The Medical Letter ® on Drugs and Therapeutics Objective Drug Reviews Since 1959 August 4, 2014 Volume 56 ISSUE ISSUE No IN THIS ISSUE 1433 1448 Drugs for Inflammatory Bowel Disease Volume 56 Important Copyright Message FORWARDING OR COPYING IS A VIOLATION OF U.S AND INTERNATIONAL COPYRIGHT LAWS The Medical Letter, Inc publications are protected by U.S 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 U.S 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 Published by The Medical Letter, Inc • A Nonprofit Organization 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 The Medical Letter ® on Drugs and Therapeutics Objective Drug Reviews Since 1959 Volume 56 ISSUE ISSUE No August 4, 2014 Take CME exams IN THIS ISSUE 1433 1448 Drugs for Inflammatory Bowel Disease Volume 56 Related article(s) since publication RECOMMENDATIONS Ulcerative Colitis: An aminosalicylate is generally used first for induction and maintenance of remission in mild to moderate disease Azathioprine or mercaptopurine is used for maintenance of remission in patients with moderate to severe disease Corticosteroids are used to induce remission in patients with severe disease, or with moderate disease refractory to other drugs Patients with corticosteroid-refractory disease may respond to a TNF inhibitor Crohn’s Disease: Corticosteroids are used to induce remission Azathioprine or mercaptopurine is used for maintenance of remission A TNF inhibitor alone or in combination with azathioprine or mercaptopurine can be used for both induction and maintenance of remission in patients with moderate to severe disease AMINOSALICYLATES Aminosalicylates are effective for induction and maintenance of remission in mild to moderate ulcerative colitis They are not recommended for treatment of Crohn’s disease FORMULATIONS — Oral mesalamine is rapidly absorbed in the small intestine and most of the drug does not reach the colon Pentasa releases mesalamine gradually throughout the gastrointestinal tract Delzicol, Asacol HD, Lialda, and Apriso delay the release of the drug until it reaches the distal ileum and colon Sulfasalazine (Azulfidine, and generics), 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 generics) and as a rectal suppository (Canasa) EFFICACY — Aminosalicylates generally induce remission in about 35-50% of patients with mild to moderate ulcerative colitis and maintain the remission for ≥6 months in 55-75% In distal ulcerative colitis and proctitis, mesalamine suppositories or enemas may be more effective than oral formulations at both inducing and maintaining remission Combination therapy with oral and rectal mesalamine may be more effective for distal ulcerative colitis than either formulation used alone ADVERSE EFFECTS — The most common adverse effects of mesalamine have been nausea, vomiting, diarrhea, headache, and abdominal pain Nephrotoxicity can occur Pancreatitis, hepatotoxicity, pericarditis, pneumonitis, and a lupus-like syndrome have been reported PREGNANCY — Most formulations of aminosalicylates are classified as category B (no evidence of harm in animals; no adequate human studies) for use during pregnancy Asacol HD is classified as category C (risk cannot be ruled out); in animal studies, dibutyl phthalate, an ingredient in its enteric coating, was associated with fetal malformations and adverse effects on the male reproductive system Olsalazine is also classified as pregnancy category C (embryofetal toxicity in animals; no adequate human studies) DRUG INTERACTIONS — Mesalamine inhibits thiopurine methyltransferase in vitro and may interfere with the metabolism of azathioprine and mercaptopurine, which could increase their toxicity, but seldom does except in patients with an inherited deficiency of thiopurine methyltransferase Extended- and delayed-release mesalamine formulations with pH-sensitive coatings (Delzicol, Asacol HD, Lialda, Apriso) should not be coadministered with antacids because premature dissolution of the coating could occur 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) 65 Published by The Medical Letter, Inc • A Nonprofit Organization The Medical Letter ® Table Drugs for Ulcerative Colitis Recommended Drugs Some Alternatives Mild to Moderate Induction of Remission Mesalamine, oral Balsalazide Olsalazine Mesalamine, rectal Hydrocortisone, rectal Maintenance of Remission Mesalamine, oral Balsalazide Olsalazine Mesalamine, rectal Moderate to Severe Induction of Remission Prednisone Hydrocortisone Methylprednisolone Maintenance of Remission Azathioprine Mercaptopurine Infliximab Adalimumab Budesonide Prednisone Sulfasalazine Infliximab Adalimumab Golimumab Vedolizumab Azathioprine Mercaptopurine Sulfasalazine Infliximab Adalimumab Golimumab Vedolizumab Infliximab Adalimumab Golimumab Cyclosporine Tacrolimus Vedolizumab Sulfasalazine Golimumab Vedolizumab Pouchitis Induction of Remission Ciprofloxacin Metronidazole Maintenance of Remission Probiotics: VSL #3 Metronidazole Ciprofloxacin Rifaximin Rifaximin Budesonide Infliximab Mesalamine, rectal Infliximab CORTICOSTEROIDS Corticosteroids are effective in both ulcerative colitis and Crohn’s disease for induction of 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 inflammatory bowel disease respond to systemic corticosteroids In one retrospective study in 146 patients who required treatment with corticosteroids, 51% of patients with ulcerative colitis and 40% of those with Crohn’s disease had a complete response at 30 days; 31% and 35% had a partial response.1 Most patients who respond to corticosteroids relapse if not given maintenance therapy ADVERSE EFFECTS — Corticosteroids can cause fluid retention, increased risk of infection, osteoporosis, osteonecrosis, cataracts, glaucoma, impaired 66 Vol 56 (1448) August 4, 2014 skin healing, acne, insomnia, mood disorders, Cushing’s syndrome, hyperglycemia, and hypothalamicpituitary-adrenal (HPA) axis suppression RECTAL CORTICOSTEROIDS — Rectally administered corticosteroids are effective for treatment of distal ulcerative colitis Enemas can reach the splenic flexure, while foam coats only the last 15-20 cm of the colon BUDESONIDE — A synthetic corticosteroid with a strong affinity for glucocorticoid receptors and a high ratio of local anti-inflammatory to systemic effects, budesonide has been used orally in an ileal-release formulation (Entocort EC, and generics) to induce remission in mild to moderate Crohn’s disease of the ileum and/or ascending colon While also approved for maintenance, it does not appear to be effective for preventing relapse beyond months of use Budesonide is also available in an extended-release formulation (Uceris) that distributes the drug throughout the colon and is FDA-approved for induction of remission in mild to moderate ulcerative colitis In patients with active mild to moderate ulcerative colitis for at least months, remission occurred more frequently with Uceris (17.9%) than with Asacol (12.1%) or placebo (7.4%).2 Budesonide enemas are effective for distal ulcerative colitis; they are available in Canada, but not in the US Adverse Effects – Budesonide causes less short-term corticosteroid toxicity than prednisone Whether it is safer in the long term is not clear Pregnancy – Budesonide is classified as category C (evidence of toxicity in animals; no adequate human studies) for use during pregnancy Drug Interactions – Budesonide is a CYP3A4 substrate and should be used with caution or avoided in combination with drugs that inhibit CYP3A4, which could increase its toxicity.3 Drugs that change the pH of the gastrointestinal tract (antacids, PPIs, H2-receptor antagonists) may affect the release and absorption of oral budesonide IMMUNOMODULATORY AGENTS AZATHIOPRINE AND MERCAPTOPURINE — The thiopurines azathioprine (Imuran, and generics) and mercaptopurine (6-MP; Purinethol, and generics), which is the active metabolite of azathioprine, are effective for maintaining remission in both ulcerative colitis and Crohn’s disease Since they 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 The Medical Letter ® Efficacy – In controlled trials, azathioprine and mercaptopurine have been significantly more effective than placebo in maintaining remission in both ulcerative colitis and Crohn’s disease.4,5 In a study in patients with moderate to severe Crohn’s disease not previously exposed to immunosuppressive or biologic therapy, the combination of azathioprine plus infliximab was more effective than either drug alone; after 26 weeks of therapy, 56.8% of patients receiving combination therapy were in steroid-free clinical remission, compared to 44.4% of patients receiving infliximab alone and 30% of those receiving azathioprine alone.6 The results of another study suggest that the combination of infliximab plus azathioprine is also superior to either agent alone in the treatment of ulcerative colitis.7 Adverse Effects – Azathioprine and mercaptopurine can cause myelosuppression, infection, nausea, vomiting, diarrhea, hepatotoxicity, rash, pulmonary edema, pancreatitis, and a hypersensitivity reaction Long-term use has been associated with a small increase in the risk of non-melanoma skin cancer and lymphoma Hepatosplenic T-cell lymphoma has been reported in patients taking azathioprine or mercaptoprine both alone and in combination with a TNF inhibitor Pregnancy – Azathioprine and mercaptopurine are both classified as category D (positive evidence of fetal harm) for use during pregnancy Drug Interactions – Allopurinol (Zyloprim, and generics) 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 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 Vol 56 (1448) August 4, 2014 Table Drugs for Crohn's Disease Recommended Drugs Mild to Moderate Induction of Remission Budesonide Maintenance of Remission Azathioprine Mercaptopurine Moderate to Severe Induction of Remission Prednisone Methylprednisolone Infliximab Adalimumab Certolizumab pegol Maintenance of Remission Infliximab Adalimumab Certolizumab pegol Azathioprine Mercaptopurine Some Alternatives Prednisone Metronidazole Ciprofloxacin Rifaximin Budesonide Methotrexate Vedolizumab Natalizumab Methotrexate Vedolizumab Natalizumab Perianal and Fistulizing Disease Induction of Remission Metronidazole ± Ciprofloxacin Infliximab Maintenance of Remission Azathioprine Mercaptopurine Infliximab Methotrexate Efficacy – Several studies have found methotrexate effective in maintaining remission in patients with Crohn’s disease.8 In one study, a combination of methotrexate and infliximab was no more effective than either drug alone.9 Adverse Effects – Methotrexate can cause myelosuppression, alopecia, rash, stomatitis, vomiting, diarrhea, gastrointestinal hemorrhage, hepatotoxicity, renal failure, interstitial pneumonia, liver failure, toxic epidermal necrolysis, Stevens-Johnson syndrome, hypotension, blurred vision, headache, nephropathy, and hyperuricemia Pregnancy – Methotrexate is contraindicated for use during pregnancy (category X) Pregnancy should be avoided if either partner is receiving the drug Severe leukopenia has been reported during concomitant therapy with angiotensin-converting enzyme (ACE ) inhibitors or trimethoprim/sulfamethoxazole (Bactrim, and others) Azathioprine and mercaptopurine may decrease the anticoagulant effect of warfarin (Coumadin, and others) Drug Interactions – 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 increase serum concentrations of methotrexate and possibly its toxicity METHOTREXATE — In Crohn's disease, methotrexate can be used as an alternative to azathioprine or mercaptopurine to maintain remission and permit withdrawal of corticosteroids It has not been clearly shown to be effective in ulcerative colitis CYCLOSPORINE — The calcineurin inhibitor cyclosporine (Sandimmune, and others) is used as rescue therapy to avoid colectomy in patients with severe steroid-resistant ulcerative colitis Use of cyclosporine in Crohn’s disease has been limited 67 The Medical Letter ® Vol 56 (1448) August 4, 2014 Table Drugs for Inflammatory Bowel Disease Drug Aminosalicylates2 Mesalamine – delayed- or extended-release Apriso (Salix) Delzicol 3 (Actavis) Some Formulations Usual Adult Dosage Cost1 375 mg ER caps 400 mg DR caps Maintenance: 1.5 g once/d Induction: 800 mg tid Maintenance: 1.6 g daily in divided doses Induction: 1.6 g tid Induction: 2.4 or 4.8 g once/d Maintenance: 2.4 g once/d Induction: g qid $348.00 430.20 Induction: 2.25 g tid Maintenance: 3-6 g daily in divided doses Induction: 3.3 g bid Induction: 1.5-3 g daily in divided doses Maintenance: 500 mg bid Induction: g qid Maintenance: g bid Induction: 3-4 g daily in divided doses Maintenance: g daily 76.10 127.80 864.00 1087.20 g/60 mL enema Induction: g rectally once/d at bedtime Maintenance: 2-4 g rectally once/d at bedtime 1000 mg rectal suppository Induction and maintenance: 1000 mg rectally once/d 370.404 1096.304 997.004 709.20 1, 2.5, 5, 10, 20, 50 mg tabs; mg/5 mL oral solution Induction: 40-60 mg once/d 15.90 1, 2, mg DR tabs mg caps Induction: 40-60 mg once/d Induction: mg once/d Maintenance: mg once/d6 7464.00 1263.00 2070.90 mg ER tabs 100 mg/60 mL enema Induction: mg once/d Induction: enema nightly 10% rectal foam Induction: application once/d or bid 1333.80 182.90 255.80 544.607 Asacol HD (Actavis) Lialda (Shire) 800 mg DR tabs 1.2 g DR tabs Pentasa (Shire) 250, 500 mg ER caps Mesalamine – prodrugs Balsalazide – generic Colazal (Salix) Giazo (Salix) Olsalazine – Dipentum (Meda) Sulfasalazine – generic Azulfidine (Pfizer) delayed-release – generic Azulfidine En-tabs (Pfizer) Mesalamine – rectal generic Rowasa (Meda) SF Rowasa (Meda) Canasa (Aptalis) Corticosteroids Prednisone – generic delayed-release Rayos (Horizon) Budesonide – generic Entocort EC (AstraZeneca)5 extended-release Uceris (Santarus)2 Hydrocortisone2 – generic Colocort (Paddock) Cortifoam (Meda) 750 mg caps 1.1 g tabs 250 mg caps 500 mg tabs 500 mg enteric-coated DR tabs 445.50 405.00 876.00 49.20 196.80 41.40 192.60 ER = extended-release; DR = delayed-release Approximate wholesale acquisition cost (WAC) for 30 days' treatment at the lowest induction dosage Prices for Apriso, azathioprine, and mercaptopurine are based on the lowest maintenance dosage Source: Analy$ource® Monthly (Selected from FDB MedKnowledge™) July 5, 2014 Reprinted with permission by FDB, Inc All rights reserved ©2014 www.fdbhealth.com/policies/drug-pricing-policy Actual retail prices may be higher Not FDA-approved for use in Crohn's disease Delzicol has replaced Asacol due to reproductive safety concerns associated with dibutyl phthalate, a plasticizer in the enteric coating of Asacol Delzicol does not contain dibutyl phthalate Cost for 28 days' treatment Not FDA-approved for use in ulcerative colitis FDA-approved for up to months Cost of two 15-gram aerosol containers (each contains ~14 applications) Efficacy – One open-label randomized trial comparing cyclosporine to infliximab for treatment of patients with an acute severe flare of ulcerative colitis refractory to IV steroids found the two drugs equally effective.10 Adverse Effects – Cyclosporine can cause diarrhea, nausea, vomiting, infection, gingival hyperplasia, pruritus, headache, seizures, tremors, visual disturbances, hypertension, hepatotoxicity, nephrotoxicity, paresthesias, and anaphylaxis Pregnancy – Cyclosporine is classified as category C (embryofetal toxicity in animals; no adequate human studies) for use during pregnancy 68 Drug Interactions – Nephrotoxic effects may be additive when cyclosporine is used in conjunction with other nephrotoxic drugs such as aminoglycoside antibiotics Concurrent use of potassium-sparing diuretics such as spironolactone (Aldactone, and generics) may increase the risk of hyperkalemia Cyclosporine is both a substrate and an inhibitor of CYP3A4 and P-glycoprotein; CYP3A4 inhibitors may increase its toxicity and CYP3A4 inducers may decrease its effectiveness.3 TACROLIMUS — Tacrolimus (Prograf, and generics), another calcineurin inhibitor, has been used as an alternative to cyclosporine to treat patients with refractory ulcerative colitis Data are limited on its use in Crohn’s disease The Medical Letter ® Vol 56 (1448) August 4, 2014 Table Drugs for Inflammatory Bowel Disease (continued) Drug Immunosuppressants8 Azathioprine – generic Imuran (Prometheus) Mercaptopurine – generic Purinethol (Teva) Methotrexate10 – generic Otrexup (Antares) Rasuvo (Medac) Cyclosporine – generic Sandimmune (Novartis) Tacrolimus – generic Prograf (Astellas) TNF Inhibitors Adalimumab – Humira (Abbvie) Certolizumab pegol – Cimzia5 (UCB) Golimumab – Simponi2 (Janssen) Infliximab – Remicade (Janssen) Integrin Receptor Antagonists Natalizumab – Tysabri 5 (Elan/Biogen) Vedolizumab – Entyvio (Takeda) Some Formulations Usual Adult Dosage Cost1 25, 50, 75, 100 mg tabs 50 mg tabs 50 mg tabs Maintenance: 2-2.5 mg/kg once/d $36.709 567.909 170.309 543.309 8.80 548.00 50 mg/2 mL ampule 15 mg/0.4 mL; 25 mg/0.4 mL autoinjector 15 mg/0.3 mL; 25 mg/0.5 mL autoinjector 50 mg/mL ampule 50 mg/mL ampule 0.5, 1, mg caps 40 mg/0.8 mL prefilled syringe; 40 mg/0.8 mL single-use pen 200 mg vial (lyophilized powder); 200 mg/mL prefilled syringe 50 mg/0.5 mL, 100 mg/1 mL autoinjector; 50 mg/ 0.5 mL, 100 mg/1 mL prefilled syringe 100 mg vial (lyophilized powder) Maintenance: 1-1.5 mg/kg once/d Induction: 25 mg IM/SC11 once/wk Maintenance: 15-25 mg IM/SC11 once/wk N.A.12 Induction: 2-4 mg/kg IV daily Induction: 0.05-0.2 mg/kg/d in divided doses14 Induction: 160 mg SC at wk 0, then 80 mg at wk Maintenance: 40 mg SC every other wk starting at wk Induction: 400 mg SC at wks 0, 2, and Maintenance: 400 mg SC q4 wks Induction: 200 mg SC at wk 0, then 100 mg SC at wk Maintenance: 100 mg SC q4 wks 91.609,13 173.909,13 398.409 522.009 5400.6015 5538.4015 6234.2015 Induction: mg/kg IV at wks 0, 2, and Maintenance: 5-10 mg/kg IV q8 wks 3539.509,15 300 mg/15 mL vial (lyophilized powder) 300 mg/20 mL vial (lyophilized powder) Induction and maintenance: 300 mg IV q4 wks 9358.0015 Induction: 300 mg IV at wks 0, 2, and Maintenance: 300 mg IV q8 wks 4819.0015 250, 500 mg tabs; 375 mg caps 250 mg tid16 100, 250, 500, 750 mg tabs 500 mg bid 200, 550 mg tabs 600-2000 mg daily in divided doses Antibiotics8 Metronidazole – generic Flagyl (Pfizer) Ciprofloxacin – generic Cipro (Bayer) Rifaximin – Xifaxan (Salix) 32.00 422.10 13.90 344.20 1202.40 N.A = Not available Not FDA-approved for inflammatory bowel disease Cost based on a 75-kg patient 10 Use of supplements containing folic acid (1-4 mg daily) or folinic acid (2.5-10 mg weekly 24 hours after the methotrexate dose) may decrease some of methotrexate's adverse effects 11 Otrexup and Rasuvo are for subcutaneous injection only 12 Rasuvo has been approved by the FDA, but is not yet available 13 Cost for days' treatment 14 Adjust dose to maintain target trough levels of 5-15 ng/mL 15 Cost for weeks' treatment at the lowest maintenance dosage 16 250 mg tid for induction and maintenance of remission in pouchitis; 10-20 mg/kg daily in divided doses for induction of remission in Crohn's disease; 500 mg tid for induction of remission in perianal and fistulizing disease Efficacy – Tacrolimus appears to be effective in producing clinical improvement in some patients with corticosteroid-refractory ulcerative colitis In one doubleblind, randomized trial, clinical response occurred after weeks in 16 of 32 such patients treated with tacrolimus, compared to of 30 taking a placebo.11 One retrospective study found that about 60% of patients with steroidrefractory ulcerative colitis treated with tacrolimus had a clinical remission or showed clinical improvement and that 33% achieved mucosal healing.12 In one small retrospective study in 24 patients with severe Crohn’s disease refractory to TNF inhibitors, tacrolimus treatment resulted in clinical response in 16 (67%) patients and steroid-free remission in (21%).13 Adverse Effects – Tacrolimus can cause tremors, renal dysfunction, gastrointestinal discomfort, headache, infection, hypomagnesemia, hypertension, insomnia, and seizures It has 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 may increase its toxicity and CYP3A4 inducers may decrease its effectiveness.3 Tacrolimus can cause QT interval prolongation; it should be used with caution when other drugs that prolong the QT interval are taken concurrently.14 69 The Medical Letter ® TNF INHIBITORS Three tumor necrosis factor (TNF) inhibitors – infliximab (Remicade), adalimumab (Humira), and certolizumab pegol (Cimzia) – are used for treatment of moderate to severe Crohn’s disease.15 Infliximab is the only one of the three approved by the FDA for use in children Infliximab, adalimumab, and golimumab (Simponi) are approved by the FDA for treatment of moderate to severe ulcerative colitis not responsive to conventional therapies.16 Drug and antibody levels may sometimes be helpful in the use of these agents.17 EFFICACY — Crohn’s Disease – Infliximab has been effective for the treatment of moderate to severe Crohn’s disease that has not responded to other drugs, including systemic corticosteroids It has been more effective than placebo in inducing and maintaining remission and in producing closure of fistulas Infliximab has also been shown to reduce Crohn’s disease recurrence after ileocolonic resection In an open-label 5-year follow-up study, 22% of patients treated with infliximab had recurrences, compared to 94% of untreated patients.18 The rates of response and remission in Crohn’s disease treated with other TNF inhibitors appear to be comparable to those with infliximab In one study, 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%) were in remission after 12 months.19 In a study with certolizumab pegol, 428 of 668 patients (64%) responded to induction, and after maintenance treatment for 26 weeks, 103 of 215 (48%) responders were in remission.20 Head-to-head comparisons of TNF inhibitors are lacking Adalimumab has been effective in some patients who had become refractory to infliximab.21 Certolizumab pegol has also been effective in some patients who had become refractory or intolerant to infliximab.22 In general, however, the rate of response to a second TNF inhibitor has been lower than the rate of response to the first Use of a TNF inhibitor in combination with azathioprine or mercaptopurine may be more effective than either drug alone (see page 61) Ulcerative Colitis – TNF inhibitors have also been effective for treatment of ulcerative colitis Infliximab, adalimumab, and golimumab have all been shown to be significantly more effective than placebo in inducing and maintaining remission in patients with moderate to severe ulcerative colitis.23 In a meta-analysis of clinical trials of biologic agents including infliximab, adali70 Vol 56 (1448) August 4, 2014 mumab, golimumab, and the integrin receptor antagonist vedolizumab, there was no conclusive evidence that any one of these was more effective than any other in maintaining clinical remission in moderate to severe ulcerative colitis.24 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, such as those caused by Legionella and Listeria Tuberculin skin testing and chest radiography are recommended before starting and periodically during therapy Inhibition of TNF has also been associated with reactivation of hepatitis B virus in patients who are chronic carriers; 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 new onset psoriasis, hematologic cytopenias, non-ischemic congestive heart failure, demyelinating disorders, and induction of a lupus-like syndrome An increased risk of cancer, including lymphoma, melanoma, and non-melanoma skin cancers, has been reported with use of TNF inhibitors, but a causeand-effect relationship has not been established.25 A nationwide study in Denmark found that patients with inflammatory bowel disease treated with TNF inhibitors and followed for a median of 3.7 years did not have an increased risk of cancer.26 PREGNANCY — Adalimumab, certolizumab pegol, golimumab, and infliximab are all classified as category B (no evidence of harm in animals; no adequate human studies) for use during pregnancy Placental transfer of anti-TNF antibodies may be higher during the late second and third trimesters, especially with infliximab, adalimumab, and golimumab DRUG INTERACTIONS — Concomitant administration of a TNF inhibitor with another biologic may increase the risk of serious infections and neutropenia Patients being treated with TNF inhibitors should not receive live vaccines INTEGRIN RECEPTOR ANTAGONISTS Two integrin receptor antagonists – natalizumab (Tysabri) and vedolizumab (Entyvio) – are approved by the FDA for treatment of inflammatory bowel disease Natalizumab is approved for induction and maintenance treatment of moderate to severe Crohn’s disease Vedolizumab is approved for use in both Crohn’s disease and ulcerative colitis.27 Vedolizumab is a humanized monoclonal antibody that binds to -4-ß-7 The Medical Letter ® integrin Specifically blocking the ß-7 integrin is thought to inhibit leukocyte migration in the intestine, but not in the central nervous system, thereby decreasing the risk of progressive multifocal leukoencephalopathy (PML), which has occurred with natalizumab EFFICACY — Natalizumab has been modestly effective in some studies as an induction agent in patients with moderate to severe Crohn’s disease with active inflammation It appears to be more effective at maintaining response and remission, with significant steroid-sparing effects.28 Vedolizumab has been approved by the FDA for treatment of Crohn’s disease and ulcerative colitis in patients who have not responded to or could not tolerate corticosteroids, immunosuppressants, or TNF inhibitors In a randomized, controlled trial in patients with Crohn’s disease, a clinical remission occurred after weeks of treatment in 14.5% of vedolizumabtreated patients and in 6.8% of those taking placebo A clinical response occurred in 31.4% of patients treated with vedolizumab and in 25.7% of those randomized to placebo; this difference was not statistically significant Responders received maintenance therapy with vedolizumab every or weeks, or placebo, for 52 weeks; 36.4% and 39% of patients receiving vedolizumab every and weeks, respectively, were in clinical remission at 52 weeks, compared to 21.6% of those receiving placebo.29 In patients with ulcerative colitis, a clinical response occurred in 47.1% of vedolizumab-treated patients after weeks of therapy, compared to 25.5% of those taking placebo Among responders, continued treatment with vedolizumab every or weeks resulted in clinical remission at 52 weeks in 44.8% and 41.8%, respectively, compared to 15.9% with placebo.30 ADVERSE EFFECTS — Use of natalizumab in clinical practice has been limited by the rare occurence of progressive multifocal leukoencephalopathy (PML) and severe hepatic toxicity No cases of PML have been reported with vedolizumab to date In clinical trials of vedolizumab, hypersensitivity reactions have occurred, including one case of anaphylaxis Severe infections including tuberculosis, sepsis (sometimes fatal), and meningitis have occurred Increased transaminase and bilirubin levels have been reported PREGNANCY — Natalizumab is classified as category C (toxicity in animals; no adequate human studies) for use during pregnancy Vedolizumab is classified as category B (no evidence of risk in animals; no human studies) Vol 56 (1448) August 4, 2014 DRUG INTERACTIONS — Other biologic agents or immunomodulators may increase the risk of infectious complications with natalizumab or vedolizumab and should not be used concomitantly ANTIBIOTICS Many experts believe that alterations in the balance of enteric bacteria (dysbiosis) play a role in the development of inflammatory bowel disease, but the evidence that antibiotics are effective in treating Crohn’s disease or ulcerative colitis is limited, and they might make dysbiosis worse.31 Metronidazole (Flagyl, and generics), ciprofloxacin (Cipro, and generics), and rifaximin (Xifaxan) are used, sometimes together, to treat Crohn’s disease microperforations and fistulas, and to treat pouchitis in ulcerative colitis They have also been used following resections to prevent recurrence of Crohn’s disease.32,33 EFFICACY — One meta-analysis found antibiotics more effective than placebo in inducing remission in active Crohn’s disease, particularly in fistulizing disease.34 A randomized, double-blind trial in more than 400 patients found that 12 weeks of rifaximin 800 mg twice daily induced remission in 62% of patients with moderately active Crohn’s disease, compared to 43% of those receiving placebo.35 The evidence that antibiotics are effective in maintaining remission in Crohn’s disease is limited The use of antibiotics is not recommended for ulcerative colitis, except pouchitis, for which ciprofloxacin, metronidazole, and rifaximin all appear to be effective, but large controlled trials are lacking.36 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, QT interval prolongation, altered mental status, lowering of the seizure threshold, spontaneous tendon rupture, and an increased risk of Clostridium difficile infection Rifaximin is minimally absorbed and has an incidence of adverse effects similar to that of 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.6 Ciprofloxacin is a moderate inhibitor of CYP1A2 and may increase serum concentrations of CYP1A2 substrates 71 The Medical Letter ® such as tizanidine (Zanaflex, and generics) 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.14 Rifaximin is minimally absorbed and does not appear to cause any clinically significant interactions PROBIOTICS Probiotics are live, nonpathogenic microorganisms (usually bacteria or yeasts) They have been tried for prevention and treatment of a variety of disorders, including inflammatory bowel disease.37 Probiotics have been used in ulcerative colitis to maintain remission, particularly in patients with pouchitis after ileoanal anastomosis for severe disease In small trials in patients with ulcerative colitis and pouchitis, VSL #3 was more effective than a placebo for maintenance of remission.38,39 Probiotics have been less effective for maintenance of remission in Crohn’s disease Probiotics can cause bloating, flatulence, diarrhea, and hiccups Antibiotics can inactivate bacteria-derived probiotics ■ 10 11 12 13 72 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 Budesonide (Uceris) for ulcerative colitis Med Lett Drugs Ther 2013; 55:23 Inhibitors and inducers of CYP enzymes and P-glycoprotein Med Lett Drugs Ther 2013; 55:e44 A Timmer et al Azathioprine and 6-mercaptopurine for maintenance of remission in ulcerative colitis Cochrane Database Syst Rev 2012; 9:CD000478 E Prefontaine et al Azathioprine or 6-mercaptopurine for maintenance of remission in Crohn’s disease Cochrane Database Syst Rev 2009; 1:CD000067 JF Colombel et al Infliximab, azathioprine, or combination therapy for Crohn’s disease N Engl J Med 2010; 362:1383 R Panaccione et al Combination therapy with infliximab and azathioprine is superior to monotherapy with either agent in ulcerative colitis Gastroenterology 2014; 146:392 V Patel et al Methotrexate for maintenance of remission in Crohn’s disease Cochrane Database Syst Rev 2009; 4:CD006884 BG Feagan et al Methotrexate in combination with infliximab is no more effective than infliximab alone in patients with Crohn’s disease Gastroenterology 2014; 146:681 D Laharie et al Ciclosporin versus infliximab in patients with severe ulcerative colitis refractory to intravenous steroids: a parallel, open-label randomised controlled trial Lancet 2012; 380:1909 H Ogata et al Double-blind, placebo-controlled trial of oral tacrolimus (FK506) in the management of hospitalized patients with steroid-refractory ulcerative colitis Inflamm Bowel Dis 2012; 18:803 J Miyoshi et al Mucosal healing with oral tacrolimus is associated with favorable medium- and long-term prognosis in steroid-refractory/dependent ulcerative colitis patients J Crohns Colitis 2013; 7:e609 ME Gerich et al Tacrolimus salvage in anti-tumor necrosis factor antibody treatment-refractory Crohn’s disease Inflamm Vol 56 (1448) August 4, 2014 Bowel Dis 2013; 19:1107 14 Combined list of all QTdrugs and the list of drugs to avoid for patients with congenital long QT syndrome Available at http:// www.crediblemeds.org Accessed July 23, 2014 15 TNF inhibitors for Crohn’s disease: when, which, and for how long? Med Lett Drugs Ther 2013; 55:102 16 Golimumab (Simponi) for ulcerative colitis Med Lett Drugs Ther 2014; 56:25 17 JF Colombel et al Therapeutic drug monitoring of biologics for inflammatory bowel disease Inflamm Bowel Dis 2012; 18:349 18 M Regueiro et al Postoperative therapy with infliximab prevents long-term Crohn’s disease recurrence Clin Gastroenterol Hepatol 2014 January 16 (epub) 19 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 20 S Schreiber et al Maintenance therapy with certolizumab pegol for Crohn’s disease N Engl J Med 2007; 357:239 21 WJ Sandborn et al Adalimumab induction therapy for Crohn disease previously treated with infliximab: a randomized trial Ann Intern Med 2007; 146:829 22 WJ Sandborn et al Certolizumab pegol in patients with moderate to severe Crohn's disease and secondary failure to infliximab Clin Gastroenterol Hepatol 2010; 8:688 23 WJ Sandborn et al Subcutaneous golimumab induces clinical response and remission in patients with moderate-to-severe ulcerative colitis Gastroenterology 2014; 146:85 24 S Danese et al Biological agents for moderately to severely active ulcerative colitis: a systematic review and network metaanalysis Ann Intern Med 2014; 160:704 25 X Mariette et al Malignancies associated with tumour necrosis factor inhibitors in registries and prospective observational studies: a systematic review and meta-analysis Ann Rheum Dis 2011; 70:1895 26 NN Andersen et al Association between tumor necrosis factor antagonists and risk of cancer in patients with inflammatory bowel disease JAMA 2014; 311:2406 27 Vedolizumab (Entyvio) for inflammatory bowel disease Med Lett Drugs Ther 2014; in press 28 Natalizumab (Tysabri) for Crohn's disease Med Lett Drugs Ther 2008; 50:34 29 WJ Sandborn et al Vedolizumab as induction and maintenance therapy for Crohn’s disease N Engl J Med 2013; 369:711 30 BG Feagan et al Vedolizumab as induction and maintenance therapy for ulcerative colitis N Engl J Med 2013; 369:699 31 D Gevers et al The treatment-naive microbiome in new-onset Crohn’s disease Cell Host Microbe 2014; 15:382 32 HH Herfarth et al Ciprofloxacin for the prevention of postoperative recurrence in patients with Crohn’s disease: a randomized, double-blind, placebo-controlled pilot study Inflamm Bowel Dis 2013; 19:1073 33 M Mañosa et al Addition of metronidazole to azathioprine for the prevention of postoperative recurrence of Crohn’s disease: a randomized, double-blind, placebo-controlled trial Inflamm Bowel Dis 2013; 19:1889 34 KJ Khan et al Antibiotic therapy in inflammatory bowel disease: a systematic review and meta-analysis Am J Gastroenterol 2011; 106:661 35 C Prantera et al Rifaximin-extended intestinal release induces remission in patients with moderately active Crohn’s disease Gastroenterology 2012; 142:473 36 P Gionchetti et al The role of antibiotics and probiotics in pouchitis Ann Gastroenterol 2012; 25:100 37 Probiotics revisited Med Lett Drugs Ther 2013; 55:3 38 M Guslandi Role of probiotics in the management of pouchitis Curr Pharm Des 2014; 20:4561 39 J Shen et al Effect of probiotics on inducing remission and maintaining therapy in ulcerative colitis, Crohn’s disease, and pouchitis: meta-analysis of randomized controlled trials Inflamm Bowel Dis 2014; 20:21 The Medical Letter ® Continuing Medical Education Program medicalletter.org/cme Earn Up To 52 Credits Per Year Choose CME from The Medical Letter in the format that’s right for you! ▶ Comprehensive Exam – Available online or in print to Medical Letter subscribers, this 78 question test enables you to earn 13 credits immediately upon successful completion of the test A score of 70% or greater is required to pass the exam Our comprehensive exams allow you to test at your own pace in the comfort of your home or office Comprehensive tests are offered every January and July enabling you to earn up to 26 credits per year 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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: Activity participants will read and assimilate unbiased reviews of FDA-approved and off-label uses of drugs and other treatment modalities Activity 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 The Medical Letter with specific attention to clinical trials, pathophysiology, dosage and administration, drug metabolism and interactions, and patient management Activity participants will make independent and informed therapeutic choices in their practice Upon completion of this program, the participant will be able to: Explain the current approach to the management of a patient with ulcerative colitis or Crohn’s disease Discuss the pharmacologic options available for treatment of inflammatory bowel disease and compare them based on their mechanisms 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 XP/Vista/7/8, Mac OS X+; current versions of Microsoft IE, Mozilla Firefox, Google Chrome, Safari or any other compatible web browser 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 The Medical Letter ® Online Continuing Medical Education DO NOT FAX OR MAIL THIS EXAM To take CME exams and earn credit, go to: medicalletter.org/CMEstatus Issue 1448 Questions (Correspond to questions #21-30 in Comprehensive Exam #71, available January 2015) Aminosalicylates are: a generally used first for induction and maintenance of remission in mild to moderate ulcerative colitis b generally used first for induction and maintenance of remission in mild to moderate Crohn’s disease c available only in oral formulations d effective in about 90% of patients with mild to moderate ulcerative colitis Which of the following is an option for maintenance of remission in a 26-year-old male patient with moderate Crohn’s disease: a golimumab b tacrolimus c azathioprine d cyclosporine Adverse effects associated with azathioprine and mercaptopurine include: a hepatotoxicity b myelosuppression c rash d all of the above Combining azathioprine with infliximab: a has been shown to be more effective than either drug alone in achieving steroid-free remission in Crohn’s disease b was not more effective than either drug alone in treatment of ulcerative colitis c can lower serum concentrations of infliximab d all of the above A 32-year-old man is hospitalized with severe steroid-resistant ulcerative colitis Which of the following drugs could be used to avoid colectomy? a cyclosporine b budesonide c metronidazole d certolizumab A 23-year-old female patient with severe Crohn’s disease saw an advertisement for adalimumab and asks you for some information about TNF inhibitors You could tell her that: a TNF inhibitors have been effective for induction and maintenance of remission in moderate to severe Crohn’s disease b TNF inhibitors can produce closure of fistulas c she should not receive live vaccines while taking a TNF inhibitor d all of the above Adverse events that have been associated with TNF inhibitors include: a reactivation of TB b injection and infusion reactions c new onset psoriasis d all of the above Progressive multifocal leukoencephalopathy (PML) has limited the use of which of the following drugs: a vedolizumab b natalizumab c infliximab d all of the above Which of the following drugs is contraindicated for use during pregnancy? a infliximab b mesalamine c methotrexate d vedolizumab 10 A patient asks you about using probiotics for treatment of ulcerative colitis You could tell her that: a they have been shown to be highly effective for induction of remission in ulcerative colitis b probiotics can cause bloating, flatulence, diarrhea, and hiccups c they are composed of pathogenic organisms d all of the above ACPE UPN: Per Issue Exam: 0379-0000-14-448-H01-P; Release: August 4, 2014, Expire: August 4, 2015 Comprehensive Exam 71: 0379-0000-15-071-H01-P; Release: January 2015, Expire: January 2016 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 Z Morrison, Pharm.D., Michael P Viscusi, Pharm.D.; CONSULTING EDITORS: Brinda M Shah, Pharm.D., F Peter Swanson, M.D; SENIOR ASSOCIATE EDITOR: Amy Faucard 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; Jane P Gagliardi, M.D., M.H.S., F.A.C.P., Duke University School of Medicine; Jules Hirsch, M.D., Rockefeller University; David N Juurlink, BPhm, M.D., Ph.D., 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; Esperance A.K Schaefer, M.D., M.P.H., Harvard Medical School; F Estelle R Simons, M.D., University of Manitoba; 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 MANAGING EDITOR: Susie Wong; ASSISTANT MANAGING EDITOR: Liz Donohue; EDITORIAL ASSISTANT: Cheryl Brown EXECUTIVE DIRECTOR OF SALES: Gene Carbona; FULFILLMENT & 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, Inc 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, Inc 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 Address: The Medical Letter, Inc 145 Huguenot St Ste 312 New Rochelle, NY 10801-7537 www.medicalletter.org Customer Service: Call: 800-211-2769 or 914-235-0500 Fax: 914-632-1733 E-mail: custserv@medicalletter.org Permissions: To reproduce any portion of this issue, please e-mail your request to: permissions@medicalletter.org Copyright 2014 ISSN 1523-2859 Subscriptions (US): year - $98; years - $189; years - $279 $49 per year for students, interns, residents, and fellows in the US and Canada Reprints - $12 each Site License Inquiries: E-mail: info@medicalletter.org Call: 800-211-2769 Special rates available for bulk subscriptions ... information call: 800-211-2769 The Medical Letter ® on Drugs and Therapeutics Objective Drug Reviews Since 1959 Volume 56 ISSUE ISSUE No August 4, 20 14 Take CME exams IN THIS ISSUE 143 3 144 8 Drugs. .. 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 designates... information presented in materials contained in The Medical Letter The Medical Letter will strive to continually improve the CME program through periodic assessment of the program and activities The Medical