Induction and maintenance therapies commonly used in the treatment of Crohn disease in children

Drug	United States trade name(s)	Dose in children	Dose in adults	Indication	Important side effects	Comments
Glucocorticoids
Prednisone or prednisolone		1 to 2 mg/kg/day orally (maximum 60 mg/dose), then taper after 2 weeks if patient is in remission.	40 to 60 mg/day orally, then taper after 2 weeks if patient is in remission.	Short-term induction therapy for moderate Crohn disease.	Facial swelling, moodiness, sleep disturbance, hirsutism, adrenal suppression (with physiologic doses for more than 2 to 3 weeks), hyperglycemia, osteoporosis, increased risk of varicella infection, cataracts, aseptic necrosis of bone.	Onset of action rapid (3 to 14 days). Long-term use causes growth failure; not appropriate for long-term use.
Budesonide (enteric coated)	Entocort EC Ortikos	Age ≥6 years: 9 mg/day orally, then taper^[1]. OR 0.45 mg/kg/day orally (maximum dose 9 mg/day), then taper^[2].	9 mg/day orally, then taper.	Short-term induction therapy for mild to moderate Crohn disease affecting the ileum and right colon.	Similar to prednisone but fewer systemic effects including adrenal suppression.	May be less effective than prednisone. Pediatric dosing is based on limited data from clinical trials in children 6 years and older. Taper by 3 mg increments as tolerated for a total course of up to 3 months.
Budesonide MMX	Uceris	9 mg/day orally, then taper.	9 mg/day orally, then taper.	FDA-approved for UC in adults; occasionally used for Crohn colitis.	Similar to prednisone but fewer systemic effects including adrenal suppression.	May be less effective than prednisone. Only available in 9 mg dose, so use is generally limited to older adolescents and adults.
Methylprednisolone	Solu-Medrol	1 mg/kg every 12 hours IV (maximum 30 mg/dose).	25 to 35 mg every 12 hours IV.	Induction of remission in severe Crohn disease of the small bowel and colon.	As described above for other systemic corticosteroids.
Nutritional therapy
Elemental or polymeric formula (no other food by mouth)		Dose to meet nutritional needs for 4 to 6 weeks.		Mucosal Crohn disease, growth failure.	Formulas may be administered orally or by nasogastric tube.	Efficacy 50 to 80%^[4]. Patients may refuse or have difficulty adhering to regimen; may relapse rapidly after resuming regular diet.
Anti-TNF inhibitors
Infliximab (chimeric monoclonal antibody, 75% humanized)	Remicade and biosimilars (Renflexis, Inflectra)	*Induction:* 5 mg/kg/dose IV at weeks 0, 2, and 6 (may increase to 10 mg/kg if response is incomplete). *Maintenance:* 5 mg/kg/dose IV every 8 weeks (may increase to 10 mg/kg if response is incomplete, and/or decrease the interval between infusions).	*Induction:* 5 mg/kg/dose IV at weeks 0, 2, and 6 (may increase to 10 mg/kg if response is incomplete). *Maintenance:* 5 mg/kg/dose IV every 8 weeks (may increase to 10 mg/kg if response is incomplete, and/or decrease the interval between infusions).	Refractory Crohn disease.	Infusion reactions, infections, psoriasis. Increased risk of tuberculosis, histoplasmosis, and other opportunistic lung infections. Increased risk of lymphoma, including hepatosplenic T cell lymphoma. However, lymphoma risk has primarily been reported with the combination of thiopurines and infliximab.	Evaluate with tuberculin skin test or chest radiograph prior to starting therapy. Monitor CBC, AST, and ALT during therapy. Some experts use a higher initial dose (10 mg/kg) for patients with severe colitis and protein loss.
Adalimumab (humanized monoclonal antibody)	Humira	Dose used in clinical trials in children^[7]: *Induction:* <40 kg – 80 mg/dose subcutaneously on week 0, followed by 40 mg on week 2. ≥40 kg – 160 mg/dose subcutaneously on week 0, followed by 80 mg on week 2. *Maintenance:* (Start on week 4) <40 kg – 20 mg/dose subcutaneously every 2 weeks. ≥40 kg – 40 mg subcutaneously every 2 weeks.	*Induction:* 160 mg subcutaneously on week 0, followed by 80 mg subcutaneously 2 weeks later. *Maintenance:* 40 mg subcutaneously on alternate weeks thereafter. Some patients may require weekly maintenance therapy^[8] or a higher maintenance dose.	FDA-approved for Crohn disease not responding to conventional therapies. May be used as first-line anti-TNF therapy (not only those who have failed infliximab).	Infections, increased risk of lymphoma and tuberculosis.	Evaluate with tuberculosis skin test prior to starting therapy. Monitor CBC, AST, and ALT during therapy. A citrate-free preparation is available, which reduces pain at the injection site.
Other biologic agents
Ustekinumab	Stelara	Dose not well established for children. One report that focused on adolescents used the same dosing that is recommended for Crohn disease in adults^[9].	*Induction:* <55 kg – 260 mg IV. 55 to 85 kg – 390 mg IV. >85 kg – 520 mg IV. *Maintenance:* 90 mg subcutaneously every 8 weeks.	Refractory Crohn disease.	Infections, headache.	Primarily used for nonresponders to anti-TNF therapy.
Vedolizumab	Entyvio	Dose not well established for children, but 6 mg/kg IV has been used off-label^[10]. Give one dose at 0, 2, and 6 weeks, then every 8 weeks thereafter.	300 mg IV at 0, 2 and 6 weeks, then every 8 weeks thereafter. Escalation by decreasing frequency to every 4 weeks has been reported.	Refractory Crohn disease.	Infections, development of anti-vedolizumab antibodies.	Favorable safety profile in adults.
Immunomodulators
Mercaptopurine (also known as 6-mercaptopurine [6-MP])	Purinethol	1 to 1.5 mg/kg/day orally^¶ (maximum dose 150 mg/day)^[3]. Much lower doses are used for patients with reduced TPMT activity (refer to "Comments").	1 to 1.5 mg/kg/day orally (maximum dose 150 mg/day)^[3]. Much lower doses are used for patients with reduced TPMT activity (refer to "Comments").	Maintenance of remission in medically refractory Crohn disease, especially for patients with growth failure or fistulizing disease.	Pancreatitis, myelosuppression, hepatitis, pneumonitis, opportunistic infections. Hypersensitivity (drug fever, arthritis, or rash), anorexia, nausea, vomiting. Increased risk of lymphoma (sometimes related to concomitant EBV infection).	Assess TPMT genotype or enzyme activity prior to starting therapy. Dose should then be modified based on the TPMT genotype or activity. Starting dosage of mercaptopurine should be modified based on the TPMT genotype or activity^[5]: TPMT genotype 1/1 (normal or increased activity) – 1 to 1.5 mg/kg/day TPMT genotype 1/3a (reduced activity) – 0.5 mg/kg/day TPMT genotype 3a/3a (absent activity) – Mercaptopurine or azathioprine should not be used Monitor CBC, AST, ALT, and amylase/lipase during therapy. Slow onset of therapeutic effects (3 to 4 months). Therapeutic drug level monitoring available. Possible risks of birth defects. Increased risk of lymphoma.
Azathioprine		1.5 to 2.5 mg/kg/day orally (maximum dose 200 mg/day)^[3]. Much lower doses are used for patients with reduced TPMT activity (refer to "Comments").	1.5 to 2.5 mg/kg/day orally (maximum dose 200 mg/day)^[3]. Much lower doses are used for patients with reduced TPMT activity (refer to "Comments").	Same as mercaptopurine; these are maintenance agents only.	Same as mercaptopurine.	Assess TPMT genotype or enzyme activity prior to starting therapy. Starting dosage of azathioprine should then be modified based on the TPMT genotype or activity^[5]: TPMT genotype 1/1 (normal or increased activity) – 2 to 2.5 mg/kg/day TPMT genotype 1/3a (reduced activity) – 1 mg/kg/day TPMT genotype 3a/3a (absent activity) – Mercaptopurine or azathioprine should not be used Monitor CBC, AST, ALT, and amylase/lipase during therapy. Azathioprine is metabolized to mercaptopurine in the liver. Slow onset of therapeutic effects (3 to 4 months). Adverse effects are the same as mercaptopurine.
Methotrexate	Reumatrex Trexall	*Induction:* 15 to 25 mg/m²/week subcutaneously (maximum dose 25 mg once weekly). *Maintenance:* 15 mg once weekly.	*Induction:* 15 to 25 mg subcutaneously weekly. *Maintenance:* 15 mg subcutaneously weekly.	Refractory Crohn disease. Primarily used as maintenance therapy.	Bone marrow suppression, hepatotoxicity, oral ulcers, nausea, pneumonitis.	Contraindicated in pregnancy. Monitor CBC, AST, and ALT during therapy. Folic acid 1 mg daily should be given to all patients. The oral route of administration also has been used for maintenance of remission^[6].
Aminosalicylates (derivatives of 5-ASA)
Mesalamine (time-released)*	Pentasa	50 to 75 mg/kg/day orally in 3 to 4 divided doses (maximum 1 g/dose)^[3].	*Induction:* 4 to 6 g/day orally in 3 to 4 divided doses. *Maintenance:* 2 to 4 g/day orally in 3 to 4 divided doses.	Maintenance of remission in mild mucosal Crohn disease in small bowel or colon. May also be useful for initial therapy in patients with mild disease.	Generally well tolerated. Rare reactions include rashes, pancreatitis, and interstitial nephritis (rare but serious).	Low efficacy (35 to 40% versus 30% for placebo in randomized studies). Capsules may be opened and sprinkled on soft food. Patient adherence can be a problem because of requirement for frequent dosing. Suggest monitoring BUN/creatinine, urine analysis, CBC, AST, and ALT (eg, twice yearly).
Mesalamine (pH-released)*	Asacol	50 to 80 mg/kg/day orally in 3 to 4 divided doses (maximum 1 g/dose).	3.6 to 4.8 g/day orally in 3 to 4 divided doses.	Maintenance of remission in mild mucosal Crohn disease in ileum or colon. May also be useful for initial therapy in patients with mild disease.	As above.	Low efficacy (35 to 40% versus 30% for placebo in randomized studies). Patient adherence can be a problem because of requirement for frequent dosing. Suggest monitoring BUN/creatinine, urine analysis, CBC, AST, and ALT (eg, twice yearly).
Sulfasalazine	Azulfidine Sulfazine	50 to 75 mg/kg/day orally in 3 to 4 divided doses (maximum 1 g/dose).	*Induction:* 1 g orally 3 to 4 times daily. *Maintenance:* 1 g orally 2 to 3 times daily.	Maintenance of remission in mild mucosal colonic Crohn disease. May also be useful for initial therapy in patients with mild disease.	Sulfasalazine consists of a 5-ASA component linked to sulfapyridine; hypersensitivity to the sulfonamide component is common (drug fever, arthritis, or rash). Headache, photosensitivity, leukopenia, hepatitis. Rare but serious reactions include pancreatitis, pericarditis, myocarditis, and pneumonitis.	To minimize side effects, start treatment at a low dose and increase to full dose as tolerated over 1 to 2 weeks. Low efficacy (35 to 40% versus 30% for placebo in randomized studies). Also give folic acid, 1 mg/day. Suggest monitoring BUN/creatinine, urine analysis, CBC, AST, and ALT (eg, twice yearly). Can be compounded into a suspension for children who cannot swallow pills.
Antibiotics
Ciprofloxacin	Cipro	*Induction of remission:* Dose not established in children^Δ. *Treatment of infectious complications:* 20 to 30 mg/kg/day orally divided in 3 doses (up to 500 mg/dose)^[3].	*Induction of remission:* 250 to 500 mg orally 2 or 3 times daily^Δ.	Induction of remission in perianal or mucosal disease. Treatment of infectious complications (eg, abdominal or perianal abscess).	Hypersensitivity reactions. Risk of C. difficile colitis. Tendon inflammation and rupture, arthropathy, photosensitivity.	Moderate efficacy. Avoid in pregnancy.
Metronidazole	Flagyl	*Induction of remission:* Dose not established in children^Δ. *Treatment of infectious complications:* 20 to 30 mg/kg/day orally divided in 3 doses (up to 500 mg/dose)^[3,11,12].	*Induction of remission:* 250 to 500 mg orally 2 or 3 times daily^Δ.	Same as ciprofloxacin, postoperative recurrence.	Nausea, disulfiram reaction (occurs with ingestion of alcohol), alteration of taste. Peripheral neuropathy often develops with chronic use.	May delay recurrence of mucosal disease after surgical resection. Avoid in pregnancy^◊.
Azithromycin	Zithromax	*Induction of remission:* 7.5 mg/kg (max 500 mg).		Active Crohn disease, given in combination with metronidazole.	Nausea, potential cardiac toxicity.	Used off-label to treat active Crohn disease.

MMX: Multi-Matrix System technology; FDA: US Food and Drug Administration; UC: ulcerative colitis; IV: intravenously; anti-TNF: anti-tumor necrosis factor; CBC: complete blood count; AST: aspartate aminotransferase; ALT: alanine aminotransferase; TPMT: thiopurine methyltransferase; EBV: Epstein-Barr virus; 5-ASA: 5-aminosalicylate; BUN: blood urea nitrogen; C. difficile: Clostridioides (formerly Clostridium) difficile.
* Outside of the United States, mesalamine is known as mesalazine.
¶ Some patients (especially younger children) may benefit from mercaptopurine doses above this range (eg, up to 2 mg/kg/day), if appropriately monitored for toxicity.
Δ There is some evidence in adults that ciprofloxacin and/or metronidazole have modest efficacy to induce remission in Crohn disease; typical doses used for this purpose are 10 to 20 mg/kg/day divided in 2 or 3 doses, with courses ranging from 2 to 6 months^[10]. The efficacy and doses of these antibiotics for induction of remission in children with Crohn disease have not been established. (Refer to the UpToDate topic review on antibiotics for treatment of inflammatory bowel disease.)
◊ We are reluctant to prescribe metronidazole during pregnancy because existing safety information is based on short duration of treatment.

References:

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Levine A, Broide E, Stein M, et al. Evaluation of oral budesonide for treatment of mild and moderate exacerbations of Crohn's disease in children. J Pediatr 2002; 140:75.
Rufo PA, Denson LA, Sylvester FA, et al. Health supervision in the management of children and adolescents with IBD: NASPGHAN recommendations. J Pediatr Gastroenterol Nutr 2012; 55:93.
Narula N, Dhillon A, Zhang D, et al. Enteral nutritional therapy for induction of remission in Crohn's disease. Cochrane Database Syst Rev 2018; 4:CD000542.
Levesque BG, Loftus EV. Initiating azathioprine for Crohn's disease. Clin Gastroenterol Hepatol 2012; 10:460.
Stevens MC, Baldassano RN, York A, et al. The bioavailability of oral methotrexate in children with inflammatory bowel disease. J Pediatr Gastroenterol Nutr 2005; 40:445.
Hyams JS, Griffiths A, Markowitz J, et al. Safety and efficacy of adalimumab for moderate to severe Crohn's disease in children. Gastroenterology 2012; 143:365.
Panaccione R, Colombel JF, Sandborn WJ, et al. Adalimumab sustains clinical remission and overall clinical benefit after 2 years of therapy for Crohn's disease. Aliment Pharmacol Ther 2010; 31:1296.
Dayan JR, Dolinger M, Benkov K, Dunkin D, Jossen J et al. Real world experience with ustekinumab in children and young adults at a tertiary care pediatric IBD center. J Pediatr Gastroenterol Nutr 2019; Apr 29.
Ledder O, Assa A, Levine A, et al. Vedolizumab in Paediatric Inflammatory Bowel Disease: A Retrospective Multi-Centre Experience From the Paediatric IBD Porto Group of ESPGHAN. J Crohns Colitis 2017; 11:1230.
Levine A, Turner D. Combined azithromycin and metronidazole therapy is effective in inducing remission in pediatric Crohn's disease. J Crohns Colitis 2011; 5:222.
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