The Medical Letter. on Drugs and Therapeutics. Sulfasalazine can cause reversible. therapy may be more effective Lialda (Shire)

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1 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: Last updated: June 26, 2018 The Medical Letter on Drugs and Therapeutics Expanded Table: Some Drugs for Inflammatory Bowel Disease Some Drugs for Inflammatory Bowel Disease Oral Aminosalicylates (5-ASAs) 3 Mesalamine Apriso (Salix) 375 mg ER caps Maintenance: 1.5 g PO once/d Most formulations generally considered Nausea, vomiting, diarrhea, Effective for induction and main- $ safe headache, and abdominal pain tenance of remission in mild to Asacol HD (Allergan) 800 mg DR tabs Induction: 1.6 g PO tid are most common moderate UC Sulfasalazine can cause reversible oligospermia; stop 4 months before conception Pancreatitis, hepatotoxicity, In distal UC, rectal formulations Delzicol 4 (Allergan) 400 mg DR caps Induction: 800 mg PO tid pericarditis, pneumonitis, and a are more effective than oral Maintenance: 1.6 g PO daily in divided doses lupus-like syndrome have been formulations; combination Pregnant women taking sulfasalazine may need higher doses of reported therapy may be more effective Lialda (Shire) 1.2 g DR tabs Induction: g PO once/d than use of either formulation Maintenance: 2.4 g PO once/d folic acid Nephrotoxicity can occur rarely alone Pentasa (Shire) 250, 500 mg ER caps Induction: 1 g PO qid Fetal developmental toxicity Acute intolerance syndrome that occurred when pregnant rats were can mimic a UC flare has been Sulfasalazine may be effective given high doses of olsalazine reported for relief of symptoms of mild to moderate colonic CD, but it does not appear to be more effective than placebo in achieving mucosal healing and it is poorly tolerated Pentasa releases drug gradually throughout the GI tract Asacol HD, Apriso, Delzicol, and Lialda delay release of the drug until the distal ileum and colon e117

2 5-ASA prodrugs Balsalazide Colazal (Salix) Giazo (Salix) Olsalazine Dipentum (Meda) Sulfasalazine Azulfidine (Pfizer) delayed-release Azulfidine En-tabs (Pfizer) 750 mg caps Induction: 2.25 g PO tid Maintenance: 3-6 g PO daily in divided doses 1.1 g tabs Induction: 3.3 g PO bid 250 mg caps Induction: g PO daily in 2 divided doses Maintenance: 500 mg PO bid 500 mg tabs 500 mg enteric-coated DR tabs Induction: 1 g PO qid Maintenance: 1 g PO bid Induction: 3-4 g PO daily in divided doses Maintenance: 2 g PO daily Most formulations generally considered safe Sulfasalazine can cause reversible oligospermia; stop 4 months before conception Pregnant women taking sulfasalazine may need higher doses of folic acid Fetal developmental toxicity occurred when pregnant rats were given high doses of olsalazine Nausea, vomiting, diarrhea, headache, and abdominal pain are most common Pancreatitis, hepatotoxicity, pericarditis, pneumonitis, and a lupus-like syndrome have been reported Nephrotoxicity can occur rarely Acute intolerance syndrome that can mimic a UC flare has been reported with mesalamine Effective for induction and maintenance of remission in mild to moderate UC In distal UC, rectal mesalamine formulations are more effective than oral formulations; combination therapy may be more effective than use of either formulation alone Sulfasalazine may be effective for relief of symptoms of mild to moderate colonic CD, but it does not appear to be more effective than placebo in achieving mucosal healing and it is poorly tolerated Balsalazide, olsalazine, and sulfasalazine release drug in the colon $ Rectal Aminosalicylates Mesalamine Rowasa (Meda) SF Rowasa (Meda) Canasa (Allergan) 4 g/60 ml enema 1000 mg rectal suppository Induction: 4 g rectally once/d at bedtime Maintenance: 2-4 g rectally once/d at bedtime Induction and maintenance: 1000 mg rectally once/d Generally considered safe Incidence of adverse effects is generally lower with rectal mesalamine than with oral formulations. In distal UC, rectal mesalamine formulations are more effective than oral formulations; combination therapy may be more effective than either formulation alone e118

3 Oral Corticosteroids Prednisone delayed-release Rayos (Horizon) Budesonide Entocort EC (Perrigo) 7 extended-release Uceris (Salix) 3 1, 2.5, 5, 10, 20, 50 mg tabs; 5 mg/5 ml, 5 mg/1 ml oral solution 1, 2, 5 mg DR tabs 6 3 mg caps 9 mg ER tabs Induction: mg PO once/d Induction: mg PO once/d Induction: 9 mg PO once/d Maintenance: 6 mg PO once/d 8 Induction: 9 mg PO once/d Data are conflicting, but experts suggest the risks associated with disease outweigh the low risk of adverse pregnancy outcomes Budesonide may result in lower fetal exposure than systemic corticosteroids Increased risk of infection, fluid retention, osteoporosis, osteonecrosis, cataracts, glaucoma, impaired skin healing, acne, insomnia, mood disorders, Cushing s syndrome, hyperglycemia, and hypothalamic-pituitary-adrenal (HPA) axis suppression Budesonide causes less shortterm corticosteroid toxicity than prednisone Effective for induction of remission in active UC or CD Not recommended for maintenance of remission Budesonide is not recommended for maintenance of remission beyond 4 months in CD $ , Rectal Corticosteroids Budesonide Uceris (Salix) 3 Hydrocortisone 3 Colocort (Perrigo) Cortenema (Ani) Cortifoam (Meda) 2 mg/actuation rectal foam 100 mg/60 ml enema 10% rectal foam Induction: 2 mg rectally bid x 2 wks Maintenance: 2 mg rectally once/d x 4 wks Induction: 1 enema rectally nightly Induction: 1 application rectally once/d or bid Data are conflicting, but experts suggest the risks associated with disease outweigh the low risk of adverse pregnancy outcomes Budesonide may result in lower fetal exposure than systemic corticosteroids Increased risk of infection, fluid retention, osteoporosis, osteonecrosis, cataracts, glaucoma, impaired skin healing, acne, insomnia, mood disorders, Cushing s syndrome, hyperglycemia, and hypothalamic-pituitary-adrenal (HPA) axis suppression Budesonide causes less shortterm corticosteroid toxicity than prednisone Incidence of adverse effects is lower with rectal formulations than with oral corticosteroids Effective for treatment of distal UC Enemas reach the splenic flexure, while foams only reach the distal part of the sigmoid colon Budesonide rectal foam can be used for patients with disease extending up to 40 cm from the anal verge Immunosuppressants 10 Azathioprine Azasan (Salix) Imuran (Sebela) Mercaptopurine Purixan (Nova) 50 mg tabs 75, 100 mg tabs 50 mg tabs 50 mg tabs 20 mg/ml oral susp Maintenance: mg/kg PO once/d Adverse pregnancy outcomes such as preterm birth have been reported, Myelosuppression and hepatotoxicity Used for maintenance of remission in moderate to severe Maintenance: mg/kg PO once/d but recent data suggest that use of UC or CD Increased risk of infection, azathioprine or mercaptopurine is nausea, vomiting, diarrhea, rash, They are not used for induction not associated with adverse birth pulmonary edema, pancreatitis, outcomes 11, hypersensitivity reaction Increased risk of non-melanoma skin cancer; risk is reduced after the drug is stopped Increased risk of lymphoma; risk is greater when used in combination with a TNF inhibitor Hepatosplenic T-cell lymphoma has been reported in patients taking azathioprine or mercaptopurine, both alone and in combination with a TNF inhibitor of remission because they take 3-6 months to achieve maximal effect Consider thiopurine methyltransferase (TPMT) testing before starting therapy Routinely monitor CBC and liver function tests during therapy (every 1-2 weeks during dose titration, then every 3 months after the patient is on a stable dose) May be more effective when used in combination with a TNF inhibitor e119

4 Immunosuppressants 10 (continued) Methotrexate 14 Otrexup (Antares) Rasuvo (Medac) 25 mg/ml vials 15 mg, 17.5 mg, 20 mg, 22.5 mg, 25 mg/0.4 ml autoinjectors 15 mg/0.3ml, 25 mg/0.5 ml autoinjectors 16 Induction: 25 mg IM/SC 15 once/wk Maintenance: mg IM/SC 15 once/wk Contraindicated; avoid pregnancy if either partner is taking methotrexate Myelosuppression, alopecia, rash, stomatitis, vomiting, diarrhea, GI hemorrhage, hepatotoxicity, renal failure, interstitial pneumonia, toxic epidermal necrolysis, Stevens-Johnson syndrome, hypotension, blurred vision, headache, nephropathy, and hyperuricemia Intramuscular methotrexate is an alternative to azathioprine or mercaptopurine for maintenance of remission in CD Supplementation with folic acid may reduce toxicity $ Cyclosporine Sandimmune (Novartis) 50 mg/ml ampules Induction: 2-4 mg/kg IV daily Embryofetal toxicity in animals at high doses Congenital malformations not found in pregnant women treated with the drug after an organ transplant Nephrotoxicity Can also increase the risk of infection and cause diarrhea, nausea, vomiting, infection, gingival hyperplasia, pruritus, headache, seizures, tremors, visual disturbances, hypertension, hepatoxicity, paresthesias, and anaphylaxis Used as rescue therapy to avoid colectomy in patients with severe steroid-resistant UC Has not been effective for treatment of CD , ,17 Tumor Necrosis Factor (TNF) Inhibitors Adalimumab 18 Humira (Abbvie) Certolizumab pegol 7 Cimzia (UCB) Golimumab 3 Simponi (Janssen) Infliximab Remicade (Janssen) biosimilar Infliximab-abda Renflexis (Merck) Infliximab-dyyb Inflectra (Pfizer) Infliximab-qbtx Ixifi (Pfizer) 40 mg/0.8 ml prefilled syringes; 40 mg/ 0.8 ml single-use pens 200 mg vials (lyophilized powder); 200 mg/ml prefilled syringes 50 mg/0.5 ml, 100 mg/1 ml auto-injectors; 50 mg/0.5 ml, 100 mg/1 ml prefilled syringes 100 mg vials (lyophilized powder) Induction: 160 mg SC at wk 0, then 80 mg at wk 2 Maintenance: 40 mg SC every other wk starting at wk 4 Not associated with adverse pregnancy outcomes Placental transfer of anti-tnf antibodies higher in late second and third trimesters, especially with infliximab, adalimumab, and golimumab In women at low risk for relapse, consider stopping the TNF inhibitor at 22 weeks gestation 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 Reactivation of hepatitis B virus in patients who are chronic carriers Injection and infusion reactions, new-onset psoriasis, hematologic cytopenias, non-ischemic congestive heart failure, demyelinating disorders, and induction of a lupus-like syndrome Increased risk of malignancy, including lymphoma, melanoma, and non-melanoma skin cancers, has been reported, but a causal relationship has not been established; long-term studies have not found an increased risk Infliximab, adalimumab, or certolizumab pegol can be used alone or in combination with azathioprine or mercaptopurine for induction and maintenance of remission in moderate to severe CD Infliximab, adalimumab, or golimumab can be used for induction and maintenance of remission in moderate to severe UC in patients who have not responded to other therapies or are corticosteroid-dependent Measuring drug and antibody levels can be helpful, particularly in patients with treatment failure Use in combination with azathio prine or mercaptopurine may be more effective than use of either drug alone for treatment of UC and CD Induction: 400 mg SC at wks 0, 2, and 4 Maintenance: 400 mg SC q4 wks Induction: 200 mg SC at wk 0, then 100 mg SC at wk 2 Maintenance: 100 mg SC q4 wks Induction: 5 mg/kg IV at wks 0, 2, and 6 Maintenance: 5-10 mg/kg IV q8 wks 10, , , ,19 N.A. e120

5 Integrin Receptor Antagonists Natalizumab 7,24 Tysabri (Elan/Biogen) Vedolizumab Entyvio (Takeda) 300 mg/15 ml vial (lyophilized powder) 300 mg/20 ml vial (lyophilized powder) Induction: 300 mg IV at wk 0 Maintenance: 300 mg IV q4 wks Induction: 300 mg IV at wks 0, 2, and 6 Maintenance: 300 mg IV q8 wks No adequate studies in pregnant women with vedolizumab or natalizumab No fetal harm in animal studies with vedolizumab Fetal immunologic and hematologic adverse effects and fetal mortality in animal studies with natalizumab Progressive multifocal leukoencephalopathy (PML) has occurred with natalizumab; JC virus antibody testing should be performed every 6 months during treatment Hypersensitivity reactions Severe infections, including tuberculosis and meningitis Increased transaminase and bilirubin levels In moderate to severe CD or UC, vedolizumab may be effective for induction and maintenance of remission when other drugs are ineffective or intolerable Use of natalizumab, which is FDA-approved for use in CD, has been limited to patients with negative JC virus testing because of the risk of PML $12, Interleukin (IL)-12 and -23 Antagonist Ustekinumab 3 Stelara (Janssen) 5 mg/ml vials; 45 mg/0.5 ml vials; 45 mg/0.5 ml, 90 mg/1 ml prefilled syringes Induction: 260, 390, or 520 mg 25 IV at wk 0 Maintenance: 90 mg SC q8 wks No adequate studies in pregnant women; no teratogenic effects in monkeys Vomiting was the most common with induction treatment Nasopharyngitis, injection-site erythema, vulvovaginal candidiasis, bronchitis, pruritus, urinary tract infection, sinusitis were the most common with maintenance treatment Noninfectious interstitial pneumonia, eosinophilic pneumonia, and cryptogenic organizing pneumonia have been reported following 1-3 doses Serious infections (including tuberculosis), malignancies, hypersensitivity reactions, and reversible posterior leukoencephalopathy syndrome have occurred In moderate to severe CD, ustekinumab may be effective for induction and maintenance of remission when other drugs are ineffective or intolerable FDA-approved for treatment of patients with moderately to severely active CD after failure with corticosteroids, thiopurines, methotrexate, or TNF inhibitors 20, Janus Kinase (JAK) Inhibitor Tofacitinib 3 Xeljanz (Pfizer) 5, 10 mg tabs Induction: 10 mg PO bid for at least 8 wks 26 Maintenance: 5 or 10 mg PO bid 26,27 No adequate studies in pregnant women; teratogenic effects and fetal deaths in animal studies Nasopharyngitis, upper respiratory tract infection, increased blood creatinine phosphokinase, elevated cholesterol levels, rash, headache, diarrhea, herpes zoster Tuberculosis and other opportunistic infections Lymphocytopenia, neutropenia, and low hemoglobin levels Increased risk of malignancies GI perforation has been reported during clinical trials for other indications In moderate to severe UC, tofacitinib may be used for induction and maintenance of remission when other drugs are intolerable or ineffective Lymphocytes should be monitored at baseline and then every 3 months; neutrophil and hemoglobin levels should be monitored at baseline, after 4-8 weeks, and then every 3 months Cholesterol levels should be checked 4-8 weeks after starting treatment e121

6 CD = Crohn s disease; DR = delayed-release; ER = extended-release; N.A. = cost not yet available; TNF = tumor necrosis factor; UC = ulcerative colitis 1. GC Nguyen et al. The Toronto Consensus Statements for the management of inflammatory bowel disease in pregnancy. Gastroenterology 2016; 150: Approximate WAC for 30 days treatment at the lowest maintenance dosage. Prices for Asacol HD, Pentasa, Giazo, prednisone, hydrocortisone, and cyclosporine are based on the lowest induction dosage. WAC = wholesaler acquisition cost or manufacturer s published price to wholesalers; WAC represents a published catalogue or list price and may not represent an actual transactional price. Source: AnalySource Monthly. June 5, Reprinted with permission by First Databank, Inc. All rights reserved Not FDA-approved for use in Crohn s disease. 4. Delzicol has replaced Asacol because of reproductive safety concerns associated with dibutyl phthalate, a plasticizer in the enteric coating of Asacol. Delzicol does not contain dibutyl phthalate. 5. Cost for 28 days treatment. 6. The delayed-release tablets release active drug about 4 hours after ingestion. 7. Not FDA-approved for use in ulcerative colitis. 8. FDA-approved for up to 3 months. 9. Cost of two 15-gram aerosol containers (each contains ~14 applications). 10. Not FDA-approved for inflammatory bowel disease. 11. MJ Casanova et al. Safety of thiopurines and anti-tnf-α drugs during pregnancy in patients with inflammatory bowel disease. Am J Gastroenterol 2013; 108: J Coelho et al. Pregnancy outcome in patients with inflammatory bowel disease treated with thiopurines: cohort from the CESAME Study. Gut 2011; 60: Cost based on a 75-kg patient. 14. Use of supplements containing folic acid (1-4 mg daily) or folinic acid ( mg weekly 24 hours after the methotrexate dose) may decrease adverse effects. 15. Otrexup and Rasuvo are for subcutaneous injection only. 16. Also available in 7.5 mg/0.15 ml, 10 mg/0.2 ml, 12.5 mg/0.15 ml, 17.5 mg/0.35 ml, 20 mg/0.4 ml, and 22.5 mg/0.45 ml. 17. Cost for 7 days treatment. 18. A biosimilar (adalimumab-adbm; Cyltezo) has been approved by the FDA, but is not yet marketed. 19. Cost for 8 weeks treatment at the lowest maintenance dosage. 20. 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: N Nyboe Andersen et al. Association between tumor necrosis factor-α antagonists and risk of cancer in patients with inflammatory bowel disease. JAMA 2014; 311: GR Lichtenstein et al. Infliximab for Crohn s disease: more than 13 years of real-world experience. Inflamm Bowel Dis 2018; 24: G D Haens et al. Lymphoma risk and overall safety profile of adalimumab in patients with Crohn s disease with up to 6 years of follow-up in the Pyramid Registry. Am J Gastroenterol 2018 June 5 (epub). 24. Providers must be registered with the CD TOUCH program to prescribe and dispense Tysabri for Crohn s disease mg for patients <55 kg, 390 mg for those >55-85 kg, and 520 mg for patients >85 kg. 26. Dose reductions are needed for patients with moderate to severe renal impairment, moderate hepatic impairment, lymphopenia, neutropenia, or anemia, and for those taking CYP2C19 and/or CYP3A4 inhibitors. 27. Discontinue if response is inadequate after 16 weeks of treatment with 10 mg twice daily. e122