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MP 5.01.100 Treatment of Inflammatory Bowel Diseases with Biologic Response Modifiers

 

 

Medical Policy    
Section
Prescription Drugs
 
Original Policy Date
03/18/2008
Last Review Status/Date
Reviewed with literature search (local policy)/8:2010
Issue
8:2010
  Return to Medical Policy Index

Disclaimer

Our medical policies are designed for informational purposes only and are not an authorization, or an explanation of benefits, or a contract.  Receipt of benefits is subject to satisfaction of all terms and conditions of the coverage.  Medical technology is constantly changing, and we reserve the right to review and update our policies periodically.


Description

Crohn's Disease
Crohn’s disease is one of two major inflammatory bowel diseases of uncertain etiology. It has both similarities and differences from ulcerative colitis. Crohn’s disease is characterized by transmural inflammation of the gastrointestinal tract that can involve any area from the mouth to the perianal area of the gastrointestinal tract. The inflammation can lead to fibrosis and to obstructive clinical presentations. Clinical presentation is quite variable due to transmural involvement and varying extent of the disease. Fatigue, prolonged diarrhea with abdominal pain, weight loss, and fever, with or without gross bleeding are the hallmarks of Crohn’s.  Patients may have symptoms for years prior to diagnosis.20

Ulcerative Colitis
Ulcerative colitis is characterized by recurring inflammation to the mucosal layer of the colon. The rectum is almost always involved, but inflammation can extend to any area of the colon. Severity ranges from mild to severe depending on what area of the colon is affected, and to what degree. Between 9% and 35% of patients will undergo colectomy within 5 years after diagnosis. 37 Presentation typically occurs gradually but can present with any degree of severity.  Normal presentation includes pallor, evidence of weight loss, abdominal tenderness, and red blood on the examining finger on rectal examination.13

 

 

 


Policy

 

Adalimumab (Humira®) may be considered medically necessary for the following FDA approved inflammatory bowel disease indications:

  • As a treatment of Crohn’s disease to reduce signs and symptoms, as well as induce and maintain clinical remission in the moderately to severely active patient, who has had an inadequate response to conventional therapy.
  • As induction and maintenance of remission in patients with moderately to severely active Crohn’s disease who are intolerant or have had an inadequate response to infliximab.

The use of adalimumab for ulcerative colitis or of other TNF-alpha antagonists (e.g., etanercept) for the general treatment of inflammatory bowel diseases is considered investigational at this time.

Infliximab (Remicade®) may be considered medically necessary for the following FDA-approved inflammatory bowel disease indications:

  • Crohn’s disease to reduce signs and symptoms, as well as induce and maintain clinical remission in the moderately to severely active patient who has had an inadequate response to conventional therapy.
  • To reduce the number of draining enterocutaneous and rectovaginal fistula(s) in patients with fistulizing Crohn`s disease
  • Ulcerative colitis to reduce signs and symptoms, as well as to achieve clinical remission and mucosal healing, and to reduce corticosteroid use in the patient with moderate to severe ulcerative colitis who has had an inadequate response to conventional therapy.

Certulizamab Pegol (Cimzia®) may be considered medically necessary to lessen the signs and symptoms of moderately to severely active Crohn's Disease in adults who have not had a response to conventional therapy.

 


Policy Guidelines

 

Moderately to Severely Active Crohn`s Disease

Adalimumab, certoloizumab pegol, and infliximab may be considered medically necessary for the treatment of Crohn’s Disease to reduce signs and symptoms as well as induce and maintain clinical remission when there has been an inadequate response or adverse reaction to conventional therapy. This includes the use of three or more of the following: 

  • Corticosteroids
  • Sulfasalazine
  • 5-aminosalicylic acid 
  • Antibiotics

The most cost-effective drug should be utilized as first line therapy.

The use of adalimumab and certolizumab pegol is considered investigational for the general treatment of other inflammatory bowel disease.

Moderately to Severely Active Ulcerative Colitis

The administration of infliximab may be considered medically necessary when there has been inadequate response or adverse reaction to conventional therapy.  Inadequate response or adverse reaction to conventional therapy includes the use of at least one agent from all three of the following classes, unless therapy with some of these agents is contraindicated: 

  • corticosteroids 
  • immunomodulatory drugs (azathioprine, mercaptopurine, cyclosporine, methotrexate); and
  • 5-aminosalicylic acid

Sulfasalazine may also be used.

Efficacy- Crohn’s Disease

  • Induction:
    • Patients potentially appropriate for induction treatment with the biologic agents are those with moderate to severe disease for more than 3 to 6 months with an inadequate response to conventional therapy or cannot tolerate conventional therapy. Patients suitable for maintenance therapy must have experienced successful induction.
    • There is fair or good evidence that adalimumab (Humira®), infliximab (Remicade®), and certolizumab (Cimzia®) are superior to placebo in increasing the likelihood of achieving remission with induction therapy.
    • There is no reliable evidence supporting use of a second agent when a patient has not experienced a primary response or remission with any of the agents reviewed here.
  • Maintenance:
    • A recent Cochrane review found all three drugs superior to placebo in maintaining remission or response.
  • Fistulas:
    • Only infliximab has been shown to be efficacious for treating fistulas in Crohn’s disease; patients studied had fistulas for ≥3 months and were not previously treated with infliximab.
  • Pediatric Patients:
    • Only infliximab has been studied in pediatric patients with Crohn’s disease and is FDA-labeled for use in pediatric patients, although evidence in the pediatric population is limited. Approved FDA labeling states: “REMICADE is indicated for reducing signs and symptoms and inducing and maintaining clinical remission in pediatric patients with moderately to severely active Crohn’s disease who have had an inadequate response to conventional therapy. Remicade has been studied only in combination with conventional immunosuppressive therapy in children with Crohn’s disease. REMICADE has not been studied in children with Crohn’s disease • There are no head-to-head comparative trials for either induction or remission and insufficient indirect evidence to discriminate between the products in the management of Crohn’s disease.
      • For patients experiencing induction of response with infliximab who then either become intolerant or maintenance therapy fails, adalimumab has been shown more effective than placebo in inducing a subsequent remission.¹

Efficacy – Ulcerative Colitis

  • Induction
    • Existing evidence supports superiority of infliximab (Remicade®) in producing response or remission in patients with moderate to severe active ulcerative colitis despite corticosteroids with or without aminosalicylates or immunosuppressive agents or cannot tolerate conventional therapy.
  • Maintenance
    • The evidence that remission or response maintained with infliximab (Remicade®) is superior to placebo is poor.

AGA Guideline –Crohn’s Disease19
The guideline provides recommendations for the treatment of inflammatory bowel disease with corticosteroids, immunomodulators, and infliximab (Remicade®). Adalimumab (Humira®) is not mentioned. For the purposes of this review, the focus will be on infliximab (Remicade®). Current indications (per guideline) for infliximab include the following:

  • Treatment of moderately to severely active Crohn’s disease inpatient who have not responded despite complete and adequate therapy with a corticosteroid or an immunosuppressive agent. (Grade A) Individuals who are resistant to medical therapy (complete and adequate therapy with a corticosteroid or an immunosuppressive agent) or patients who cannot receive such therapies due to intolerance to medications (corticosteroids or medical contraindications (therapy intolerant).
  • For induction therapy,  the administration of infliximab at time 0, 2 and 6 weeks is recommended; in the case of nonresponse to 3 infusions, further treatment with infliximab is not recommended. (Grade A)
  • Withdrawal or tapering of concomitant corticosteroid therapy: if a patient is treated with infliximab and achieves remission, an attempt to withdraw or taper any concomitant corticosteroid therapy is appropriate. (Grade B)
  • Treatment with corticosteroids, AZA, 6-MP, or methotrexate before and concomitantly with infliximab can reduce the formation of antibodies to infliximab (Grade B)
  • In maintenance therapy, if there is an initial response to infliximab (Grade A).  Scheduled maintenance administration of infliximab at 8-week intervals is superior to episodic therapy in several clinical end points; lower antibodies to infliximab rates, fewer hospital stays, and fewer operations speak in favor of regular administration of infliximab, especially in patients who cannot receive concomitant immunosuppressive therapy due to intolerance.
  • Treatment of Crohn’s disease with fistulas in patients who have not responded despite complete and adequate therapy with conventional treatments (including antibiotics, surgical drainage with examination under anesthesia, and/or immunosuppressive therapy) (Grade A). An initial infusion of infliximab at 5 mg/.kg is followed by subsequent infusions of infliximab at 5 mg/kg at weeks 2 and 6. If the patient does not have a response to the induction regimen, infliximab should be discontinued. However, patients achieving fistula response should receive scheduled maintenance therapy ever 8 weeks with 5 mg/kg. In the case of a loss of effect of infliximab in terms of a clinical exacerbation during regular 8-week administration, the intervals between doses should be shortened in accordance with the authorization for 5 mg/kg. Shortening the intervals to less than 4 weeks is not recommended. If an individual does not receive benefit with a change in medication-dosing frequency (with a maximum frequency of every 4 weeks), an increase in the dose by 5 mg/kg (10 mg/kg daily) could be considered.
  • Appropriate screening for latent and active tuberculosis should be  performed on all patients before administration of infliximab.

²Grade A: Homogenous evidence from multiple well designed, randomized (therapeutic) or cohort (descriptive) controlled trials, each involving a number of participants to be of sufficient statistical power.
Grade B: Evidence from at least one large well-designed, clinical trial with or without randomized from cohort or case-control analytic studies or well-designed meta-analysis.
Grade C: Evidence based on clinical experience, descriptive studies, or reports of expert committees.

Dosing considerations:

  • There are no reliable clinical data to suggest that doses or frequencies exceeding those recommended in each product’s prescribing information are safe or more effective than recommended doses.
  • There is no reliable evidence that doses of infliximab exceeding 5 mg/kg infused every 8 weeks is more effective or safer for  the maintenance of remission in Crohn’s disease.
    • Doses of infliximab up to 10 mg/kg infused every 8 weeks did not result in increased rates of clinical remission in patients treated for Crohn’s disease.
  • For maintenance of remission, doses of adalimumab exceeding more than 40 mg every other week in Crohn’s disease have not been demonstrated to improve efficacy. The benefit of increasing adalimumab dose from 40 mg every other week to 40 mg weekly as monotherapy is uncertain.
    • Studies have not found a significant difference in improvement as defined by improvement in CDAI scores.2-4
    • Importantly, trials were not designed to compare effectiveness of higher doses, so the comparison between weekly and every other week adalimumab, done through post hoc analysis, is considered exploratory.2-4
  • Infliximab (Remicade®) quantity limitations:
    • Initial use: Evidence supports up to 6 infusions in a 6-month period.
    • For continued use, the maximum number of infusions that may be utilized per year for Crohn’s disease is a maximum of 7 infusions in a 12-month period, based on a recommended infusion interval of every 8 weeks.
  • Adalimumab (Humira®) quantity limitations for Crohn’s disease:
    • Initial use: Evidence supports utilization of quantities up to 12 of the 40 mg vials in the initial 3-month period (induction period).
    • Continued use: If clinical documentation is provided  that the initial 3 month treatment period was effective, adalimumab may be utilized in quantities of 40 mg every 2 weeks.
  • Certolizumab pegol (Cimzia®) quantity limitations for Crohn’s disease:
    • Initial use: Evidence supports utilization of certolizumab pegol use in quantities up to 10 of the 200 mg vials in the first 12 weeks.
    • Continued use: If clinical documentation is provided that the initial treatment period has been effective, certolizumab pegol may be utilized in quantities of 2 of the 200mg vials or syringes each month.

Ulcerative Colitis

  • There is no cure for ulcerative colitis, and treatment regimens are directed toward inducing remission, maintaining remission and addressing complications.15
  • “Topical treatment” (i.e., rectal administration) of 5-ASA or corticosteroid foams or suppositories bring remission rates as high as 93%, and help maintain remission in 75% of these patients.15
  • Oral medications, such as sulfasalazine and various oral 5-ASA agents can be used as an alternative to, or in addition to, rectal administration.15
  • Due to the potential for severe adverse effects, the use of conventional corticosteroids such as prednisone is generally reserved for patients with moderate to severe disease who failed to respond to first-line therapies. Use is generally limited to duration and frequency. Dosages in the range of 40-60 mg/day or 1 mg/kg per day of prednisone or equivalent are effective for induction of remission.15
  • Bowel rest, nutrition, and Parenteral corticosteroids are used in more severe forms.
  • Infliximab (Remicade), an anti-tumor necrosis factor (TNF), is a biologic response modifier used in steroid refractory ulcerative colitis.15

References:

  1. Sandborn WJ, Rutgeerts P, Enns R et al. Adalimumab induction therapy for Crohn disease previously treated with infliximab: a randomized trial. Ann Intern Med 2007; 146:829-838.
  2. Hanauer SB, Feagan BG, Lichtenstein GR et al. Maintenance infliximab for Crohn's disease: the ACCENT I randomised trial. Lancet 2002; 359:1541-1549.
  3. Behm BW, Bickston SJ. Tumor necrosis factor-alpha antibody for maintenance of remission in Crohn's disease. Cochrane Database Syst Rev. 2008CD006893.
  4. Sandborn WJ, Hanauer SB, Rutgeerts P et al. Adalimumab for maintenance treatment of Crohn's disease: results of the CLASSIC II trial. Gut 2007; 56:1232-1239.
  5. Rutgeerts P, Sandborn WJ, Feagan BG et al. Infliximab for induction and maintenance therapy for ulcerative colitis. N Engl J Med 2005; 353:2462-2476.
  6. Tysabri® [package insert]. May, 2010; http://www.tysabri.com/.
  7. Drug Facts and Comparisons. Drug Facts and Comparisons 4.0: Wolters Kluwer Health, Inc; 2006. Accessed February 16, 2009.
  8. Remicade® [package insert]. December 2009; http://www.cimzia.com/crohns-disease/hcp/pdf/Prescribing_Information.pdf.
  9. Cimzia® [package insert]. May 2009; http://www.cimzia.com/crohns-disease/hcp/pdf/Prescribing_Information.pdf.
  10. Humira® [package insert]. November, 2009; http://www.rxabbott.com/pdf/humira.pdf.
  11. Klasco RK. DRUGDEX® System (electronic version). In: Klasco RK, ed. Colorado, USA: Thomson Micromedex; 2009: http://www.thomsonhc.com.
  12. Cohen RD, Stein AC. Approach to adults with steroid-refractory and steroid-dependent ulcerative colitis. In: Basow DS, ed. UpToDate. Waltham, MA, 2010: UpToDate.
  13. Peppercorn MA. Clinical manifestations, diagnosis and prognosis of ulcerative colitis in adults. In: Basow DS, ed. UpToDate. Waltham, MA: UpToDate; 2010
  14. Peppercorn MA. Clinical manifestations, diagnosis and prognosis of Crohn’s disease in adults. In: Basow DS, ed. UpToDate. Waltham, MA: UpToDate; 2010.
  15. Peppercorn MA. Medical management of ulcerative colitis. In: Basow DS, ed. UpToDate. Waltham, MA: UpToDate; 2010.
  16. Lawson MM, Thomas AG, Akobeng AK. Tumour necrosis factor alpha blocking agents for induction of remission in ulcerative colitis. Cochrane Database Syst Rev 2006; CD005112.
  17. Targan SR, Hanauer SB, van Deventer SJ 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; 337:1029-1035.
  18. Gartlehner G, Thieda P, Morgan LC, Thaler K, Hansen RA, Jonas B. Targeted immune modulators. Update 2 final report. 2009. 
  19. Lichtenstein GR, Abreu MT, Cohen R et al. American Gastroenterological Association Institute technical review on corticosteroids, immunomodulators, and infliximab in inflammatory bowel disease. Gastroenterology 2006; 130:940-987.
  20. Peppercorn MA. Clinical manifestations, diagnosis and prognosis of Crohn’s disease in adults. In: Basow DS, ed. UpToDate. Waltham, MA, 2010: UpToDate.
  21. Snapper SB, Podolsky DK. Epidemiology and genetic and environmental factors in inflammatory bowel disease in adults. In: Basow DS, ed. UpToDate. Waltham, MA, 2010: UpToDate.
  22. Hanauer SB, Sandborn WJ, Rutgeerts P et al. Human anti-tumor necrosis factor monoclonal antibody (adalimumab) in Crohn's disease: the CLASSIC-I trial. Gastroenterology 2006; 130:323-333. 
  23. Sandborn WJ, Feagan BG, Stoinov S et al. Certolizumab pegol for the treatment of Crohn's disease. N Engl J Med 2007; 357:228-238.
  24. Schreiber S, Rutgeerts P, Fedorak RN et al. A randomized, placebo-controlled trial of certolizumab pegol (CDP870) for treatment of Crohn's disease. Gastroenterology 2005; 129:807-818.
  25. Colombel J-F, Sandborn WJ, Rutgeerts P et al. Adalimumab for maintenance of clinical response and remission in patients with Crohn's disease: the CHARM trial. Gastroenterology 2007; 132:52-65
  26. Rutgeerts P, D'Haens G, Targan S et al. Efficacy and safety of retreatment with anti-tumor necrosis factor antibody (infliximab) to maintain remission in Crohn's disease. Gastroenterology 1999; 117:761-769.
  27. Sands BE, Anderson FH, Bernstein CN et al. Infliximab maintenance therapy for fistulizing Crohn's disease. N Engl J Med 2004; 350:876-885.
  28. Schreiber S, Khaliq-Kareemi M, Lawrance IC et al. Maintenance therapy with certolizumab pegol for Crohn's disease. N Engl J Med 2007; 357:239-250.
  29. Lichtenstein GR, Yan S, Bala M, Blank M, Sands BE. Infliximab maintenance treatment reduces hospitalizations, surgeries, and procedures in fistulizing Crohn's disease. Gastroenterology 2005; 128:862-869. 
  30. Present DH, Rutgeerts P, Targan S et al. Infliximab for the treatment of fistulas in patients with Crohn's disease. N Engl J Med 1999; 340:1398-1405.
  31. Colombel J-F, Schwartz DA, Sandborn WJ et al. Adalimumab for the treatment of fistulas in patients with Crohn's disease. Gut 2009; 58:940-948.
  32. Gartlehner G, Thieda P, Morgan LC et al. Targeted immune modulators. Update 2 final report 2009; http://www.ohsu.edu/drugeffectiveness/reports/final.cfm.
  33. Hyams J, Crandall W, Kugathasan S et al. Induction and maintenance infliximab therapy for the treatment of moderate-to-severe Crohn's disease in children. Gastroenterology 2007; 132:863-873.
  34. Bodger K, Kikuchi T, Hughes D. Cost-effectiveness of biological therapy for Crohn's disease: Markov cohort analyses incorporating United Kingdom patient-level cost data. Aliment Pharmacol Ther 2009; 30:265-274.
  35. Clark W, Raftery J, Song F et al. Systematic review and economic evaluation of the effectiveness of infliximab for the treatment of Crohn's disease. Health Technol Assess 2003; 7:1-67.
  36. Yu AP, Johnson S, Wang ST et al. Cost utility of adalimumab versus infliximab maintenance therapies in the United States for moderately to severely active Crohn's disease. Pharmacoeconomics 2009; 27:609-621.
  37. Langholz E, Munkholm P, Davidsen M et al.. Colorectal cancer risk and mortality in patients with ulcerative colitis. Gastroenterology 1992; 103:1444-1451.
  38. Tsai HH, Punekar YS, Morris J et al. A model of the long-term cost effectiveness of scheduled maintenance treatment with infliximab for moderate-to-severe ulcerative colitis. Aliment Pharmacol Ther 2008; 28:1230-1239.

 


Codes

 

 Codes  Number  Description
CPT 90760 Intravenous infusion, hydration; initial, up to 1 hour
  90761

each additional hour, up to 8 hours (list separately in addition to code for primary procedure)

  90765

Intravenous infusion, for therapy, prophylaxis, or diagnosis (specify substance or drug); initial up to 1 hour

  90766

each additional hour, up to 8 hours (list separately in addition to code for primary procedure)

  96413

Chemotherapy administration, intravenous infusion technique; up to 1hour, single or initial substance/drug

  96415

Chemotherapy administration, intravenous infusion technique; eachadditional hour, 1 to 8 hours (list separately in addition to code forprimary procedure)

  99070

Supplies and materialsNote: Medicare, many Medicaid programs, and some private payers donot accept claims for CPT code 99070.

ICD-9 Procedure 99.29 Injection or infusion of other therapeutic or prophylactic substance
HCPCS J7050 Infusion, normal saline solution, 250 mg.
  J0135 Injection, Adalimumab (Humira), 20mg
  J1438 Injection, Etanercept (Enbrel), 25 mg
  J1745 Injection, infliximab (Remicade), 10mg
  J3590 Unclassified biologics
ICD-9 diagnosis 555.0-555.9 Regional enteritis including Crohn's disease
  556.0-556.9 Ulcerative colitis

Policy History

 

 

03/18/08 Policy added to Prescription Drug section - local New Policy
08/20/10 Replace policy policy statement unchanged; rationale extensively revised