamine – prodrugs Balsalazide – generic Colazal (Salix) Olsalazine – Dipentum (Meda) Sulfasalazine – generic Azulfidine (Pfizer) delayed-release – generic Azulfidine En-tabs (Pfizer) Mesalamine – rectal generic Rowasa (Meda) SF Rowasa (Meda) Canasa (Aptalis) Antibiotics Metronidazole – generic Flagyl (GD Searle) Ciprofloxacin – generic Cipro (Bayer) Rifaximin Xifaxin (Salix) Corticosteroids Prednisone – generic Maintenance of remission in UC Treatment of mild to moderate UC; maintenance of remission 800 mg delayed-release tabs Treatment of moderate UC 1.2 g delayed-release tabs Treatment of mild to moderate UC; maintenance of remission 250, 500 mg extended-release caps Treatment of mild to moderate UC Pregnancy Category1 B C C B B 750 mg caps Treatment of mild to moderate UC B 250 mg caps Maintenance of remission in UC patients intolerant of sulfasalazine Treatment of mild to moderate UC; adjunctive therapy in severe disease; maintenance of remission C 500 mg tabs 500 mg delayed-release tabs B 40 g/60 mL enema Treatment of mild to moderate distal UC, proctosigmoiditis or proctitis B 1000 mg rectal suppository Treatment of ulcerative proctitis B 250, 500 mg tabs; 375 mg caps Not FDA-approved for IBD B 100, 250, 500, 750 mg tabs Not FDA-approved for IBD C 200, 550 mg tabs Not FDA-approved for IBD C 1, 2.5, 5, 10, 20, 50 mg tabs; mg/5 mL oral solution Treatment of acute flares of UC and CD Budesonide – generic Entocort EC (AstraZeneca) mg controlled-release caps Treatment of mild to moderate active CD involving the ileum and/or the ascending colon; maintenance of remission for up to months Hydrocortisone – generic Colocort (Paddock) 100 mg/60 mL enema Adjunctive therapy for UC, ulcerative proctitis, ulcerative proctosigmoiditis, and left-sided UC Adjunctive therapy for ulcerative proctitis of the distal portion of the rectum in patients who cannot retain hydrocortisone or other corticosteroid enemas Cortifoam (Meda) 10% rectal foam See Footnote C See Footnote C IBD = inflammatory bowel disease; UC = ulcerative colitis; CD = Crohn’s disease FDA Pregnancy Categories: A = controlled studies show no risk; B = no evidence of risk; C = risk cannot be ruled out; D = positive evidence of risk; X = contraindicated in pregnancy Not officially categorized diarrhea, headache and abdominal pain Nephrotoxicity can occur Pancreatitis, hepatotoxicity and a lupus-like syndrome have been reported DRUG INTERACTIONS — Mesalamine inhibits thiopurine methyltransferase in vitro and may interfere 20 with the metabolism of azathioprine and mercaptopurine, which might increase their toxicity, but seldom does except in patients with an inherited deficiency of thiopurine methytransferase Extendedand delayed-release mesalamine formulations with pH-sensitive coatings (Asacol, Asacol HD, Lialda, Treatment Guidelines from The Medical Letter • Vol 10 ( Issue 115) • March 2012 Drugs for Inflammatory Bowel Disease Table Drugs for Inflammatory Bowel Disease (continued) Some Formulations Drug Immunosuppressants Azathioprine – generic Imuran (Prometheus) Mercaptopurine – generic Purinethol (Teva) Methotrexate – generic Cyclosporine – generic Sandimmune (Novartis) Tacrolimus – generic Prograf (Astellas) TNF Inhibitors Adalimumab Humira (Abbott) Certolizumab pegol Cimzia (UCB) Infliximab Remicade (Centocor) 25, 50, 75, 100 mg tabs 50 mg tabs 50 mg tabs Not FDA-approved for IBD D Not FDA-approved for IBD D 50 mg/2 mL vial 50 mg/mL vial 50 mg/mL ampule 0.5, 1, mg caps 0.5, 1, mg caps; mg/mL ampule Not FDA-approved for IBD Not FDA-approved for IBD X C Not FDA-approved for IBD C 40 mg/0.8 mL pre-filled syringe; 40 mg/0.8 mL single-use pen Treatment and maintenance of remission in adults with moderate to severe CD who have had an inadequate response to conventional therapy or have lost response to, or cannot tolerate, infliximab B 200 mg vial (lyophilized powder); 200 mg/mL pre-filled syringe Treatment and maintenance of remission in adults with moderate to severe active CD who have had an inadequate response to conventional therapy B 100 mg vial (lyophilized powder) Treatment and maintenance of remission in adults and children with moderate to severe CD who have had an inadequate response to conventional therapy; treatment of fistulas; treatment and maintenance of remission in adults and children with moderate to severe UC who have had an inadequate response to conventional therapy B Treatment and maintenance of remission in adults with moderate to severe CD who have had an inadequate response to, or are unable to tolerate, conventional therapy and TNF inhibitors C Integrin Receptor Antagonist Natalizumab Tysabri (Elan/Biogen) 300 mg/15 mL vial Probiotics3 VSL #34 (VSL Pharmaceuticals) VSL #3-DS4 Culturelle5 (Amerfit) Florastor6 (Biocodex) Align7 (Procter & Gamble) Pregnancy Category1 Indications 450 billion CFU packets; 112.5 billion CFU caps 900 billion CFU packets 10 billion cells/capsule 250 mg caps; 250 mg packet billion CFU caps Not FDA-approved for IBD Not Not Not Not FDA-approved FDA-approved FDA-approved FDA-approved for for for for IBD IBD IBD IBD See Footnote CFU = colony forming units Some available probiotic products VSL #3 and VSL#3-DS contain lyophilized Bifidobacterium breve, B longum, B infantis, Lactobacillus acidophilus, L plantarum, L paracasei, L bulgaricus and Streptococcus thermophilus Culturelle contains Lactobacillus GG Florastor contains Saccharomyces boulardii lyo Align contains Bifidobacterium infantis 35624 Apriso) should not be co-administered with antacids, which might cause premature dissolution of the coating Theoretically, a similar interaction could occur with proton-pump inhibitors (PPIs), such as omeprazole (Prilosec, and others), or with H2-receptor antagonists, such as ranitidine (Zantac, and others) ANTIBIOTICS Many experts believe that alterations in the balance of enteric bacteria play a role in the development of IBD and that antibiotic treatment can be helpful, particularly in CD Metronidazole is active against anaerobic Treatment Guidelines from The Medical Letter • Vol 10 ( Issue 115) • March 2012 21 Drugs for Inflammatory Bowel Disease bacteria, such as Bacteroides fragilis Ciprofloxacin is active against both gram-positive and gram-negative bacteria Rifaximin is a minimally-absorbed antibiotic (less than 0.4% oral bioavailability) with activity against enteric gram-positive and gram-negative organisms These agents are used, sometimes together, to treat CD colitis and ileocolitis, microperforations and fistulas, and to treat pouchitis in UC Although data are limited, they are also used following resections to prevent recurrence of CD EFFICACY — A meta-analysis indicated that antibiotics are more effective than placebo in inducing remission in active CD, particularly in fistulizing disease.8 The evidence that they are effective in maintaining remission in CD is limited The use of antibiotics is not recommended in UC, except for pouchitis, in which both ciprofloxacin and metronidazole appear to be effective ADVERSE EFFECTS — Metronidazole can cause abdominal discomfort, metallic taste, nausea, vomiting, diarrhea, loss of appetite, ataxia and peripheral neuropathy Ciprofloxacin can cause nausea, vomiting, diarrhea, abdominal discomfort, headache, dizziness, QTc prolongation, altered mental status and lowering of the seizure threshold It has been associated with an increased risk of developing Clostridium difficile infection The FDA has issued a black-box warning regarding the association between ciprofloxacin and spontaneous tendon rupture Rifaximin is minimally absorbed, and has an incidence of adverse effects similar to that with placebo DRUG INTERACTIONS — Taken with alcohol, metronidazole can cause a disulfiram-like reaction (flushing, headache, nausea, vomiting, abdominal cramping) It is a moderate CYP2C9 inhibitor and may increase serum concentrations of CYP2C9 substrates such as warfarin (Coumadin, and others) Ciprofloxacin is a moderate inhibitor of CYP1A2 and may increase serum concentrations of CYP1A2 substrates such as tizanidine (Zanaflex) Antacids and products containing iron, calcium or magnesium may prevent full absorption of ciprofloxacin and should not be taken within hours before or hours after taking the drug Taking ciprofloxacin with other drugs that prolong the QT interval may have an additive effect In vitro studies show that rifaximin does not inhibit cytochrome P450 enzymes; it might induce CYP3A4, but it is minimally absorbed and does not appear to cause clinically significant interactions with drugs metabolized by CYP3A4, including oral contraceptives 22 CORTICOSTEROIDS Corticosteroids are often effective in both UC and CD in inducing remission in persistent disease Because of their severe adverse effects, they are used systemically only until acute inflammation is under control, and then are tapered and discontinued EFFICACY — Not all patients with IBD respond to systemic corticosteroids In one retrospective study, among 146 patients who required treatment with corticosteroids, 51% of patients with UC and 40% of those with CD had a complete response at 30 days, while 31% and 35% had a partial response.9 Most patients who respond to corticosteroids relapse within a year if not given maintenance therapy Systemic corticosteroids are ineffective for maintenance treatment of CD.10 ADVERSE EFFECTS — Corticosteroids can cause hypertension, fluid retention, increased risk of infection, osteoporosis, cataracts, impaired skin healing, insomnia, mood disorder, glaucoma, Cushing’s syndrome, hyperglycemia and hypothalamic-pituitaryadrenal (HPA) suppression RECTAL CORTICOSTEROIDS — Rectally instilled corticosteroids are effective in the treatment of distal UC Enemas can reach the splenic flexure, while foam coats only the last 15-20 cm of the colon Hydrocortisone is available in the US as a 100 mg enema or a 10% foam Budesonide enemas are also effective; they are available in Canada, but not in the US BUDESONIDE — A synthetic corticosteroid with a strong affinity for glucocorticoid receptors, budesonide is used orally in a dosage of mg/day to treat mild to moderate active CD of the ileum and/or ascending colon.1,11 Because of extensive first-pass metabolism, budesonide has a high ratio of local antiinflammatory to systemic effects It is somewhat less effective than conventional oral corticosteroids in inducing remission, and while approved for maintenance at mg/day, it does not appear to be effective at preventing relapse beyond months of use.1 Adverse Effects – Budesonide causes less short-term toxicity than prednisone Whether it is safer in the long term is not clear; its greater affinity for receptors might outweigh its limited systemic availability Drug Interactions – Budesonide is a CYP3A4 substrate and should be used with caution in combination with agents that induce CYP3A4, such as rifamycin derivatives, or inhibit it, such as grapefruit juice or Treatment Guidelines from The Medical Letter • Vol 10 ( Issue 115) • March 2012 Drugs for Inflammatory Bowel Disease Table Drugs for Crohn’s Disease Condition Crohn’s Disease Mild to Moderate: Induction of Remission Maintenance of Remission Moderate to Severe: Induction of Remission Maintenance of Remission Recommended Drugs Alternatives Budesonide mg PO once/d Mesalamine 2.4-4 grams PO daily in divided doses Metronidazole 10-20 mg/kg PO daily in divided doses Ciprofloxacin 500 mg PO bid Rifaximin 800 mg PO bid Budesonide mg PO once/d Methotrexate 15-25 mg IM once/wk Azathioprine 2-3 mg/kg PO once/d Mercaptopurine 1.5 mg/kg PO once/d Prednisone 40-60 mg PO once/d Methylprednisolone 60 mg IV once/d Infliximab 5-10 mg/kg IV (weeks 0, and 6) Azathioprine 2-3 mg/kg PO once/d Mercaptopurine 1.5 mg/kg PO once/d Infliximab 5-10 mg/kg IV q8 weeks Adalimumab 160 mg SC at week 0, then 80 mg SC at week Certolizumab pegol 400 mg SC (weeks 0, and 4) Methotrexate 25 mg IM once/wk Natalizumab 300 mg IV q4 weeks Adalimumab 40 mg SC every other week or weekly Certolizumab pegol 400 mg SC q4 weeks Methotrexate 15-25 mg IM once/wk Natalizumab 300 mg IV q4 weeks Perianal and Fistulizing Disease Induction of Remission Metronidazole 500 mg PO tid ± Ciprofloxacin 500 mg PO bid Infliximab 5-10 mg/kg IV (weeks 0, and 6) Maintenance of Remission Azathioprine 2-3 mg/kg PO once/d Mercaptopurine 1.5 mg/kg PO once/d Infliximab 5-10 mg/kg IV q8 weeks ketoconazole (Nizoral, and others) Drugs that change the pH of the gastrointestinal tract (antacids, PPIs, H2receptor antagonists) may affect the release and absorption of budesonide IMMUNOMODULATORY AGENTS AZATHIOPRINE AND MERCAPTOPURINE — Azathioprine (Imuran, and others) and mercaptopurine (6-MP; Purinethol, and others), which is the active metabolite of azathioprine, are both effective in maintaining remission in both UC and CD They are also used to decrease formation of antibodies to TNF inhibitors, prevent CD recurrence following surgical resection of diseased bowel and to assist with steroid tapering in corticosteroid-dependent disease These agents can take 3-6 months to achieve their maximal effect; they are primarily used for long-term therapy and not for immediate suppression of active inflammation Mechanism of Action – Both azathioprine and mercaptopurine inhibit purine synthesis; they have antiproliferative effects and induce apoptosis in T-cells Methotrexate 15-25 mg IM once/wk Efficacy – In a 30-year review of experience with azathioprine in 622 patients with active IBD, overall remission rates were 45% for CD and 58% for UC Patients treated for more than months had remission rates of 64% and 87%, respectively With continued maintenance treatment, the percentages of IBD patients remaining in remission were 95% after year, 69% after years and 55% after years When the drug was stopped, the percentages of patients remaining in remission at 1, and years were 63%, 44% and 35%, respectively.12 In patients with moderate to severe CD not previously exposed to immunosuppressive or biologic therapy, the combination of azathioprine plus infliximab was more effective in maintaining steroid-free remission than either drug alone; after 26 weeks of therapy, 56.8% of patients receiving combination therapy were in steroid-free remission, compared to 44.4% of patients receiving infliximab alone and 30% of those receiving azathioprine alone.13 Adverse Effects – Azathioprine and mercaptopurine can cause myelosuppression, nausea, vomiting, Treatment Guidelines from The Medical Letter • Vol 10 ( Issue 115) • March 2012 23 Drugs for Inflammatory Bowel Disease Table Drugs for Ulcerative Colitis Condition Ulcerative Colitis Mild to Moderate: Induction of Remission Maintenance of Remission Severe: Induction of Remission Maintenance of Remission Recommended Drugs Alternatives Mesalamine PO Asacol 2.4 grams daily in divided doses Asacol HD 4.8 grams daily in divided doses Lialda 2.4 or 4.8 grams once/d Pentasa gram qid Balsalazide 2.25 grams PO tid Olsalazine 1.5-3 grams PO daily in divided doses Mesalamine rectally Canasa 500 mg bid or 1000 mg once/d Rowasa grams once/d Hydrocortisone rectally Colocort enema nightly Cortifoam application once/d or bid Prednisone 40-60 mg PO once/d Azathioprine 2-3 mg/kg PO once/d Mercaptopurine 1.5 mg/kg PO once/d Sulfasalazine gram PO qid Infliximab mg/kg IV (weeks 0, and 6) Mesalamine PO Apriso 1.5 grams once/d Asacol 1.6 grams daily in divided doses Lialda 2.4 grams once/day Balsalazide 3-6 grams daily in divided doses Olsalazine 500 mg PO bid Mesalamine rectally Canasa 500 mg 1-2 x/d Rowasa 2-4 grams once/d Azathioprine 2-3 mg/kg PO once/d Mercaptopurine 1.5 mg/kg PO once/d Sulfasalazine gram PO bid Infliximab mg/kg IV q8 weeks Prednisone 40-60 mg PO once/d Hydrocortisone 300 mg IV once/d Methylprednisolone 60 mg IV once/d Infliximab mg/kg IV (weeks 0, and 6) Cyclosporine 2-4 mg/kg IV once/d Tacrolimus 0.05-0.2 mg/kg/d PO in divided doses (target trough levels 5-15 ng/mL)1 Sulfasalazine gram PO qid Sulfasalazine gram PO bid-qid Azathioprine 2-3 mg/kg PO once/d Mercaptopurine 1.5 mg/kg PO once/d Infliximab mg/kg IV q8 weeks Pouchitis Induction of Remission Metronidazole 250 mg PO tid Ciprofloxacin 500 mg PO bid Maintenance of Remission Probiotics: VSL #3 6-18 caps PO once/d Mesalamine rectally Canasa 500 mg bid or 1000 mg once/d Rowasa grams once/d x 3-6 weeks Infliximab 5mg/kg IV (weeks 0, and 6) Infliximab mg/kg IV q8 weeks More data are needed to determine optimal dosing and duration of treatment diarrhea, hepatotoxicity, rash, Raynaud’s disease, pulmonary edema, pancreatitis and a hypersensitivity reaction Long-term use of azathioprine and mercaptopurine has been associated with a small increase in the risk of non-melanoma skin cancer and lymphoma.14,15 Cases of hepatosplenic T-cell lymphoma have been reported in patients taking azathioprine or mercaptoprine either alone or in combination with TNF inhibitors.16,17 24 Drug Interactions – Azathioprine and mercaptopurine may decrease the anticoagulant effect of warfarin; the mechanism is not known Allopurinol (Zyloprim, and others) and febuxostat (Uloric) inhibit the metabolism of azathioprine and mercaptopurine by xanthine oxidase and can cause bone marrow depression with pancytopenia; the dose of azathioprine or mercaptopurine should be reduced if allopurinol is used concurrently, and concomitant use Treatment Guidelines from The Medical Letter • Vol 10 ( Issue 115) • March 2012 Drugs for Inflammatory Bowel Disease of febuxostat is contraindicated Mesalamine inhibits thiopurine methyltransferase and may decrease the metabolism of azathioprine and mercaptopurine, which theoretically could also increase their myelotoxicity, but seldom does except in patients with an inherited deficiency of thiopurine methyltransferase Severe leukopenia has been reported during concomitant therapy with angiotensin-converting enzyme (ACE) inhibitors or trimethoprim/sulfamethoxazole (Bactrim, and others) METHOTREXATE — Methotrexate is used to treat moderate to severe steroid-dependent and steroidresistant CD The mechanism of its effectiveness is unclear, but it blocks the action of dihydrofolate reductase, inhibits DNA synthesis and causes cell death When used in combination with a TNF inhibitor, it decreased formation of antibodies to the inhibitor.18 Methotrexate has not been shown to be effective in UC Efficacy – In one study in patients with active CD despite >3 months’ treatment with prednisone, 37 of 94 patients (40%) treated with intramuscular (IM) methotrexate 25 mg weekly were in clinical remission after 16 weeks.19 Among 40 responders to methotrexate induction who received maintenance treatment with methotrexate 15 mg IM weekly, 26 (65%) were still in remission 40 weeks later.20 Adverse Effects – Methotrexate can cause alopecia, stomatitis, rash, diarrhea, gastrointestinal hemorrhage, hepatotoxicity, renal failure, interstitial pneumonia, liver failure, toxic epidermic necrolysis, StevensJohnson syndrome, hypotension, blurred vision, headache, nephropathy and hyperuricemia Drug Interactions – Trimethoprim/sulfamethoxazole, trimethoprim and other drugs that interfere with folate metabolism may increase bone marrow suppression caused by methotrexate Drugs that diminish renal function, particularly NSAIDs, may raise serum concentrations of methotrexate and increase its toxicity CYCLOSPORINE — The calcineurin inhibitor cyclosporine (Sandimmune, and others) is given IV to treat patients with severe steroid-resistant UC who are candidates for proctocolectomy Its mechanism of action is thought to be interference with lymphocyte activation Use of cyclosporine in CD has been limited Efficacy – In one study, of 11 patients (82%) with severe refractory UC treated with cyclosporine improved within a mean of days and avoided immediate surgery.21 Adverse Effects – Cyclosporine can cause diarrhea, nausea, vomiting, infection, gingival hyperplasia, pruritus, headache, seizures, tremors, visual disturbances, hypertension, hepatotoxicity, nephrotoxicity, paresthesias and anaphylaxis Drug Interactions – Nephrotoxic effects may be additive when cyclosporine is used in conjunction with nephrotoxic drugs such as aminoglycoside antibiotics Hyperkalemia may develop in the presence of potassium-sparing diuretics such as spironolactone (Aldactone, and others) Cyclosporine is both a substrate and inhibitor of CYP3A4 and P-glycoprotein; CYP3A4 inhibitors such as ketoconazole may increase its toxicity TACROLIMUS — Tacrolimus (Prograf, and others), another calcineurin inhibitor, has been used as an alternative to cyclosporine to treat patients with refractory UC.22 Its mechanism of action may involve interference with lymphocyte activation Data are limited on its use in CD.1 Efficacy – In one study in patients with moderate to severe refractory UC, improvement occurred within weeks in 68% (13/19) of those treated with oral tacrolimus and in 10% (2/20) of placebo-treated patients.23 Adverse Effects – Tacrolimus can cause tremors, renal dysfunction, gastrointestinal discomfort, headache, infection, hypomagnesemia, hypertension, insomnia and seizures It has also been associated with an increased risk of lymphoma Drug Interactions – Additive nephrotoxicity may occur if tacrolimus is used in combination with other nephrotoxic drugs such as aminoglycosides Tacrolimus is a substrate of CYP3A4 and P-glycoprotein; CYP3A4 inhibitors such as ketoconazole may increase its toxicity TNF INHIBITORS Three tumor necrosis factor (TNF) inhibitors — infliximab, adalimumab and certolizumab pegol — are used for treatment of moderate to severe CD Infliximab is also approved by the FDA for treatment of moderate to severe UC not responsive to conventional therapies MECHANISM OF ACTION – Tumor necrosis factor alpha (TNF-) is a pro-inflammatory cytokine Infliximab is a human/murine chimeric monoclonal antibody that binds to membrane-bound and soluble TNF- Adalimumab is a genetically engineered human IgG1 monoclonal antibody that binds to TNF Certolizumab pegol is a PEGylated Fab’ fragment of a humanized TNF- antibody.24 Antibodies and antibody fragments that bind TNF- block the inflammatory cascade.25 Treatment Guidelines from The Medical Letter • Vol 10 ( Issue 115) • March 2012 25 Drugs for Inflammatory Bowel Disease EFFICACY — Crohn’s Disease – Infliximab has been effective in the treatment of moderate to severe CD that had not responded to other drugs, including systemic corticosteroids.26 In one study, a single mg/kg dose of the drug produced a clinical response in 22 of 27 patients (81%) with refractory moderate to severe CD.27 In a randomized trial among responders to infliximab who continued to receive mg/kg of the drug, 44 of 113 (39%) were in remission at 30 weeks, compared to 23 of 110 (21%) on placebo.28 In patients with moderate to severe CD not previously exposed to immunosuppressive or biologic therapy, the combination of azathioprine plus infliximab was more effective in maintaining steroidfree remission than either drug alone; after 26 weeks of therapy, 56.8% of patients receiving combination therapy were in steroid-free remission, compared to 44.4% of patients receiving infliximab alone and 30% of patients receiving azathioprine alone.13 Infliximab is highly effective in fistulizing CD In one study, among 94 patients with fistulizing disease, doses of infliximab at weeks 0, and produced closure of all fistulas in 55% of patients, compared to 13% with placebo.29 In another trial, patients whose fistulas responded to infliximab were then randomized to infliximab or placebo given every weeks; after year, 19 of 98 placebo-treated patients (19%) and 33 of 91 infliximab-treated patients (36%) were free of draining fistulas.30 Infliximab has been shown to reduce CD recurrence after ileocolonic resection; after year, of 11 patients (9.1%) treated with infliximab had endoscopic recurrence, compared to 11 of 13 patients (84.6%) treated with placebo.31 The rates of response and remission in CD with other TNF inhibitors appear to be comparable to those with infliximab In one study (CHARM), a response to induction with adalimumab occurred in 499 of 854 patients (58%) Among responders who received adalimumab every other week for maintenance, 62 of 172 (36%) of the patients were still in remission after 12 months.32 In a study with certolizumab pegol (PRECISE 2), 428 of 668 patients (64%) responded to induction, and after maintenance treatment for 26 weeks, 103 of 215 (48%) of the responders were still in remission.33 Head-to-head comparisons of these agents are lacking.34 Adalimumab has been effective in some patients who had become refractory to infliximab.35 Certolizumab pegol has also been effective in some patients who had become refractory or intolerant to infliximab.36 The TNF inhibitor etanercept (Enbrel), which is approved for use in rheumatoid arthritis, has not been effective in Crohn’s disease 26 Ulcerative Colitis – TNF inhibitors have also been effective for treatment of UC Among patients with treatment refractory disease treated with infliximab, 6570% responded, and about 45% of responders who continued infliximab had a sustained clinical response 54 weeks later.37 Induction of remission with adalimumab occurred in 18.5% of patients with moderate to severe UC who were anti-TNF naive, compared to 9.2% of placebo-treated patients.38 In another study (ULTRA 2) in 494 patients with moderate to severe UC that had not responded to conventional therapy or immunosuppressants, rates of clinical remission after 52 weeks were 17.3% with adalimumab and 8.5% with placebo.39 ADVERSE EFFECTS — Patients treated with TNF inhibitors are at increased risk for serious infections, including reactivated and disseminated tuberculosis, invasive or disseminated fungal infection, and other opportunistic infections, including those caused by Legionella and Listeria Tuberculin skin testing and chest radiography are recommended before starting therapy Inhibition of TNF- has also been associated with reactivation of hepatitis B virus in patients who are chronic carriers, and serologic testing for active hepatitis B infection is recommended before treatment Anti-TNF- therapies have also been associated with injection and infusion reactions and with an increased risk of lymphoma, leukemia, new onset psoriasis, hematologic cytopenias, non-ischemic congestive heart failure and demyelinating disorders Cases of hepatosplenic T-cell lymphoma have been reported in patients taking azathioprine, mercaptopurine and/or a TNF inhibitor.16,17 DRUG INTERACTIONS — Concomitant administration of any TNF inhibitor with other biologics may increase the risk of serious infections and neutropenia INTEGRIN RECEPTOR ANTAGONIST Natalizumab (Tysabri) is a humanized monoclonal antibody against alpha-4 integrin, a molecule on leukocytes that mediates adhesion to endothelial receptors and migration into the intestine By blocking leukocyte diapedesis, natalizumab reduces intestinal inflammation It is approved by the FDA for induction and maintenance treatment of moderate to severe CD EFFICACY — In a controlled trial, natalizumab was somewhat more effective than placebo in inducing a response in subgroups of CD patients with elevated Creactive protein (CRP) at baseline, active disease despite immunosuppressants, or prior anti-TNF treatment Among responders maintained on natalizumab, 61% (103/168) had a sustained response at week 36 compared to 28% (48/170) of those maintained on placebo.40 Another trial (ENCORE) that randomized Treatment Guidelines from The Medical Letter • Vol 10 ( Issue 115) • March 2012 Drugs for Inflammatory Bowel Disease 509 patients with moderate to severe active CD and elevated CRP to natalizumab or placebo at weeks 0, and found that a response at weeks maintained through week 12 occurred in 48% of patients treated with natalizumab and in 32% of those given a placebo.41 and in 100% with placebo.50 Probiotics have been less effective in maintenance of CD ADVERSE EFFECTS — Use of natalizumab in clinical practice has been limited by the rare occurence of progressive multifocal leukoencephalopathy (PML) and severe hepatic toxicity Current FDA approval restricts use of the drug to CD patients who have not responded to or could not tolerate anti-TNF agents.42 Patients at highest risk for PML are those who have received natalizumab for >2 years, those who took other immunosuppressants before receiving natalizumab, and those who have antibodies to JC Virus, which has been associated with PML A test for JC Virus antibodies has been approved by the FDA.43 DRUG INTERACTIONS — Antibiotics can inactivate bacteria-derived probiotics Florastor, which contains S boulardii, should not be taken with oral systemic antifungal medications, such as fluconazole (Diflucan, and others).44 ADVERSE EFFECTS — Probiotics can cause bloating, flatulence, diarrhea and hiccups DRUG INTERACTIONS — Anti-TNF agents and immunomodulators such as azathioprine or mercaptopurine may increase the risk of infectious complications with natalizumab and should not be used concomitantly Patients taking corticosteroids chronically should be tapered over months while taking natalizumab PROBIOTICS Probiotics are live, nonpathogenic microorganisms (usually bacteria or yeasts) They are currently marketed for prevention and treatment of a variety of disorders, including diarrhea, irritable bowel syndrome and inflammatory bowel disease.44 MECHANISM OF ACTION — Several mechanisms of action have been proposed to explain how probiotics could have beneficial effects Acetic, lactic and propionic acid produced by Lactobacillus can lower intestinal pH and inhibit growth of pathogenic bacteria such as Escherichia coli and Clostridium spp The presence of probiotics in the intestinal tract may physically or chemically prevent adhesion of and colonization by pathogenic bacteria They may also induce or enhance an immune response.45 Saccharomyces boulardii, which is a yeast, has been shown to inhibit the pathogenicity of bacterial toxins.46 EFFICACY — Probiotics have been used in inflammatory bowel disease to maintain remission, particularly in patients with pouchitis after ileoanal anastomosis for severe UC In controlled trials in a total of more than 600 patients with UC, probiotics (Escherichia coli Nissle 1917 and Lactobacillus GG) appeared to be as effective as mesalamine in maintaining remission.47-49 In a 9-month controlled trial in 40 patients with chronic pouchitis, relapses occurred in 15% of patients treated with probiotics (VSL #3) 10 11 12 13 14 15 16 17 18 19 20 21 22 GR Lichtenstein et al Management of Crohn’s disease in adults Am J Gastroenterol 2009; 104:465 A Kornbluth et al Ulcerative colitis practice guidelines in adults: American College of Gastroenterology, Practice Parameters Committee Am J Gastroenterol 2010; 105:501 C Campregher and C Gasche Aminosalicylates Best Pract Res Clin Gastroenterol 2011; 25:535 Once-daily mesalamine (Lialda) for ulcerative colitis Med Lett Drugs Ther 2007; 49:25 Encapsulated mesalamine granules (Apriso) for ulcerative colitis Med Lett Drugs Ther 2009; 51:38 P Marteau et al Combined oral and enema treatment with Pentasa (mesalazine) is superior to oral therapy alone in patients with extensive mild/moderate active ulcerative colitis: a randomised, double blind, placebo controlled study Gut 2005; 54:960 AC Ford et al Efficacy of 5-aminosalicylates in Crohn’s disease: systematic review and meta-analysis Am J Gastroenterol 2011; 106:617 KJ Khan et al Antibiotic therapy in inflammatory bowel disease: a systematic review and meta-analysis Am J Gastroenterol 2011; 106:661 GT Ho et al The efficacy of corticosteroid therapy in inflammatory bowel disease: analysis of a 5-year UK inception cohort Aliment Pharmacol Ther 2006; 24:319 AH Steinhart et al Corticosteroids for maintenance of remission in Crohn’s disease Cochrane Database Syst Rev 2003; (4): CD000301 Budesonide (Entocort EC) for Crohn’s disease Med Lett Drugs Ther 2002; 44:6 AG Fraser et al The efficacy of azathioprine for the treatment of inflammatory bowel disease: a 30 year review Gut 2002; 50:485 JF Colombel et al Infliximab, azathioprine, or combination therapy for Crohn’s disease N Engl J Med 2010; 362:1383 L Peyrin-Biroulet et al Increased risk for nonmelanoma skin cancers in patients who receive thiopurines for inflammatory bowel disease Gastroenterology 2011; 141:1621 L Beaugerie et al Lymphoproliferative disorders in patients receiving thiopurines for inflammatory bowel disease: a prospective observational cohort study Lancet 2009; 374:1617 A Thai and T Prindiville Hepatosplenic T-cell lymphoma and inflammatory bowel disease J Crohn’s Colitis 2010; 4:511 FDA drug safety communication: safety review update on reports of hepatosplenic T-cell lymphoma in adolescents and young adults receiving tumor necrosis factor (TNF) blockers, azathioprine, and/or mercaptopurine Available at http://www.fda.gov/Drugs/DrugSafety/ ucm2501913.htm Accessed February 7, 2012 S Vermeire et al Effectiveness of concomitant immunosuppressive therapy in suppressing the formation of antibodies to infliximab in Crohn’s disease Gut 2007; 56:1226 BG Feagan et al Methotrexate for the treatment of Crohn’s disease N Engl J Med 1995; 332:292 BG Feagan et al A comparison of methotrexate with placebo for the maintenance of remission in Crohn’s disease N Engl J Med 2000; 342:1627 S Lichtiger et al Cyclosporine in severe ulcerative colitis refractory to steroid therapy N Engl J Med 1994; 330:1841 M Naganuma et al The use of traditional and newer calcineurin inhibitors in inflammatory bowel disease J Gastroenterol 2011; 46:129 Treatment Guidelines from The Medical Letter • Vol 10 ( Issue 115) • March 2012 27 Drugs for Inflammatory Bowel Disease 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 28 H Ogata et al A randomised dose finding study of oral tacrolimus (FK506) therapy in refractory ulcerative colitis Gut 2006; 55:1255 Certolizumab (Cimzia) for Crohn’s disease Med Lett Drugs Ther 2008; 50:81 D Tracey et al Tumor necrosis factor antagonist mechanisms of action: a comprehensive review Pharmacol Ther 2008; 117:244 GR Lichtenstein et al American Gastroenterological Association Institute medical position statement on corticosteroids, immunomodulators, and infliximab in inflammatory bowel disease Gastroenterology 2006; 130:935 SR Targan et al A short-term study of chimeric monoclonal antibody cA2 to tumor necrosis factor alpha for Crohn’s disease Crohn’s Disease cA2 Study Group N Engl J Med 1997; 337:1029 SB Hanauer et al Maintenance infliximab for Crohn’s disease: the ACCENT I randomised trial Lancet 2002; 359:1541 DH Present et al Infliximab for the treatment of fistulas in patients with Crohn’s disease N Engl J Med 1999; 340:1398 BE Sands et al Infliximab maintenance therapy for fistulizing Crohn’s disease N Engl J Med 2004; 350:876 M Regueiro et al Infliximab prevents Crohn’s disease recurrence after ileal resection Gastroenterology 2009; 136:441 JF Colombel et al Adalimumab for maintenance of clinical response and remission in patients with Crohn’s disease: the CHARM trial Gastroenterology 2007; 132:52 S Schreiber et al Maintenance therapy with certolizumab pegol for Crohn’s disease N Engl J Med 2007; 357:239 L Peyrin-Biroulet et al Efficacy and safety of tumor necrosis factor antagonists in Crohn’s disease: meta-analysis of placebo-controlled trials Clin Gastroenterol Hepatol 2008; 6:644 WJ Sandborn et al Adalimumab induction therapy for Crohn disease previously treated with infliximab: a randomized trial Ann Intern Med 2007; 146:829 S Danese et al Successful induction of clinical response and remission with certolizumab pegol in Crohn’s disease patients refractory or intolerant to infliximab: a real-life multicenter experience of compassionate use Inflamm Bowel Dis 2008; 14:1168 P Rutgeerts et al Infliximab for induction and maintenance therapy for ulcerative colitis N Engl J Med 2005; 353:2462 W Reinisch et al Adalimumab for induction of clinical remission in moderately to severely active ulcerative colitis: results of a randomised controlled trial Gut 2011; 60:780 WJ Sandborn et al Adalimumab induces and maintains clinical remission in patients with moderate-to-severe ulcerative colitis Gastroenterology 2012; 142:257 WJ Sandborn et al Natalizumab induction and maintenance therapy for Crohn’s disease N Engl J Med 2005; 353:1912 SR Targan et al Natalizumab for the treatment of active Crohn’s disease: results of the ENCORE trial Gastroenterology 2007; 132:1672 Natalizumab (Tysabri) for Crohn's disease Med Lett Drugs Ther 2008; 50:34 US Food & Drug Administration FDA News Release: FDA permits marketing of first test for risk of rare brain infection in some people treated with Tysabri January 20, 2012 Available at: http://www.fda gov/NewsEvents/Newsroom/PressAnnouncements/ucm288471.htm Accessed February 7, 2012 Probiotics Med Lett Drugs Ther 2007; 49:66 JP Buts and N De Keyser Effects of Saccharomyces boulardii on intestinal mucosa Dig Dis Sci 2006; 51:1485 MH Floch and DC Montrose Use of probiotics in humans: an analysis of the literature Gastroenterol Clin North Am 2005; 34:547 BJ Rembacken et al Non-pathogenic Escherichia coli versus mesalazine for the treatment of ulcerative colitis: a randomised trial Lancet 1999; 354:635 W Kruis et al Maintaining remission of ulcerative colitis with the probiotic Escherichia coli Nissile 1917 is as effective as with standard mesalazine Gut 2004; 53:1617 MA Zocco et al Efficacy of Lactobacillus GG in maintaining remission of ulcerative colitis Aliment Pharmacol Ther 2006; 23:1567 P Gionchetti et al Oral bacteriotherapy as maintenance treatment in patients with chronic pouchitis: a double-blind, placebo-controlled trial Gastroenterology 2000; 119:305 Mobile App Now Available Download The Medical Letter’s free App for the iPhone, iPad and Android through your device’s App store BlackBerry coming soon For more information: medicalletter.org/apps or scan the code below Treatment Guidelines ® from The Medical Letter EDITOR IN CHIEF: Mark Abramowicz, M.D EXECUTIVE EDITOR: Gianna Zuccotti, M.D., M.P.H., F.A.C.P., Harvard Medical School EDITOR: Jean-Marie Pflomm, Pharm.D ASSISTANT EDITORS, DRUG INFORMATION: Susan M Daron, Pharm.D., Corinne E Zanone, Pharm.D CONSULTING EDITORS: Brinda M Shah, Pharm.D., F Peter Swanson, M.D CONTRIBUTING EDITORS: Carl W Bazil, M.D., Ph.D., Columbia University College of Physicians and Surgeons Vanessa K Dalton, M.D., M.P.H., University of Michigan Medical School Eric J Epstein, M.D., Albert Einstein College of Medicine Jules Hirsch, M.D., Rockefeller University David N Juurlink, BPhm, M.D., PhD, Sunnybrook Health Sciences Centre Richard B Kim, M.D., University of Western Ontario Hans Meinertz, M.D., University Hospital, Copenhagen Sandip K Mukherjee, M.D., F.A.C.C., Yale School of Medicine Dan M Roden, M.D., Vanderbilt University School of Medicine F Estelle R Simons, M.D., University of Manitoba Jordan W Smoller, M.D., Sc.D., Harvard Medical School Neal H Steigbigel, M.D., New York University School of Medicine Arthur M.F Yee, M.D., Ph.D., F.A.C.R, Weill Medical College of Cornell University SENIOR ASSOCIATE EDITORS: Donna Goodstein, Amy Faucard ASSOCIATE EDITOR: Cynthia Macapagal Covey EDITORIAL FELLOW: Esperance A K Schaefer, M.D., M.P.H., Harvard Medical School MANAGING EDITOR: Susie Wong ASSISTANT MANAGING EDITOR: Liz Donohue PRODUCTION COORDINATOR: Cheryl Brown EXECUTIVE DIRECTOR OF SALES: Gene Carbona FULFILLMENT AND SYSTEMS MANAGER: Cristine Romatowski DIRECTOR OF MARKETING COMMUNICATIONS: Joanne F Valentino VICE PRESIDENT AND PUBLISHER: Yosef Wissner-Levy Founded in 1959 by Arthur Kallet and Harold Aaron, M.D Copyright and Disclaimer: The Medical Letter is an independent nonprofit organization that provides healthcare professionals with unbiased drug prescribing recommendations The editorial process used for its publications relies on a review of published and unpublished literature, with an emphasis on controlled clinical trials, and on the opinions of its consultants The Medical Letter is supported solely by subscription fees and accepts no advertising, grants or donations No part of the material may be reproduced or transmitted by any process in whole or in part without prior permission in writing The editors not warrant that all the material in this publication is accurate and complete in every respect The editors shall not be held responsible for any damage resulting from any error, inaccuracy or omission Subscription Services Mailing Address: The Medical Letter, Inc 145 Huguenot Street, Ste 312 New Rochelle, NY 10801-7537 Customer Service: Call: 800-211-2769 or 914-235-0500 Fax: 914-632-1733 Web Site: www.medicalletter.org E-mail: custserv@medicalletter.org Permissions: To reproduce any portion of this issue, please e-mail your request to: permissions@medicalletter.org Subscriptions (US): year - $98; years - $189; years - $279 $49/yr for students, interns, residents and fellows in the US and Canada E-mail site license inquiries to: info@medicalletter.org or call 800-211-2769 x315 Special fees for bulk subscriptions Special classroom rates are available Back issues are $12 each Major credit cards accepted Copyright 2012 ISSN 1541-2792 Treatment Guidelines from The Medical Letter • Vol 10 ( Issue 115) • March 2012 Treatment Guidelines: Online Continuing Medical Education Up to 24 credits included with your subscription medicalletter.org/cme Choose CME from Treatment Guidelines from The Medical Letter and earn up to 24 Category Credits per year: Free Individual Exams - Free to active subscribers of Treatment Guidelines from The Medical Letter Answer 12 questions per issue and submit answers online Earn up to credits/exam Paid Individual Exams - Available to non-subscribers Answer 12 questions per issue and submit answers online Earn up to credits/exam $12/exam ACCREDITATION INFORMATION: ACCME: The Medical Letter is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians The Medical Letter Inc designates this enduring material for a maximum of AMA PRA Category Credit(s)™ Physicians should claim only the credit commensurate with the extent of their participation in the activity This CME activity was planned and produced in accordance with the ACCME Essentials and Policies AAFP: This Enduring Material activity, Treatment Guidelines from the Medical Letter Continuing Medical Education Program, has been reviewed and is acceptable for up to 15 Prescribed credits by the American Academy of Family Physicians AAFP accreditation begins January 1, 2012 Term of approval is for year from this date Each issue is approved for 1.25 Prescribed credits Credit may be claimed for year from the date of each issue ACPE: The Medical Letter is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education This exam is acceptable for 2.0 hour(s) of knowledge-based continuing education credit (0.2 CEU) ® AANP and AAPA: The American Academy of Nurse Practitioners (AANP) and the American Academy of Physician Assistants (AAPA) accept AMA Category Credit for the Physician’s Recognition Award from organizations accredited by the ACCME AOA: This activity, being ACCME (AMA) approved, is acceptable for Category 2-B credit by the American Osteopathic Association (AOA) Physician Assistants: The National Commission on Certification of Physician Assistants (NCCPA) accepts AMA PRA Category Credit(s)™ from organizations accredited by ACCME NCCPA also accepts AAFP Prescribed credits for recertification Treatment Guidelines is accredited by both ACCME and AAFP Physicians in Canada: Members of The College of Family Physicians of Canada residing in the US are eligible to receive Mainpro-M1 credits (equivalent to AAFP Prescribed credits), and members residing in Canada are eligible to receive Mainpro-M2 credits due to a reciprocal agreement with the American Academy of Family Physicians Treatment Guidelines CME activities are eligible for either Section or Section (when creating a personal learning project) in the Maintenance of Certification Program of the Royal College of Physicians and Surgeons of Canada (RCPSC) Physicians, nurse practitioners, pharmacists and physician assistants may earn credits with this exam MISSION: The mission of The Medical Letter's Continuing Medical Education Program is to support the professional development of healthcare professionals including physicians, nurse practitioners, pharmacists and physician assistants by providing independent, unbiased drug information and prescribing recommendations that are free of industry influence The program content includes current information and unbiased reviews of FDA-approved and off-label uses of drugs, their mechanisms of action, clinical trials, dosage and administration, adverse effects and drug interactions The Medical Letter delivers educational content in the form of self-study material The expected outcome of the CME Program is to increase the participant’s ability to know, or apply knowledge into practice after assimilating, information presented in materials contained in Treatment Guidelines The Medical Letter will strive to continually improve the CME program through periodic assessment of the program and activities The Medical Letter aims to be a leader in supporting the professional development of healthcare professionals through Core Competencies by providing continuing medical education that is unbiased and free of industry influence The Medical Letter is supported solely by subscription fees and accepts no advertising, grants or donations GOAL: Through this program, The Medical Letter expects to provide the healthcare community with unbiased, reliable and timely educational content that they will use to make independent and informed therapeutic choices in their practice LEARNING OBJECTIVES: The objective of this activity is to meet the need of healthcare professionals for unbiased, reliable and timely information on treatment of major diseases The Medical Letter expects to provide the healthcare community with educational content that they will use to make independent and informed therapeutic choices in their practice Participants will be able to select and prescribe, or confirm the appropriateness of the prescribed usage of the drugs and other therapeutic modalities discussed in Treatment Guidelines with specific attention to clinical evidence of effectiveness, adverse effects and patient management Upon completion of this activity, the participant will be able to: Explain the current approach to the management of a patient with inflammatory bowel disease Discuss the pharmacologic options available for treatment of inflammatory bowel disease and compare them based on their mechanism of action, efficacy, dosage and administration, potential adverse effects and drug interactions Determine the most appropriate therapy given the clinical presentation of an individual patient Privacy and Confidentiality: The Medical Letter guarantees our firm commitment to your privacy We not sell any of your information Secure server software (SSL) is used for commerce transactions through VeriSign, Inc No credit card information is stored IT Requirements: Windows 98/NT/2000/XP/Vista/7, Pentium+ processor, Mac OS X+ w/ compatible process; Microsoft IE 6.0+, Mozilla Firefox 2.0+ or any other compatible Web browser Dial-up/high-speed connection Have any questions? Call us at 800-211-2769 or 914-235-0500 or e-mail us at: custserv@medicalletter.org Questions start on next page Treatment Guidelines from The Medical Letter • Vol 10 ( Issue 115) • March 2012 DO NOT FAX OR MAIL THIS EXAM To take CME exams and earn credit, go to: medicalletter.org/CMEstatus Issue 115 Questions Which of the following formulations of oral mesalamine can be taken with antacids? a Dipentum b Asacol c Lialda d Apriso Issue 115 Cyclosporine: a has been used in patients with severe steroid-resistant ulcerative colitis b can cause nephrotoxicity c should be given intravenously in ulcerative colitis patients d all of the above Issue 115 A 33-year-old woman with Crohn’s disease is planning on becoming pregnant Which of the following medications would be contraindicated in this patient? a metronidazole b mesalamine c methotrexate d infliximab Issue 115 Which of the following statements about TNF inhibitors is true? a Infliximab has been shown to be effective in fistula closure in patients with Crohn’s disease b Adalimumab and certolizumab are administered subcutaneously c Infliximab and adalimumab have been shown to be effective in treatment of refractory ulcerative colitis d all of the above Issue 115 Antibiotics that may be helpful in patients with inflammatory bowel disease include: a metronidazole b ciprofloxacin c rifaximin d all of the above Issue 115 Which of the following has been shown to be effective in patients with Crohn’s disease who are refractory to infliximab? a mesalamine b etanercept c adalimumab d all of the above Issue 115 Systemic corticosteroids are tapered and discontinued in patients with inflammatory bowel disease (IBD) once acute inflammation is under control because: a they interact with many other medications used to treat IBD b they can cause severe adverse effects c they are expensive d all of the above Issue 115 10 A 28-year-old male patient with Crohn’s disease is being started on infliximab Which of the following tests are recommended before initiating therapy in this patient? a tuberculin skin testing b chest radiography c serologic testing for active hepatitis B d all of the above Azathioprine and mercaptopurine: a have been effective in maintaining remission in both Crohn’s disease and ulcerative colitis b cause myelosuppression c may take 3-6 months to achieve their maximal effect d all of the above Issue 115 11 Use of natalizumab in clinical practice has been limited because it is: a associated with seizures b associated with Stevens-Johnson syndrome c associated with progressive multifocal leukoencephalopathy d all of the above Issue 115 The combination of azathioprine and infliximab: a has been shown to be more effective in maintaining steroidfree remission than either drug alone b is safer than infliximab alone c has not been associated with cases of hepatosplenic T-cell lymphoma d all of the above Issue 115 12 Probiotics: a are highly effective in treatment of Crohn’s disease b have been used to maintain remission in patients with pouchitis c not interact with antibiotics or antifungals d not cause bloating or flatulence Issue 115 ACPE UPN: 379-0000-12-115-H01-P; Release: February 2012, Expire: February 2013 Treatment Guidelines from The Medical Letter • Vol 10 ( Issue 115) • March 2012 ... Take CME exams Tables Drugs for Inflammatory Bowel Disease Drugs for Crohn’s Disease Drugs for Ulcerative Colitis Pages 20-21 Page 23 Page 24 Drugs for Inflammatory Bowel Disease RECOMMENDATIONS... reproduction by any means and imposes severe fines 19 Drugs for Inflammatory Bowel Disease Table Drugs for Inflammatory Bowel Disease Some Formulations Drug Indications Aminosalicylates Mesalamine... The Medical Letter • Vol 10 ( Issue 115) • March 2012 Drugs for Inflammatory Bowel Disease Table Drugs for Crohn’s Disease Condition Crohn’s Disease Mild to Moderate: Induction of Remission Maintenance