MP 5.01.100

Treatment of Inflammatory Bowel Diseases with Targeted Immune Modulators

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Medical Policy
Section Prescription Drugs	Original Policy Date 03/18/2008	Last Review Status/Date Created as Local Policy/3:2008
Issue 3:2008		Return to Medical Policy Index

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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.

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Description

Ulcerative colitis (UC): a mucosal disease that usually involves the rectum and extends proximally to involve all or part of the colon.  It is One of the two major types of inflammatory bowel disease (IBD). Based on extent of disease, subgroups include:ulcerative proctitis, pproctosigmoiditis (up to 60 cm).left-sided colitis (to splenic flexure), extensive colitis (beyond splenic flexure but not to cecum), and pancolitis (to cecum).  Indeterminate colitis is a type of IBD in which distinguishing between UC and Crohn’s disease (CD) is impossible and which accounts for 10–15% of patients with colitis.

The highest rates of ulcerative colitis are seen in the U.S., United Kingdom, Norway, and Sweden.  In the U.S. the incidence is approximately 11 per 1000 population.  The peak onset is between ages 15–30 years with a second peak between ages 60–80 years.  The male:female ratio is 1:1, although men are more frequently affected than women in the elderly population. 

Risk factors include an apparent genetic predisposition with a more than 1/3 risk of IBD if both parents are affected.  Ashkenazi Jews have a two to four fold increase.  Former smokers also have an increased risk of UC.

While the etiology of UC has not been defined, it is hypothesized that mucosal immune function in genetically predisposed individuals is dysregulated by a combination of exogenous factors such as infectious agents.  Host factors may include, an impaired intestinal epithelial cell barrier function,  abnormal vascular supply, or unusual neuronal activity.  It may also be due to an inappropriate response to intestinal flora with or without some component of autoimmunity.  Symptoms may be exacerbated by psychosocial factors.

Treatment of UC is divided into active disease therapy and maintenance therapy and is dependent on the severity of the disease. There are no differences between the therapies for distal and extensive disease.  While elemental diets and total parenteral nutrition have be utilized, they are not effective during active disease.

The commonly accepted therapy for mild to moderate disease is use of 5-aminosalicylic acid (5-ASA) agents.  These are effective at induction and maintenance of remission and 50-75% of patients with improve with 2 Gm per day of one of the formulations.  The dose response continues to at least 4.8 g/d, and  50–75% of people maintain remission on 1.5–4 Gm per day.

Regional Enteritis (Crohn’s Disease):

Crohn's disease is a chronic transmural inflammatory disease that usually affects the distal ileum and colon but may occur in any part of the GI tract. Symptoms include diarrhea and abdominal pain. Abscesses, internal and external fistulas, and bowel obstruction may arise.

Crohn's disease begins with crypt inflammation and abscesses, which progress to tiny focal aphthoid ulcers. These mucosal lesions may develop into deep longitudinal and transverse ulcers with intervening mucosal edema, creating a characteristic cobblestoned appearance to the bowel.

Transmural spread of inflammation leads to lymphedema and thickening of the bowel wall and mesentery. Mesenteric fat typically extends onto the serosal surface of the bowel. Mesenteric lymph nodes often enlarge. Extensive inflammation may result in hypertrophy of the muscularis mucosae, fibrosis, and stricture formation, which can lead to bowel obstruction. Abscesses are common, and fistulas often penetrate into adjoining structures, including other loops of bowel, the bladder, or psoas muscle. Fistulas may even extend to the skin of the anterior abdomen or flanks. Independently of intra-abdominal disease activity, perianal fistulas and abscesses occur in 25 to 33% of cases; these complications are frequently the most troublesome aspects of Crohn`s disease.

Noncaseating granulomas can occur in lymph nodes, peritoneum, the liver, and all layers of the bowel wall. Although pathognomonic when present, granulomas are not detected in about half of patients with Crohn`s disease. The presence of granulomas does not seem to be related to the clinical course.

Segments of diseased bowel are sharply demarcated from adjacent normal bowel (“skip areas”); hence, the name regional enteritis. About 35% of Crohn`s disease cases involve the ileum alone (ileitis); about 45% involve the ileum and colon (ileocolitis), with a predilection for the right side of the colon; and about 20% involve the colon alone (granulomatous colitis), most of which, unlike ulcerative colitis (UC), spare the rectum. Occasionally, the entire small bowel is involved (jejunoileitis). The stomach, duodenum, or esophagus is clinically involved only rarely, although microscopic evidence of disease is often detectable in the gastric antrum, especially in younger patients. In the absence of surgical intervention, the disease almost never extends into areas of small bowel that are not involved at first diagnosis.

There is an increased risk of cancer in affected small-bowel segments. Patients with colonic involvement have a long-term risk of colorectal cancer equal to that of UC, given the same extent and duration of disease.

Symptoms and Signs

The most common initial presentation is chronic diarrhea with abdominal pain, fever, anorexia, and weight loss. The abdomen is tender, and a mass or fullness may be palpable. Gross rectal bleeding is unusual except in isolated colonic disease, which may manifest similarly to UC. Some patients present with an acute abdomen that simulates acute appendicitis or intestinal obstruction. About 33% of patients have perianal disease (especially fissures and fistulas), which is sometimes the most prominent or even initial complaint. In children, extraintestinal manifestations frequently predominate over GI symptoms; arthritis, FUO, anemia, or growth retardation may be a presenting symptom, whereas abdominal pain or diarrhea may be absent.

With recurrent disease, symptoms vary. Pain is most common and occurs with both simple recurrence and abscess formation. Patients with severe flare-up or abscess are likely to have marked tenderness, guarding, rebound, and a general toxic appearance. Stenotic segments may cause bowel obstruction, with colicky pain, distention, obstipation, and vomiting. Adhesions from previous surgery also may produce bowel obstruction, which begins rapidly, without the prodrome of fever, pain, and malaise typical of obstruction due to a Crohn's disease flare-up. An enterovesical fistula may produce air bubbles in the urine (pneumaturia). Draining cutaneous fistulas may occur. Free perforation into the peritoneal cavity is unusual.

Chronic disease produces a variety of systemic symptoms, including fever, weight loss, malnutrition, and extraintestinal manifestations (see Inflammatory Bowel Disease (IBD)).

The “Vienna Classification” and its recent “Montreal modification” categorize Crohn`s disease into three principal patterns: (1) primarily inflammatory, which after several years commonly evolves into either (2) primarily stenotic or obstructing or (3) primarily penetrating or fistulizing. These different clinical patterns dictate different therapeutic approaches. Some genetic studies suggest a molecular basis for this classification.

Laboratory tests should be obtained to screen for anemia, hypoalbuminemia, and electrolyte abnormalities. Liver function tests should be obtained; elevated alkaline phosphatase and γ–glutamyl transpeptidase levels in patients with major colonic involvement suggest possible primary sclerosing cholangitis. Leukocytosis or increased levels of acute-phase reactants (eg, ESR, C reactive protein) are nonspecific but may be used serially to monitor disease activity.

Perinuclear antineutrophil cytoplasmic antibodies are present in 60 to 70% of patients with UC and in only 5 to 20% of patients with Crohn`s disease. Anti-Saccharomyces cerevisiae antibodies are relatively specific for Crohn's disease. However, these tests do not reliably separate the two diseases. They have uncertain value in cases of “indeterminate colitis” and are not recommended for routine diagnosis.

Mild to moderate disease: This category includes ambulatory patients who tolerate oral intake and have no signs of toxicity, tenderness, mass, or obstruction. 5 Aminosalicylic acid (5 ASA, mesalamine) is commonly used as first-line treatment, although its benefits for small-bowel disease are modest at best. Pentasa is the most effective formulation for disease proximal to the terminal ileum; Asacol is effective in distal ileal disease; all formulations are roughly equivalent for Crohn`s colitis, although none of the newer preparations rival sulfasalazine.

Moderate to severe disease: Patients without fistulas or abscesses but with significant pain, tenderness, fever, or vomiting, or those who have not responded to treatment for mild disease, require corticosteroids, either oral or parenteral, depending on severity of symptoms and frequency of vomiting. Oral prednisone or prednisolone may act more rapidly and reliably than oral budesonide, but budesonide has somewhat fewer adverse effects and is considered the corticosteroid of choice in many centers, especially in Europe. Patients not responding to corticosteroids, or those whose doses cannot be tapered, should receive, 6  mercaptopurine, or possibly methotrexate. Infliximab is prreferred by some as a second-line agent after corticosteroids, and even as a first-line agent in preference to corticosteroids, but it is contraindicated in active uncontrolled infection.

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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.
• Crohn’s disease 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®) is a tumor necrosis factor (TNF) blocker and 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.

Moderately to Severely Active Crohn`s Disease

Infliximab or adalimumab 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 3 or more of the following:

• Corticosteroids (eg, prednisone, prednisolone, dexamethasone, budesonide) - these therapeutic agents are used for the treatment of active, symptomatic Crohn’s disease and to help induce disease remission.
• Sulfasalazine - this drug is also used to help induce disease remission, but its beneficial effect is confined to patients with disease involving the colon or the colon and ileum.
• Immunomodulatory drugs, such as azathioprine, mercaptopurine, cyclosporine, or methotrexate.
• 5-aminosalicylic acid - drug formulations of this compound have been developed to deliver this drug in patients with Crohn’s ileitis and ileocolitis. In particular, patients who receive 4 gm of controlled-release mesalamine daily will significantly decrease their Crohn’s Disease Activity Index (brand names include Rowasa®, Pentasa®, and Asacol®).
• Antibiotics (e.g., metronidazole, quinolones) - used for the treatment of active Crohn’s disease; the most improvement is seen in patients with colonic disease.

Moderately to Severely Active Ulcerative Colitis

The administration of infliximab may be 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 (e.g., prednisone, prednisolone, dexamethasone, budesonide)- these therapeutic agents are used for the treatment of active, symptomatic Ulcerative colitis and to help induce disease remission;
• immunomodulatory drugs (azathioprine, mercaptopurine, cyclosporine, methotrexate); and
• 5-aminosalicylic acid - (brand names include Rowasa®, Pentasa®, and Asacol®).

  Sulfasalazine may also be used.

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Policy Guidelines

Infliximab (Remicade®)

The average patient requires 3-4 single use vials (100 mg per vial) per dose, based on a recommended dose of 5 mg/kg, given as a single IV infusion. Following reconstitution, it is recommended the solution be administered over approximately 2 hours with a slow infusion pump.

Initial therapy with up to 5 infusions in a 6-month period may be approved when the criteria above are met. The 5 infusions include the recommended loading doses at weeks 0, 2, and 6, plus an infusion every 8 weeks for maintenance. Retreatment may be approved at a maximum of 6 infusions in a 12 month time period based on the following criteria:

• patient originally met criteria for initial treatment;
• there is documentation that either azathioprine or mercaptopurine was not effective at maintaining remission, use of these agents was contraindicated, or they were not tolerated; and
• there is a documented significant/sustained response to the last infliximab course (e.g., improvement or stabilization of disease in the progress notes.)

For patients with an incomplete response, adjusting the dosing frequency to as often as every 4 weeks or increasing the dose to 10 mg/kg, but not both concurrently, may be approved. Patients not responding after 14 weeks are unlikely to respond, and consideration should be given to discontinuing infliximab therapy.

Adalimumab (Humira®)

Adalimumab is self-administered by subcutaneous injection. The recommended dosing for CD is 160 mg initially at week 0, 80 mg at week 2, followed by a maintenance dose of 40 mg every other week beginning at week 4. The initial dose may be given as 4 injections on day 1 or divided over 2 days.

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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

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Policy History

03/18/08

Policy added to Prescription Drug section

New Policy

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